Exploring the Potential of Nephroprotective effect of Flavonoids present in Cassia auriculata A Review

C. Senthil Kumar¹*, Neelaveni Thangavel², D. Benito Johnson¹, Madhuranthagan M¹,

S Rahul Raj, A. Roshni, R. Abimanyu

¹INTI International University (Research Scholar), Malaysia, Department of Pharmacology,

RVS College of Pharmaceutical Sciences, Sulur, Coimbatore, Tamil Nadu, India.

²Department of Pharmaceutical Chemistry, RVS College of Pharmaceutical Sciences,

Sulur, Coimbatore, Tamil Nadu, India.

*Corresponding Author E-mail: drcsenthilkumar@rvsgroup.com

ABSTRACT:

Un control diabetes mellitus endup with microvascular complication Diabetic Neuropathy, Retinopathy and Nephropathy, among all three-complication diabetic nephropathy is a leading cause of end-stage renal disease worldwide. Current treatment approaches—such as glycemic control, RAAS inhibition, SGLT2 inhibitors, and GLP-1 receptor agonists—offer limited effectiveness and are frequently linked to adverse side effects. This limitation the urgent added by novel, multi-targeted approaches. Bioflavonoids, which are naturally occurring polyphenolic compounds, show potential as nephroprotective agents as of their strong antioxidant, anti-inflammatory and antifibrotic properties. Cassia auriculata, a medicinal plant widely used in traditional medicine, it contains bioflavonoids such as quercetin, kaempferol, luteolin, apigenin, and isorhamnetin. These compounds modulate oxidative stress, inhibit AGE–RAGE and NF-κB signaling, suppress pro-inflammatory cytokines, and improve insulin sensitivity, thereby protecting against glomerular hypertrophy, mesangial expansion, and proteinuria. Preclinical research shows that these flavonoids modulate various molecular pathways—such as MAPK, Nrf2/HO-1, STAT3, and the NLRP3 inflammasome—to reduce kidney damage in diabetic models. However, their poor bioavailability and rapid metabolism limit clinical application. Drug delivery systems based on nanotechnology offer a novel approach to improve solubility, stability, and overall therapeutic effectiveness. So far, there have been no reports of nanoformulations containing dual phytoflavonoids for the treatment of diabetic nephropathy (DN). Based on the insights from this review, we propose the formulation and evaluation of dual bioflavonoid-loaded nanocarriers as a novel treatment strategy, aiming to synergistically regulate multiple pathogenic mechanisms. Further pharmacokinetic studies, molecular investigations, and clinical validation are essential to translate these promising natural agents into effective nephroprotective therapies.

KEYWORDS: Bioflavonoids, Cassia auriculata, Diabetic nephropathy, Oxidative stress, Inflammation, Nanoformulation, Nephroprotection, advanced glycation end products (AGS), extracellular matrix (ECM), protein kinase C, oxidative stress(ros), “Oral Hypoglycemic Agents (OHAs)

INTRODUCTION:

Diabetes mellitus (DM), once viewed as a condition of limited global health impact, has now become one of the leading health challenges of the two decades¹. It is the most widely spreader non-communicable disease globally and ranks as the fourth or fifth leading cause of death in developed nations². The worldwide number of individuals with diabetes complication is projected to rise from the current evaluation of 150- 220 million in 2010 and further reported to 300 million in 2025³. Diabetes is traditionally classified into two main types: Type 1 diabetes (auto immune disease) and Type 2 diabetes (insulin resistance)⁴. Complications arising from diabetes will lead to macrovascular and microvascular complications. These microvascular issues are largely the result of structural changes in the capillary basement membrane, which becomes abnormally thickened, leading to reduced blood supply and tissue function⁵. DN is the most prevailing microvascular snags of diabetes, affecting approximately 30% to 50% of diabetic patients. It is a leading cause of (ESRD) among individuals with diabetes⁶. Drugs used in diabetic nephropathy Glycemic control, insulin, metformin, SGLT2 inhibitors⁷. GLP-1 Receptor Agonist⁸. Blood Pressure Control/RAAS Blockade, ACE Inhibitors (ACEIs) (Enalapril, Ramipril, Lisinopril)⁹.

