In recent years, there has been a growing interest in the potential of natural compounds to offer new therapeutic options for chronic kidney disease (CKD). This review aims to provide a comprehensive overview of CKD, emphasizing recent advancements in treatment options and the necessity for collaboration across healthcare sectors to enhance the detection, treatment, and prognosis of diabetes-related kidney disease. Diabetes mellitus (DM), which includes type 1 diabetes (T1D) and type 2 diabetes (T2D), is characterized by glucose dysregulation due to absolute or relative abnormalities (American Diabetes Association, 2010). Globally, there are fewer than 500 million people with diabetes, with the number expected to rise by 25% and 51% in 2030 and 2045, respectively, placing a tremendous burden on healthcare systems (Saeedi et al., 2019).

Polyphenols and other natural compounds have demonstrated promising results in both clinical and experimental settings, providing a foundation for their inclusion in CKD treatment regimens. These substances exhibit a range of beneficial mechanisms, including anti-inflammatory and antioxidant effects, which are particularly relevant in addressing the oxidative stress and inflammation associated with diabetic nephropathy (DN). DN, a common complication of diabetes mellitus, significantly contributes to the burden of CKD and is linked to detrimental effects on kidney cells (Avila-Carrasco et al., 2021). DN or diabetic kidney disease (DKD), is a consequence of DM and is primarily responsible for end-stage renal disease (ESRD), which is associated with higher morbidity and mortality in diabetes patients (Hoogeveen, 2022). Between 30-40% of diabetic patients develop DN, necessitating dialysis or a kidney transplant. These therapeutic modalities require significant financial, psychological, and medical resources, making the improvement of DN crucial from a therapeutic standpoint (Rangel et al., 2009).

Despite substantial improvements in understanding the pathophysiology and treatment of cardiovascular risk and disease, advances in patients with advanced CKD, including ESRD, have remained elusive (Jankowski et al., 2021). Patients with advanced CKD have been systematically excluded from large perspective clinical trials, leading to a lack of evidence documenting treatment benefits (Hoogeveen, 2022). The cost of renal replacement therapy (RRT), including dialysis and transplantation, constitutes significant expenses in hospital-based healthcare (Borg et al., 2023).

This review aims to provide a comprehensive overview of natural compounds, focusing on their efficacy, mechanisms of action, and clinical applications in the prevention and treatment of DM. By examining the connection between oxidative stress, inflammation, and kidney damage, this review highlights the potential of natural compounds to improve outcomes of the patients. The goal is to underscore the importance of integrating these natural therapies into existing treatment paradigms to enhance patient care and reduce the incidence of CKD-related complications.

Several methods have been described for how a patient can develop diabetes. According to a research study, insufficient and defective hormone production or inappropriate hormone secretion leads to diabetes. Nevertheless, it is also clarified that the onset of diabetes is caused by either aberrant insulin mRNA or inappropriate Ca⁺⁺ signalling. In addition to the three Ps (polyurea, polyphagia, and polydipsia) that characterize DN, other symptoms included increased albumin excretion, an aberrant glomerular filtration rate, and diabetes, also referred to as a metabolic illness. This is the cause of the incapacity of hormone secretion or endocrine gland function with rapidly declining renal function, all of which can culminate in ESRD (Nasri and Rafieian-Kopaei, 2015). Moreover, hyperglycemia can deteriorate diabetic kidney disease by producing advanced glycation end products (AGEs), activating protein kinase C, and free radicals (Singh et al., 2014). The pathology of diabetic nephropathy is depicted in Fig. 1.

Figure 1. Pathophysiology of Diabetic Kidney Disease (DKD) and the Role of Natural Compounds.

Oxidative stress

Hyperglycemia in diabetic patients leads to an increased production of reactive oxygen species (ROS), which plays a significant role in the development of DKD. Excessive ROS generation causes oxidative stress, leading to direct damage to kidney cells, including mesangial cells, podocytes, and tubular epithelial cells (Amorim et al., 2019).

This oxidative stress contributes to the breakdown of the glomerular filtration barrier, resulting in proteinuria (abnormal protein levels in urine), a hallmark of DKD. Natural compounds, particularly polyphenols, have strong antioxidant properties. They neutralize ROS, thereby reducing oxidative stress and preventing cellular damage in the kidneys (Jin et al., 2023).

Inflammation

Chronic inflammation is another key factor in DKD progression. Hyperglycemia stimulates the activation of pro-inflammatory pathways, leading to the release of cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-κB) (Donate-Correa et al., 2021). These cytokines exacerbate kidney damage by promoting fibrosis, glomerular sclerosis, and tubular injury.

Fibrosis

One of the late-stage pathological features of DKD is renal fibrosis, characterized by the accumulation of extracellular matrix (ECM) proteins, including collagen and fibronectin, in the kidney tissue (Reiss et al., 2024). Fibrosis results in the stiffening of kidney tissues, impairing normal renal function and contributing to glomerular sclerosis and tubulointerstitial fibrosis. This reduces the kidneys’ ability to filter blood effectively (Bülow and Boor, 2019).

Endothelial dysfunction

Hyperglycemia and inflammation also lead to endothelial dysfunction, reducing nitric oxide (NO) bioavailability. This contributes to impaired vascular tone and renal blood flow, leading to ischemia and kidney damage (Kolluru et al., 2012).

Glomerular hyperfiltration

In the early stages of DKD, hyperglycemia triggers glomerular hyperfiltration, where the kidneys filter blood at abnormally high rates. This overwork causes progressive damage to the glomeruli, leading to their deterioration. Over time, this hyperfiltration contributes to the loss of renal function and the progression to end-stage renal disease (ESRD) (Yang and Xu, 2022).

Natural compounds act through multiple mechanisms to counteract these pathological factors:

Antioxidants neutralize ROS, protecting kidney cells from oxidative damage.

Anti-inflammatory compounds inhibit the release of pro-inflammatory cytokines, reducing chronic inflammation in kidney tissues.

Anti-fibrotic agents prevent the excessive deposition of extracellular matrix proteins, reducing fibrosis.

Endothelial-protective compounds enhance nitric oxide bioavailability, improving blood flow and reducing ischemic damage in the kidneys (Zhou et al., 2022b; Lee et al., 2024).

By incorporating natural compounds into therapeutic strategies, these bioactive substances can help to reduce the harmful effects of oxidative stress, inflammation, and fibrosis, ultimately protecting kidney function in patients with DKD.

It is well-recognized that diabetic people with persistent hyperglycemia suffer major harm to a variety of organs and tissues (American Diabetes Association, 2010). Retinopathy, nephropathy, neuropathy, and cardiovascular problems are among the long-term effects of diabetes. About 5000 persons lose their vision due to diabetic retinopathy, a retinal condition that is the primary cause of severe visual impairment (Nentwich and Ulbig, 2015). The primary reason for ESRD globally is DN, which is also one of the most prevalent microvascular consequences of T1 and T2D (Gheith et al., 2016). One of the main diabetic consequences that damage the nerves leads to diabetic neuropathy. Furthermore, even though they are not unique to diabetes, cardiovascular problems include cardiomyopathy, peripheral arterial disease, hypertension, coronary heart disease, and stroke is more common (Zakir et al., 2023). The interplay between hypertensive stress and diabetic complications is summarized (Fig. 2).

Figure 2. Mechanism of Action of Natural Compounds in Diabetic Kidney Disease (DKD).

Furthermore, even though they are not unique to diabetes, cardiovascular problems including cardiomyopathy, peripheral artery disease, hypertension, coronary heart disease and stroke are more common and severe in people with diabetes than in people without the condition (Leon and Maddox, 2015). Recent research indicates that increase in oxidative stress linked to diabetes is the main factor playing a part in the advancement of different diabetic complications (Giacco and Brownlee, 2010). Numerous factors, including increased formation of ROS from the autoxidation of glucose, glycated proteins, and glycation of antioxidant enzymes, which reduces their ability to neutralize free radicals, supply to the onset of oxidative stress in diabetes. Particularly vulnerable are pancreatic β-cells (Pasupuleti et al., 2020).

In the human diet, polyphenols are the most prevalent type of antioxidants. Plants are household to thousands of naturally occurring polyphenols (Han et al., 2007). Plant-based foods have a wide and diverse range of phytochemicals called polyphenols, which include flavonoids, phenolic acid, and stilbenes (tea, coffee, soy, cocoa, cinnamon, cereal grains, ginger, fruits and berries) (Pandey and Rizvi, 2009). Polyphenols are divided into several groups depending on the number of phenol rings and the structural components that connect them. Increasing evidence indicates that specific dietary polyphenols can help prevent diabetes (Amalan et al., 2016; Rudrapal et al., 2022). In this article, we discussed several foods high in polyphenols and their potential impact on blood sugar levels. The ability of polyphenols to scavenge ROS is well-recognized due to their antioxidant properties. Polyphenols can reduce inflammation directly by altering signaling pathways or indirectly through their antioxidant properties (Cory et al., 2018). The potential effects of dietary polyphenols on diabetic complications are summarized (Fig. 3).

Figure 3. Polyphenols and Diabetic nephropathy.

Polyphenols primarily demonstrate their antioxidant capacity by directly scavenging reactive oxygen species and inhibiting their formation (Yan et al., 2020). Polyphenols strongly suppress the generation of superoxide anion and NOX activity. Polyphenols’ structure of phenolic ring can promptly counteract the free radicals produced during lipid peroxidation. Polyphenols possess the capability to bind metal ions through chelation, including Fe³⁺, and stop H₂O₂ from turning into the extremely hazardous HO^•. More significantly, polyphenols can enhance the natural process of antioxidant defenses through the Nrf2 pathway, leading to increased expression of antioxidant enzymes (Jin et al., 2023).

Polyphenols can directly alter inflammatory signaling pathways, while most of the research indicates that their antioxidant and free radical scavenging properties reduce inflammation (Rudrapal et al., 2022). Numerous polyphenols are strong NF-κB inhibitors. They have been shown to prevent NF-κB from binding to DNA and subsequently triggering the transcription of pro-inflammatory cytokines, prevent NF-κB from translocating to the nucleus, prevent signaling molecules from being phosphorylated or ubiquitinated, and prevent IκB from being degraded (Cory et al., 2018). Additionally, polyphenols target TLR4, which is NF-κB’s upstream, and work through the TLR4/NF-κB signaling pathway to mitigate the inflammatory response. This article explores foods rich in polyphenols and their potential impact on blood glucose levels (Yu et al., 2022). Mechanisms of actions of polyphenols on diabetic kidney diseases are summarized (Table 1).