Angiotensin Receptor Blockers (ARBs), Mineralocorticoid Receptor Antagonists (MRAs). Antihypertensives (if BP is not controlled with ACEI/ARB), CCBs, beta-blockers, water pill, lipid-lowering therapy, and statins (atorvastatin, rosuvastatin) Novel/Emerging Therapies: Endothelin Receptor Antagonists (Atrasentan) reduce proteinuria and are under trials. Bardoxolone methyl (Nrf2 activator)—antioxidant/anti-inflammatory—is investigational. Anti-fibrotic agents (e.g., pirfenidone, in research¹⁰ A major global health concern, kidney diseases pose a serious risk to human health overall and contribute to high mortality rates¹¹. The clinical presentation of diabetic nephropathy (DN) typically includes progressive proteinuria and a significant decline in GFR, reflecting gradual loss of nephron function. The pathogenesis of DN is marked by several structural abnormalities, including thickening of the GBM, formation of microaneurysms in diabetic retinopathy, and development of mesangial nodules known as Kimmelstiel–Wilson bodies. Among the contributing factors, chronic inflammation plays a central role. The progression of DN is strongly associated with the activity of innumerable pro-inflammatory cytokines, mostly IL-1, IL-6, and TNFα¹². Flavonoids have low bioavailability, which means the body may not absorb them well and hinder their health benefits. To increase the absorption, the flavonoids are converted into nanoformulations, nanoparticles, or dual-loaded in silico methods.

Etiology:

Chronic hyperglycemia initiates the production of (ROS) and activates multiple deleterious molecular pathways. These complies and formation of AGEs, increased oxidative stress, formation of radicals and activation of (NF-κB) interleukins and (PKC). Additionally, hyperglycemia promotes the upregulation of (TGF-β)/SMAD signaling pathway and contributes to lipotoxicity. Persistent hyperglycemia interferes with cellular signaling cascades, enhances extracellular matrix synthesis, and contributes to glomerular basement membrane thickening GBM^13,14. Reactive hypoglycemia is a condition characterized by abnormally low blood glucose levels occurring within 2–5 hours after eating a meal (Normal level less than 70mg/dl). SGLT2 and GLP-1 are used as target for the therapy of diabetic nephropathy^15,16. One of the symbol features is chronic inflammation, characterized by elevated levels of cytokines and chemokines, which drive fibrosis, vascular permeability, and subsequent glomerular injury. The combined effects of these mechanisms culminate in dysfunction of endothelial cells and injury to podocytes and progressive glomerulosclerosis, all of which contribute to DN. A comprehensive understanding of these pathways offers clear understanding for the development of targeted beneficial strategies aimed at mitigating renal damage in diabetes.

FIG:1 The pathogenesis of diabetic nephropathy and a novel therapeutic approach. In Type 2 diabetes, poor glycemic control leads to increased production of (AGEs), (ROS), and activation of pathways such as MAPK, NF-κB, and TGF-β, causing kidney damage and mesangial cell injury. The proposed novel nanoformulation using CASSIA auriculata extract helps downregulate harmful markers (AGEs, SGLT2, NF-κB, IGF-1) and upregulate protective factors like GLP-1. This approach may significantly control diabetes and promote the regeneration of mesangial cells in the kidney.

Pathophysiology:

Fig:2 Poor glycemic control in Type 1,2 diabetes, contribute to (AGEs) production and activation of ROS pathways. These processes stimulate inflammatory cytokines and growth factors, causing abnormal extracellular matrix accumulation and mesangial expansion in the kidneys. Increased glucose load results in glomerular hyperfiltration and podocyte injury, further damaging kidney structures. Continuous stress and injury lead to tubular fibrosis and glomerular scarring. Over time, these pathological changes reduce the glomerular filtration rate (GFR), ultimately resulting in diabetic nephropathy.

Oxidative stress imbalance between ROS\NS generation and antioxidant Défense that accumulate and cause the cell damage the excess of ROS marker found in the kidney and lead to the tissue injury the preclinical study revelsthat increase in the glucose level increase the generation of ROS  in kidney cells GPX1 is the enzyme present iin the body that neutralize the harmful ROS generation 9hydrogen peroxide and lipid peroxide )while the mouse lack of this GPX1  increase the kidney damage linked with (MCP-1,VCAM-1) and inflammation and. In reactive oxygen species (ROS) of diabetic patient Peroxynitrite and NADPH oxidase 4 (NOX4) are majorly present the research show that reduce the NOX4 to avoid the kidney injury and high level of oxidative DNA damage signs like 8-OHdG and 8-oxodG are key components for development of kidney disease  Excess ROS activate the   signalling pathways, such as NF-κB, MAPKs &PKC, which drive inflammation, fibrosis, mesangial expansion, and tubulointerstitial damage. Antioxidant healings, including GPx1 mimetics and NOX4 inhibitors, can block these destructive effects, making oxidative stress an important therapeutic target in diabetic nephropathy^17,18,19

Mapk Signalling Pathway:

MAPK fits to the group of serine/threonine protein kinase. It is responsible for the intracellular signal transduction from the extracellular stimuli signal transduction from the extracellular stimuli, and MAPK is composed of the subgroups, namely, Intracellular signal-regulated kinases 1 and 2, CJUNN terminal kinase (JNK) 1,3, P38 MAPK. These are mainly related to several cell functions. They are cell death, differentiation, proliferation, motility, stereo response, cell growth, and p38 MAPK that cause mediated RPTC. Started apoptosis. In this patient, it can be triggered and result in the increase of oxidative stress and bulding of AGS products, along with angiotensin-2 lead to several renal pathologic alternation in kidney^20,21,22