Table 1 Mechanism of Polyphenols in the treatment of kidney diseases

S. No.	Name of the Compoundand structure	Doseage	Animal model	Mechanism of action	References
1	Chrysin	10 mg/kg	Mice (C57BLKS/+)	Chrysin reduced the buildup of myofibroblast-like cells and matrix proteins in diabetic glomeruli loaded with advanced glycation end-products (AGEs).	Lee et al., 2018
2	Curcumin	150 mg/kg	Sprague-Dawley rats	Curcumin targets the modulation of the SphK1-S1P signaling pathway by inhibiting AP-1 activation, which helps prevent diabetic renal fibrosis.	Huang et al., 2013
3	Diosgenin	30 and 90 mg/kg,	db/m mice	In the early stages of DN, diosgenin might offer protection against podocyte injury by decreasing lipid accumulation through the regulation of SIRT6.	Wang et al., 2022
4	Diosmin	100 mg/kg	Wistar rats	Diosmin prevents oxidative stress caused by hyperglycemia and reduces the levels of pro-inflammatory cytokines.	Ahmed et al., 2016
5	Hesperidin	200 mg/kg	Sprague-Dawley rats	It reduced the expression of 8-OHdG in kidney tissue and lowered the levels of TGF-β1, thereby decreasing oxidative DNA damage and morphological abnormalities.	Kandemiret al., 2018
6	Hesperitin	50 and 150 mg/kg	Sprague-Dawley rats	The levels of Nrf2 and its phosphorylated form, p-Nrf2, were significantly increased, and the well-known target gene of the Nrf2/ARE signaling pathway, γ-glutamylcysteine synthetase, was upregulated.	Chen et al., 2019
7	Kaempferol	5, 10 and 50 μM	NRK-52E (rat renal proximal tubular epithelial cell) and RPTEC (primary human renal proximal tubule epithelial cells) cells	Kaempferol inhibits the activation of RhoA and lowers oxidative stress, along with reducing the levels of pro-inflammatory cytokines (IL-1β and TNF-α) and fibrosis (TGF-β1 expression and extracellular matrix protein expression) in RPTEC and NRK-52E cells, thus preventing hyperglycemia-induced effects.	Sharma et al., 2019
8	Luteolin	200 mg/kg	Male Sprague-Dawley rats.	Luteolin may help prevent the structural damage to the kidney associated with diabetes mellitus and improve the kidney's redox balance.	Wang et al., 2011
9	Myricetin	100 mg/kg	Mice (C57BL/6)	Suppressed the IκB/NF-κB (P65) signalling pathway and stopped the DM-associated reduction in Nrf2 expression.	Yang et al., 2019
10	Naringenin	25 and 50 mg/kg	Sprague-Dawley rats	Arrest the progression of DN due to its multivariate actions such as antihyperglycaemic and antioxidant	Jain and Saha, 2017
11	Naringin	20, 40 and 80 mg/kg	Male Sprague-Dawley	Naringin alleviates diabetic nephropathy by inhibiting NOX4, enhancing our understanding of DN progression.	Zhang et al., 2017
12	P-coumaric acid	100 mg/kg	Wistar rats	Suppresses IL-6 and TLR-4 to prevent renal inflammation, and it lowers renal fibrosis by lowering the control over TGFβ1 and collagen.down-regulation of COX-2, NF-κB, TNF-α, and upregulation-control of the Nrf-2 protein in the kidney tissue.	Zabad et al., 2019
13	Quercetin	10 mg/kg/day	apoE−/− male mice	Decreased DN in hypercholesterolemic rats by causing glomerulosclerosis to shrink and biochemical changes (such as a drop in serum levels of triglycerides and glucose).	Gomes et al., 2015
14	Rutin	100 mg/kg	Wistar rats	It reduces fibrosis and metabolic acidosis, preventing the progression of diabetic nephropathy and cardiomyopathy.	Ganesan et al., 2020
15	Vanillic acid	25, 50 and 100 mg/kg	Wistar rats	Protein Nrf-2 is upregulated in renal tissue while COX-2, NF-κB, and TNF-α are downregulated.	Singh et al., 2022

Luteolin

One long-term consequence of diabetes mellitus is diabetic nephropathy. A multitude of experimental findings indicates that long-term hyperglycemia produces intracellular ROS and increases the expression of transforming growth factor-b1 and extracellular matrix in mesangial and tubular epithelial cells. These processes are linked to free radicals in the etiology of diabetes, and more significantly, in the development of complications related to the disease (Fakhruddin et al., 2017). The elevation of transforming growth factor b1 and fibronectin induced by high glucose and H₂O₂ is significantly suppressed by antioxidants, indicating a significant role for ROS in high glucose-induced kidney damage (Giacco and Brownlee, 2010). Researchers speculate that because the flavonoid luteolin has been demonstrated to have direct antioxidant activity, it may help treat a variety of chronic conditions linked to oxidative stress, including diabetic nephropathy (Chen et al., 2023). According to earlier findings, luteolin administration protected against the development of DN by altering the levels of malondialdehyde (MDA), superoxide dismutase (SOD) activity, and the expression of the protein heme oxygenase-1 (HO-1). Oxidative stress has been linked to diabetes; thus, HO-1 protein levels have decreased (Wang et al., 2011). Previous studies imply that raising antioxidant levels and HO-1 expression in diabetic nephropathy may be two of the mechanisms behind luteolin’s renoprotective effects. Luteolin might be able to halt the kidneys’ morphological degradation brought on by diabetes mellitus. It may also enhance both the kidney’s redox balance and avert the kidney’s morphological degradation linked to diabetes mellitus. It does not directly lower blood glucose levels. However, by increasing the expression of the Nphs2 protein and postponing podocyte fusion and apoptosis in the presence of high glucose, it may preserve the basement membrane’s filtration function. Additionally, luteolin may prevent glomerulosclerosis and preserve the glomeruli’s comparatively normal physiological structure, which suggests that luteolin may be able to stop the rapid degeneration of DN (Yi et al., 2023).