Current Therapy:

Slgt Inhibitors:

SLGT inhibitors, two types of symporters, namely SLGT-1 and SLGT-2, are more prone to the formation of diabetes. SGLT2 inhibitors are the class of (OHAs)that lower the blood glucose level by blocking the SGLT2 acting on proximal renal tubules. This decreases the glucose reabsorption developed to glucosuria and osmotic diuresis. 90% of filtered glucose with sodium (one sodium together with one molecule of glucose) is reabsorbed in the diabetic patient's macula densa (a detector). There are present detectors that detect low levels of sodium, so the detectors dilate the afferent arteriole, dilute more, and increase the blood flow into the nephron. The GFR rate is increased, ultimately leading to increased hyperfiltration, which leads to increased diabetes complication^23,24,25

Glp-1 Agaonist:

In this GLP-1, the incretin activity is important, which involves two peptide hormones secreted by L cells. Located in ileum in colon present in gastrointestinal tract: (GIP) and GIP-1. GLP-1 is a signalling cascade pathway that plays a energetic role in the maintenance of blood glucose levels that increase the insulin secretion from beta cells of the pancreas. GLP-1 Receptors (GLP-1R) Stimulate the (adenylate cyclase) that converts the AMP into cAMP and Pyrophosphate (PPI). In this the activity of GLP-1 Receptor action is decreased and the diabetic complications is increased^{26,27,28,29,30}

Bioflavonoids, which are naturally occurring polyphenolic compounds, show potential as nephroprotective agent, antioxidant, anti-inflammatory, and antifibrotic properties. Cassia auriculata, a medicinal plant widely used in traditional medicine, is rich in bioflavonoids such as quercetin, kaempferol, luteolin, apigenin, and isorhamnetin. Flavonoids, a diverse group of polyphenolic compounds, are richly present in vegetables, fruits, nuts, tea, grains and herbs are taken as supplement of food. They have possible health-promoting properties antioxidant, anti-inflammatory. they have attracted important attention in nutritional and medical research. Flavonoids found a major class of naturally occurring polyphenolic compounds, with over 8,000 distinct structures identified to date.³¹ Flavonoids are measured a class of biologically active secondary metabolites in plants, known for creating pigments accountable for the colour and aroma of flowers. In addition to their role in plant signalling, they exhibit various biological activities, including antiviral, anti-allergic, antibacterial, and anti-inflammatory effects³². Naturally occurring herbs have been used as alternatives to allopathic drugs since ancient times, particularly in the Ayurvedic system of medicine. These herbal remedies are gaining increased attention due to their minimal or insignificant side effects compared to many allopathicTreatment³³. Cassia auriculata is a well-known medicinal herb recognized for its therapeutic potential against a variety of ailments. It is an evergreen shrub bearing bright yellow flowers and belongs to the family Caesalpiniaceae. This plant is native to Asia and is widely distributed across various regions, particularly in India³⁴ Numerous studies have documented the medicinal properties of various parts of Cassia auriculata, including its leaves, flowers, bark, and roots, highlighting activities such as antidiabetic, antioxidant, antimicrobial, and hepatoprotective effects³⁵.

Experimental studies have shown that the aqueous extract of Cassia auriculata flowers possesses significant antioxidant activity, contributing to decreased oxidative stress in diabetic rats, thereby suggesting its potential role in managing diabetes-related complications³⁶ The ethanolic extract of Cassia auriculata buds and flowers has demonstrated significant antidiabetic activity in vivo and in vitro correlation study shows that it has significant natural control over diabetes³⁷.Cassia auriculata contain several types of chemical compounds including alkaloids, flavonoids, saponins, Tannins, phytosterols, Triterpenoids, Glycosides, Anthraquinones. Among these flavonoids are especially important for the plant’s health benefits. Specific flavonoid present in cassia auriculata include Kaempferol, Quercetin, Luteolin, Apigenin, Isorhamnetin Cassia auriculata is known to contain a variety of bioactive compounds, among which flavonoids play a prominent role in its pharmacological activities. Phytochemical investigations have identified several flavonoids in different parts of the plant, including quercetin, kaempferol, luteolin, isorhamnetin, and myricetin. These flavonoids are primarily responsible for the plant’s antioxidant, antidiabetic, anti-inflammatory, and hepatoprotective properties. Flavonoids exert their beneficial effects by modulating oxidative stress, improving insulin sensitivity, and influencing key metabolic pathways. Their existence in C. auriculata supports the traditional use of the plant in managing diabetes and related metabolic disorders Diabetes is a chronic endocrine disorder caused by insulin deficiency, ineffective use of insulin, or both [^1]. It is characterized by persistent hyperglycemia (high blood glucose levels), which, if left uncontrolled, can lead to serious damage to various organs and tissues, such as the eyes, kidneys, and heart.