Myricetin

Myricetin (Myr’) is present in food and will be easily accessible for the development of new drugs. Myricetin has shown positive pharmacological effects on protein levels, and hepatic, renal, and diabetic functional indicators. Myr’ can effectively protect the liver and kidney of STZ-Cd-induced diabetic nephrotoxic rats from oxidative damage by boosting the enzymatic and nonenzymatic antioxidant defense system, preventing lipid peroxidation, and ultimately improving tissue dysfunction in diabetic nephrotoxic rats driven by oxidative stress (Gomathi et al., 2014). Myr’ prevented kidney damage and dysfunction linked to diabetes mellitus by promoting Nrf2 expression and translocation and blocking the IκBα/NF-κB pathway. Furthermore, studies demonstrated that Nrf2 had no bearing on Myr’s inhibitory action on the IκBα/NF-κB pathway. They suggested that polyphenol compounds like Myr, which have dual effects on oxidative stress and inflammatory pathways, could be promising for treating kidney damage and dysfunction linked to diabetes mellitus. The mild excretion of albumin in the nephrotoxic rats studied in various reports might be attributed to either reduced tubular reabsorption or albumin leakage caused by disruption to the glomerular basement membrane in conjunction with an increase in transglomerular filtration pressure (Yang et al., 2019). Urine albumin returned to normal after myricetin treatment, indicating less kidney damage from oxidative insult and hyperglycemia. The most frequent cause of renal impairment and the main factor contributing to the high morbidity and death rates among these diabetic individuals is diabetic nephrotoxicity. The importance of myricetin and other antioxidants in the diet for human health may help us understand the renoprotective action of this polyphenol (Guerreiro et al., 2022).

Chrysin

Earlier studies reported that chrysin has the potential to treat diabetic kidney disorders linked to tubulointerstitial fibrosis. High glucose was inhibited by nontoxic chrysin, which led to the release of collagen IV, induction of α-SMA, vimentin, and FSP-1, and loss of E-cadherin (Lee et al., 2018). Chrysin treatment inhibited the excrescence of epithelial cells and the development of myofibroblast-like cells by reducing the tissue levels of α-SMA, FSP-1, and collagen fibers in the kidneys of mice. Also, it prevented the disruption of epithelial cells that results from high glucose levels and MMP-2 inactivation (Kang et al., 2015). Chrysin was, therefore, a medicinal medication that inhibited tubulointerstitial fibrosis, tubular epithelial derangement, and epithelial thickening in kidney problems associated with diabetes in animal or cell models. Chrysin enhanced the important indices and markers of inflammation, oxidative stress, and fat accumulation, all of which are strongly linked to the onset or advancement of DN. Furthermore, by controlling (Adenosine 5′ monophosphate-activated protein kinase) AMPK and crucial downstream proteins, chrysin significantly altered lipid metabolism. Additionally, the favorable effects of chrysin on all testing indicators were partially decreased by AMPK inhibitor intervention (Zhou et al., 2022b).

Hesperidin

By lowering oxidative stress and serum urea and creatinine levels, HSP had a protective effect against DN brought on by STZ (Mahfoz et al., 2016). It decreased oxidative DNA damage and morphological defects by blocking the expression of 8-OHdG in kidney tissue and lowering TGF-b1 levels. One theory is that hesperidin pretreatment shielded the kidneys against severe increases in ROS products, depletion of superoxide dismutase, and reduced glutathione in rats exposed to renal I/R. Hesperidin pretreatment also may have inhibited renal I/R-induced lipid peroxidation. It may have a function in reducing kidney damage following internal or external renal injury in an animal model, if only slightly by its ability to scavenge free radicals or act as an antioxidant. Thus, in diabetic rats with artificially caused renal impairment, hesperidin may lessen renal complications (Kandemir et al., 2018).

Hesperitin

Hesperetin markedly reduced the functional and anatomical damage to the kidney of diabetic rats, concomitant with an increase in the Nrf2/ARE pathway. This was indicated by higher levels of p-Nrf2 in the nucleus and cytoplasm, as well as higher levels of mRNA, protein expression, and enzymatic activity (measured by GSH levels) of γ-GCS, a known target gene of Nrf2/ARE signaling (Chen et al., 2019). Furthermore, studies reveal that hesperetin reduces inflammatory responses in lipopolysaccharide-induced cells by inhibiting NF-κB and activating Nrf2/HO-1 pathways, and hesperidin inhibits H₂O₂-induced oxidative stress in hepatocytes via HO-1 induction mediated by activation of MAPK/Nrf2 pathway. It stimulates the Nrf2/ARE pathway in DN, which in turn causes Glo-1 to be up-regulated. Furthermore, it inhibits the TGF-β1 - ILK - Akt signaling pathway to reduce diabetic neuropathic pain in type 2 diabetic mice. Hesperetin’s activation of the Nrf2/ARE pathway likely contributed to the beneficial effects by either enhancing Glo-1 or inhibiting the AGEs/RAGE interaction. Hesperetin reversed the aberrant alterations in podocyte surface protein expression, inhibited the TGF-β1-ILK-Akt signaling cascade, and restored podocyte function during the treatment as well as prevented diabetic nephropathy, potentially through blocking TGF-β1-ILK-Akt signaling (Duraisamy et al., 2022; Evans et al., 2023).

Naringin

Naringin significantly decreased the levels of FN and ICAM-1 in mice with STZ-induced diabetes and GMCs stimulated by high glucose. Furthermore, naringin reduced the phosphorylation of JNK MAPK, ERK1/2, and the downstream transcription factor AP-1. The mechanism through which naringin improved diabetic renal fibrosis was closely associated with its inhibition of the ERK1/2 and JNK MAPK signaling pathways’ activation (Chen et al., 2014; Liang et al., 2016; Huang et al., 2024).

Naringenin

Naringenin administration stops the development of early DN and improves renal function in diabetic rats. This may be why naringenin has multifaceted effects such as antihyperglycemic, antioxidant, and anti-hyperlipidaemic activity. A recognized correlation exists between increased extracellular matrix formation and/or accumulation because less matrix protein is broken down in DN. Mesangial enlargement is caused by increased oxidative stress, activation of the renin-angiotensin system, and renal manufacturing of cytokines and growth factors. Mesangial hypercellularity and thickening of the capillary basement membrane have been noted in the kidneys of DC rats. These renal alterations were significantly reduced by naringenin treatment which has been associated with more significant abnormalities (Khan et al., 2022).

Curcumin

Diabetic kidney disease (DN) is linked to its inhibition of the SphK1-S1P signaling pathway. It has been found that curcumin dramatically reduced the expression and activity of SphK1 as well as the synthesis of S1P in the kidneys of diabetic rats and glomerular mesangial cells (GMCs) exposed to high glucose (HG) (Huang et al., 2013). The overproduction of fibronectin (FN) and transforming growth factor-beta 1 (TGF-β1) was reduced concurrently by SphK1-S1P. Curcumin dose-dependently decreased SphK1 expression and activity, dramatically inhibited the rise in SphK1-mediated FN levels, and prevented activator protein 1 (AP-1) from binding DNA, and c-Jun small interference RNA untied the up-regulation of SphK1 brought on by HG (Yang et al., 2012). Curcumin probably improves the progression of DN via a new mechanism involving the downregulation of the SphK1-S1P pathway. Curcumin therapy inhibits AP-1 activation to modify the SphK1-S1P signaling pathway and prevent diabetic renal fibrosis. It is crucial to clarify the relationship between curcumin’s suppression of the SphK1-S1P signaling pathway and the reduction of AP-1 activation. One of curcumin’s therapeutic goals is to modify the SphK1-S1P signaling pathway and prevent diabetic renal fibrosis by reducing AP-1 activity. Curcumin’s inhibition of SphK1-S1P was not influenced by its hypoglycemic or antioxidant properties, and it may have a direct correlation with its suppression of AP-1 activity (Huang et al., 2013).

Vanillic acid

Nevertheless, more research on proteins and genes is needed to determine the precise pathway or molecular mechanism behind the nephroprotective activity. By concurrently administering herbal remedies or dietary supplements containing VA together with traditional antidiabetic medications as soon as prediabetes or diabetes is detected, the nephroprotective action of VA can be utilized in the treatment of DN. In patients with diabetes, this will stop the development of diabetic nephropathy as well as the progression of diabetes. VA therapy reduced the rate at which diabetic nephropathy developed and improved renal functioning (Yang et al., 2012; Selby and Taal, 2020). The precise processes by which vanillic acid exerts its nephroprotective effects are not easily understood. VA had an antihyperglycemic effect and reduced renal dysfunction, microalbuminuria, and oxidative kidney damage (Kumari et al., 2021). The impact could be explained by the antioxidant properties of VA and the ensuing disruption of the downstream inflammatory cascade, which causes necroptotic renal injury. It may also lessen oxidative stress caused by glycation, which may further limit the polyol pathway and reduce the production of advanced glycation end products (Kumari et al., 2021). Reduced production of ROS can also restrict inflammation, suppress NFκB activation, and reduce the generation of inflammatory cytokines, which in turn reduces fibrosis and protects against kidney injury. Consequently, VA’s antihyperglycemic and antioxidant properties may be responsible for its nephroprotective effects.

Rutin

Rutin has been found to reduce the expression of CTGF, TGF-β1/Smad, and diabetic nephropathy (DN) symptoms in rats (Lai et al., 2012), suggesting a potential protective effect against the early onset of DN. The interaction among ROS, advanced glycation end products (AGEs), CTGF, and TGF-β1/Smads has become a key focus in DN studies. Research indicates that AGEs-RAGE-mediated ROS production leads to mesangial cell hypertrophy and extracellular matrix (ECM) accumulation, further promoting TGF-β1-Smad signaling (Jha et al., 2016). It has been observed that in the pathophysiology of DN, TGF-β1-dependent and ROS signals interact and increase each other. Rutin has shown significant effects in reducing fasting blood glucose levels, creatinine (Cr), blood urea nitrogen (BUN), urine protein, and the thickness of the glomerular basement membrane (GBM) in the renal cortex of DN rats (Hao et al., 2012). Additionally, it can increase the expression of p-Smad 7, reduce oxidative stress, prevent the accumulation of laminin and type IV collagen, and decrease levels of AGEs, p-Smad 2/3, TGF-β1, and CTGF (Hao et al., 2012). Recently, rutin has been found to relieve endothelial-to-mesenchymal transition by regulating autophagy through the inhibition of histone deacetylase 1 (HDAC1) via the PI3K/AKT/mTOR pathway in Diabetic Kidney Disease, suggesting its potential role against diabetic nephropathy (Dong et al., 2023).

Kaempferol

One of the potential explanations for kaempferol’s renoprotective and anti-fibrotic effectiveness may be its decrease in inflammation. Kaempferol administration dramatically reduced IL-1β expression in the DN, demonstrating its anti-inflammatory properties (Ren et al., 2019). The chemical of interest exhibits an anti-fibrotic and renoprotective activity in renal damage associated with diabetes at both the molecular and structural levels (Baliou et al., 2021). Research studies suggested the roles played by cAMP and Ca²⁺ as intracellular signals that facilitated kaempferol’s release of insulin and GLP-1 (Ren et al., 2019). The effects of Kaempferol for renoprotection were validated by staining specific for fibrosis, histological examination, and the expression of anti-fibrotic proteins, profibrotic, and inflammatory. As can be seen, one of the main causes of DN is hyperglycemia. The unbalanced glucose level can be restored via kaempferol’s administration, which was mediated by an increase in GLP-1 or insulin release. Furthermore, by blocking RhoA/Rho Kinase, kaempferol inhibits fibrogenesis, which explains its anti-fibrotic action in DN (Alam et al., 2020).

p-Coumaric acid

Renal fibrosis involves an abnormal collection of extracellular matrix (ECM) proteins in kidney tissues, which disrupts cellular signaling and damages kidney structure. The TGF-β superfamily, particularly TGF-β1, is crucial in promoting this fibrosis. TGF-β1 causes kidney injury by activating non-Smad-dependent and Smad-dependent pathways (Kim et al., 2022; Venkatesan et al., 2023). It directly increases the expression of ECM genes and indirectly encourages the conversion of local fibroblasts and resident cells into myofibroblasts, which boosts ECM protein deposition like collagen and fibronectin. These resident cells primarily produce ECM proteins. Moreover, TGF-β1 helps form myofibroblasts by triggering both epithelial-mesenchymal and endothelial-mesenchymal transitions.

Additionally, TGF-β1 is vital for maintaining collagen structure stability by enhancing cross-link formation between collagen fibers and elastin. This is achieved by boosting the transcription of lysyl oxidase and enhancing the expression of pro-collagen lysyl hydroxylase 2, which plays a significant role in hydroxylating lysyl residues in collagen (Trackman, 2016). Additionally, TGF-β1 inhibits the breakdown of the extracellular matrix (ECM) by enhancing the expression of tissue inhibitors of plasminogen activator inhibitor-1 and metalloproteinases-1 (Kim et al., 2018). These molecules inhibit the activity of matrix metalloproteinases, thus reducing the risk of glomerulosclerosis and interstitial fibrosis. Interestingly, P-CA considerably decreased the amount of TGF-β1 in the renal homogenate in comparison to the DN group. This outcome is consistent with P-CA’s positive effects on renal hydroxyproline and pertinent collagen quantities (Zhao et al., 2020). P-CA dramatically reduced the kidney hydroxyproline in our testing. In this study, P-CA significantly lowered kidney hydroxyproline and associated collagen levels compared to the DN group. Our findings suggested that P-CA not only had hypoglycemic effects but also reduced oxidative stress by modulating SOD and MDA levels. Additionally, it reduced the inflammatory response controlled by IL-6 and TLR-4, as well as decreased deposition of collagen and fibrosis in the kidneys regulated by TGF-β1 (Jin et al., 2023). These mechanisms collectively contributed to P-CA’s ability to arrest the progression of DN. Furthermore, p-Coumaric acid has been shown to prevent the onset of diabetic nephropathy in the rat by increasing the expression of kidney injury molecule 1 (KIM-1) and GLUT-2 (Venkatesan et al., 2022).

Diosmin

A histological analysis was used to evaluate the reno-protective effect of diosmin. Free radicals produced by alloxan result in kidney morphological abnormalities. The primary causes are extracellular matrix protein buildup, swelling of the glomerular lesions in tubular cells, necrosis in the glomerular hypertrophy, proximal tubular cells, and infiltration. Diosmin treatment, however, reverses every histological abnormality in diabetic rats produced by alloxan, demonstrating its protective properties. Considering the alloxan-induced diabetic experimental model, this study demonstrates the potent tissue-protective properties of diosmin (Zhao et al., 2024). In an experimental paradigm caused by alloxan, the current study suggests the renoprotective properties of diosmin: the likely mechanism by which diosmin ameliorates diabetic nephropathy. By preventing oxidative-nitrosative stress and inflammatory processes, diosmin enhanced renal functioning and reduced kidney damage. By blocking the NF-κB pathway driven by inflammatory cytokines and oxidative-nitrosative stress, diosmin enhanced renal functioning and reduced renal damage by returning the renal tissue’s normal architecture (Ahmed et al., 2016). It also enhances other biochemical parameters including the lipid profile. Diosmin taken orally not only helps avoid hyperglycemia in the early stages of DN, but it also inhibits the production of oxidative-nitrosative stress and pro-inflammatory cytokines by blocking NF-κB. Therefore, administering diosmin stops the oxidative stress caused by hyperglycemia and reduces pro-inflammatory cytokines (Jain et al., 2014). Considering diosmin in combination with hesperidin is frequently used for hemorrhoids and leg sores, it is striking that diosmin has the potential for the treatment of diabetic nephropathy.

Asiatic acid

Diabetic nephropathy fibrosis is a primary cause of ESRD, marked by a low 5-year survival rate and few effective treatments. The current lack of targeted and efficient therapeutic drugs underscores the need for new approaches. This study reveals that Cyclocarya paliurus contains asiatic acid (AA), a triterpenic acid with notable anti-fibrotic properties in both lab and animal studies (Zhao et al., 2020). AA treatment notably reduced blood urea nitrogen and urine albumin levels, improved glomerular fibrosis, and enhanced the mesangial matrix. When Human Kidney-2 cells were exposed to high glucose (HG) and TGF-β1 to assess AA’s anti-fibrotic effects, AA specifically restricted the interaction between Smad3 and TGF-β type I receptor (TGF-βRI) by binding to TGF-βRI (Sureshbabu et al., 2016). Additionally, AA prevented the nuclear translocation and subsequent phosphorylation of Smad3 and reduced the expression of α-smooth muscle actin (α-SMA), fibronectin, and collagen I, key fibrotic proteins, thereby influencing the epithelial-mesenchymal transition (EMT). Furthermore, AA treatment affected the levels of LAMP1 proteins and LC3, suggesting the involvement of the autophagy-lysosome system in DN fibrosis (Meng et al., 2018). However, chloroquine, an inhibitor of autophagy and lysosomes, partially reversed the anti-fibrotic effects of AA (Yao et al., 2023). These findings suggest that AA may suppress tubulointerstitial fibrosis and reduce TGF-β1 secretion by directly blocking TGF-βRI and triggering the autophagy-lysosome pathway.

Growing evidence indicates that diosgenin can influence several molecular targets, including inflammation and oxidative stress. It seems that oxidative stress brought on by hyperglycemia plays a significant role in the onset and development of diabetic kidney dysfunction. The present study looked at the protective effects of diosgenin against diabetic iatrogenic kidney damage. Diosgenin’s impact on the renal antioxidant system and oxidative indicators, such as lipid peroxidation, demonstrated its efficacy as an anti-inflammatory and antioxidant drug (Unuofin and Lebelo, 2020). As a result, diosgenin showed protective effects on the kidneys of diabetic rats, suggesting that it could be a viable therapeutic option for diabetes and its complications. To clarify the precise mechanism of action, more pharmacological and biochemical research is necessary.

The discrepancy in the research could be caused by different diabetic animal models such as mice and rats. Another factor connecting to the progression of DN in this animal experiment is that the obesity observed in db/db mice was not alleviated by diosgenin, as there were no noticeable changes in body weight across the Mod, DL, or DH groups (Kottaisamy et al., 2021). Next, the focus shifted to ectopic lipotoxicity in the kidney, and it was noted how diosgenin reduced lipid buildup in the glomerulus via controlling SIRT6. Following transcriptomics study, which was most likely SIRT6’s downstream effect on preventing podocyte damage, attention was directed toward PDK4 and ANGPTL4 (Wang et al., 2022). However, this study was limited in many ways, because the distinct function of ANGPTL4 and PDK4 in SIRT6’s downstream was not investigated or confirmed. To confirm the exclusive role of SIRT6 in vivo, it is essential to examine the effects of diosgenin on the targeted deletion of SIRT6 in podocytes. Molecular docking studies indicate a need for further investigation to confirm the binding affinity between diosgenin and SIRT6, suggesting that diosgenin may act as an agonist of SIRT6 (Wang et al., 2022; Nie et al., 2023). Lipid metabolism has been linked to both PDK4 and ANGPTL4. When HG induces podocyte damage in mice, inhibition of PDK4 may be beneficial. Moreover, ANGPTL4 is crucial in renal disorders and podocyte damage. ANGPTL4 has shown enhanced expression in podocytes stimulated by LPS in recent years (Nie et al., 2023). SIRT6 may bind to the PDK4 promotor, according to a study. Our research supported the findings of the earlier study. Furthermore, SIRT6 was linked to SREBP-1C and MTTP. However, it remained unclear how SIRT6 affected MTTP and SREBP-1C. In conclusion, diosgenin may prevent podocyte damage by lowering lipid buildup during the early stages of DN via controlling SIRT6. Several weaknesses would need to be fixed later. It is uncertain whether diosgenin has a protective effect on podocyte injury in DN associated with type 1 diabetes or other stages of DN by modulating SIRT6. Diosgenin might safeguard against podocyte damage regulation of SIRT6 managing diabetic kidney disease plays a vital role.

Ferulic acid

The seeds and leaves of most plants contain the phenolic compound ferulic acid. For instance, rice bran has a wide variety of phenolic acids along with simultaneous biological activity. Furthermore, curcumin, the compound that gives turmeric its yellow hue, has a strong chemical structure similar to that of this spice. Because free radicals are the primary factor responsible for accelerated tissue damage in individuals with diabetes, supplementing with FA at moderate doses enhances the activity of antioxidant enzymes, which helps to neutralize free radicals. Ultimately, TGF-β1 has been shown to increase MCP-1 expression in mesangial cells, promoting collagen deposition (Caturano et al., 2023). It is recognized as a key facilitator of collagen deposition, extracellular matrix growth, and fibrogenesis in diabetic nephropathy. When the expression levels of type IV collagen and TGF-β1 in the renal cortex were assessed, it was identified that FA therapy lowered these levels (Martemucci et al., 2022). Combined, these findings demonstrate that FA protects the kidneys by enhancing glucose control and inducing structural changes that reduce inflammation, oxidative stress, and the expression of type IV collagen and TGF-β1 in the kidney. All things considered, FA may be a novel treatment for DN in T2D patients and inhibit the development of DN in T2D OLETF rats.

Syringic acid

Among the diverse plant species are natural phenolic compounds, such as syringic acid (SYA). Due to its anti-inflammatory and antioxidant properties, SYA has been shown in several studies to have preventive benefits against several diseases, such as cancer, inflammation, diabetes, and infectious diseases. Moreover, it may be possible to stop the advancement of DN by modulating autophagy; therefore, it is necessary to screen for pharmaceuticals that promote autophagy in the face of hyperglycemia stress. The initiation of the phagophore is a crucial step in the autophagy process, which is triggered by the establishment of the Unc-51 Like Autophagy Activating Kinase 1 complex (Yu et al., 2018). This is followed by activating the Class II PI3K complex, which causes the nucleation of the phagophore and engulfs the damaged protein aggregates (Yu et al., 2015; Yu et al., 2018).

The autophagy-related proteins Atg5, Atg12, and Atg16 form a conjugate that facilitates the elongation of the phagophore. This process follows the action of Beclin 1, a component of the Class III PI3K complex, which is crucial for phagophore nucleation (Iriondo et al., 2023). The cytosolic form of LC3 is conjugated to phosphatidylethanolamine through ubiquitin-like processes catalyzed by Atg7 and Atg3, resulting in the formation of LC3II, a marker for autophagosome formation (Yang et al., 2017; Runwal et al., 2019) The study’s findings support the idea that SYA improved phagophore formation by upregulating the manifestation of autophagy proteins such as Atg5, Atg7, Beclin 1, and Atg3, which in turn repaired the diabetes-induced autophagy deficiency. Furthermore, SYA-induced higher expression of Atg7 and Atg3 showed improved LC-3 lipidation (Runwal et al., 2019). When SYA was administered, LC-3’s immunopositivity increased, according to more research on its expression by immunofluorescence staining, while its immunoreactivity was only slightly higher in the diabetes control group. Furthermore, increased autophagosome production induced by SYA was verified through an immuno-localization assay conducted in NRK 52E cells, as demonstrated by the increased colocalization of LC-3 and Lysotracker red. The activation of autophagy and antioxidant processes by SYA is believed to mitigate renal injury in diabetic rats, as shown by the elevated expression of autophagy proteins and Nrf2 in their renal lysates. The nephroprotective role of SYA against hyperglycemic renal injury is demonstrated by both in vivo and in vitro studies. These findings indicate the necessity for additional molecular research to elucidate the exact mechanism through which SYA induces autophagy in renal tissue.

Quercetin

The bioflavonoid demonstrated noteworthy advantages for renal function as well, as demonstrated by the notable reduction in creatininemia, the restoration of creatinine clearance, and the tendency to lessen the presence of protein in the urine of diabetic apoE−/− mice (Gai et al., 2019). The following points may explain why the uric acid and uremia parameters remained unchanged: (1) significant catabolism of purines and amino acids in this experimentally induced diabetic model; and (2) the glomerulus’s higher sensitivity to oxidative damage comparison to other segments of the nephron (Schena and Gesualdo, 2005; Gomes et al., 2015), which is consistent with the observed improvement in renal filtration in this study. The direct advantages of quercetin, such as its recently reported vasorelaxant impact in vascular tissues, could account for all these renoprotective properties. besides its indirect benefits, which include its anti-dyslipidemic and hypoglycemic properties and its ability to lower ROS production. Recently, Zhao et al. (2024) demonstrated in vitro that quercetin may positively affect the functional roles of endothelial progenitor cells in the regeneration of vascular and kidney tissues following injury. This finding offers new insights into the potential role of quercetin in antidiabetic therapy. Additionally, our study showed that low-dose oral administration of quercetin provides renal protective and antidiabetic benefits in a mouse model with concurrent apoE−/−-induced hypercholesterolemia and STZ-induced diabetic nephropathy. Our results suggest that this bioflavonoid could be a promising nutraceutical option for preventing or treating renal impairment caused by diabetes and dyslipidemia. Nevertheless, further research is required to clarify the underlying mechanisms.

Resveratrol

Natural polyphenol resveratrol is imitative from a variety of plants. Additionally, it has been established to improve diabetic heart failure. It has been demonstrated that resveratrol effectively inhibits the production and release of VEGF, potentially by blocking hypoxia-induced factor 1α (HIF-1α) (Koushki et al., 2018; Gitanjali et al., 2023). Additionally, resveratrol prevents VEGF-induced angiogenesis primarily by blocking Src-dependent vascular endothelial cadherin tyrosine phosphorylation (Gál et al., 2023; Samy et al., 2023). Furthermore, it has been shown that resveratrol down-regulates Flk-1 expression. Additionally, resveratrol has been shown to have an anti-angiogenic effect on the growth of tumors in vivo. Moreover, patients tolerate resveratrol well and it is efficiently absorbed orally (Khattar et al., 2022). The diabetic rats’ food intake, body weight, and blood glucose were unaffected by resveratrol administration, indicating that resveratrol’s positive effects on DN are independent of blood glucose levels. Not much is known about the precise method by which Sirt1 prevents VEGF and Flk-1 production in glomerular podocytes and endothelial cells. Previous work showed that Sirt1 might deacetylate HIF-1α to decrease the expression of VEGF (Wang et al., 2019). Conversely, it has been demonstrated that nuclear transcription factor κB (NF-κB), which Sirt1 can deacetylate, regulates Flk-1 expression. Resveratrol treatment of DN may also involve several additional signaling pathways, including the Akt/FOXO3 pathway. This requires more investigation (Khattar et al., 2022).

In this review, the mechanisms through which polyphenols influence blood glucose levels and diabetes-related complications have been explored and specific food sources high in dietary polyphenols have been focused. The overproduction of ROS via the mitochondrial electron transport chain (METC) is linked to various molecular pathways (AGE formation, NF-κB activation, polyol, and hexosamine pathway flux, and PKC activation) associated with the harmful effects of diabetes (Yuan et al., 2019). Given the significant role of ROS, their production at the METC triggered by hypoxia, and the subsequent inflammatory response, it can be concluded that polyphenols, acting as antioxidants, help mitigate the adverse effects of diabetes. Oxidative stress, besides causing an overproduction of ROS, also activates transcription factors and signaling pathways, promotes the process of inflammatory cell infiltration and recruitment like monocytes and macrophages, and stimulates the synthesis of inflammatory mediators (Pizzino et al., 2017). Furthermore, the production of inflammatory mediators can generate more ROS, exacerbating oxidative stress. This interplay between inflammation and oxidative stress influences the development of DN. As polyphenols are naturally occurring substances with anti-inflammatory and antioxidant properties, they are considered promising therapeutic agents against DN. They can potentially reduce or even reverse the pathological changes and cellular damage caused by DN by targeting specific signalling pathways. The increasing incidence of diabetes complications suggests that existing medical treatments for managing diabetes are insufficient. Complementary therapies, such as functional foods and their nutraceuticals, could improve diabetes management. Plant polyphenols have been suggested as potential supplements for diabetes control and prevention of its complications, based on in vitro studies, animal models, and limited clinical trials. Further human clinical research is necessary to validate the positive impacts of polyphenolic compounds as supplementary treatments for people with diabetes.

In summary, this review highlights the promising therapeutic potential of natural compounds, particularly polyphenols, in the prevention and treatment of diabetic kidney disease (Fig. 4). These bioactive substances offer antioxidant, anti-inflammatory, and anti-fibrotic effects, addressing key pathological mechanisms such as oxidative stress and inflammation that contribute to kidney damage in DKD. While traditional treatments focus on managing symptoms and slowing disease progression, natural compounds present a novel avenue for targeting the underlying causes of DKD. By integrating natural compounds into therapeutic strategies, there is potential to reduce the incidence of diabetic complications and slow the progression to end-stage renal disease. However, further clinical studies are needed to confirm the efficacy and safety of these compounds in human populations.

Figure 4. Overview of natural compounds in the drug development against kidney diseases.