Role of Kaempferol in Diabetic Nephropathy:

Kaempferol, a flavonoid commonly present in tea, cruciferous vegetables, and various fruits, is typically haul out using HPLC. In current years, it has been shown to possess multiple pharmacological properties, such as anti-inflammatory, antioxidant, and anti-atherosclerotic action^38,39,40,41.

Role of Quercetin in Diabetic Nephropathy:

Quercetin is a plant derived flavonoids abundantly distributed in various fruit and vegetables is recognized for its stability and known for its anti-inflammatory, antiviral, and antioxidant effects⁴⁶. Quercetin exerts its antioxidant effects through several mechanisms, such as increasing glutathione (GSH) levels, activating antioxidant signalling pathways, and protecting against oxidative damage caused by reactive oxygen species ROS^47,48

Table 1 Role of Kaempferol in Diabetic Nephropathy

Flavonoid	Animal/cell model	Dosage	Target/Pathways/ Mechanism	Reference
Kaempferol	STZ -DN rat	25 and 50 mg/kg day	NRF-2/HO-1axis	42
	Db\ dB mice	50mg/kg/day	AMPK/mTOR Pathway	43
	Streptozotocin-induced DN mice/GLU Tag cell lines.	50-200mg/kg;1-50Mm (invitro)	GLP-1/RhoA/Rho kinase	44
	STZ induced Diabetic rats	25-50mg/kg/Day	NLRP3 caspase RhoA\ Rho GLP-1	45

Table 2 Role of Quercetin in Diabetic Nephropathy

Flavonoid	Animal/cell model	Dosage	Target/pathways/ mechanism	Refrence.
Quercetin	STZ/ DN rat	50 mg/kg	TNF-α/IL-1β/AGE	49
	STZ/ DN rat	150-350mg/kg	TNFαp38 MAP kinase	50
	Leprdb /Leprdb(db/db) mice	100-150 mg/kg	Hippo pathway	51
	Sprague Dawley rat	10 mg/kg	IcaM-1	52
	STZ/ DN rat	100 mg/kg	NF-kB/SIRT1	53
	STZ/ DN rat	25-100mg/kg	NLRP3	54
	STZ/ DN rat	10mg\kg	PKC/MARK pathway	55

Table 3 Role of Luteolin in Diabetic nephropathy

Flavonoid	Animal/cell model	Dosage	Target/ pathways/ mechanism	Ref
Luteolin	STZ induced DN rat	80mg/kg	NPHS 2	58
	Leprdb/Leprdb (db/db) mice	50mg/kg	STAT3 pathway	59
	mesangial cells mpc-s cells	30μm invitro	Il 1-β NLRP3	60
	STZ induced DN rat	200mg/kg	SOD/MDA/ HO-1	61

Role of Luteolin in Diabetic Nephropathy:

It is a flavonoid that put on numerous therapeutic belongings including anti-inflammatory, anti-allergic, and uric acid-lowering action, on continuous use of luteolin. Given that unnecessary cytokine secretion from activated microglia is implicated in both neurodegenerative processes and behavioural abnormalities, we examined the potential of luteolin to influence IL-6 generation in these cells. Exposure of primary murine and BV-2 microglial cells to luteolin prior to LPS stimulation markedly reduced the induction of IL-6 expression. The analysis included measurement of expression at both gene (mRNA) and protein stages^56,57.

Role of Isorhamentin in Diabetic Nephropathy:

The anti-diabetic effect of IH is used in the treatment of diabetic-induced rats. IH was administered at three different doses that gradually reduce in mTOR, IGF1-R, and LncRNA-RP11-773H224. reduce the expression of Akt2 mRNA, miR-1, and miR-3163 in the adipose tissue followed by IH to inhibit the signaling activity of such NF-κB inflammatory mediators and ROS in rats.  Evidence from another study suggests that IH facilitates glucose assimilation and contributes to glucose homeostasis by limiting hyperglycemic effects within physiological ranges^.62,63.

Table 4 Role of Isorhamnetin in Diabetic Nephropathy

Flavonoid	Animal/cell model	Dosage	Target/ pathways /Mechanism	Ref
Isorhamnetin	Sprague-Dawley rat streptozotocin	30mg/kg	NF-KB	64
	Male Wistar rats streptozotocin HFD	30mg/kg	MAPK/NOX3-JNK Stress signalling pathway	65
	Male wistar rats STZ	60mg/kg	Oxidative stress (BDNF)	66

Role of Apigenin in Diabetic Nephropathy:

Apigenin (APG) is a natural flavonoid have potent anti-inflammatory and antifibrotic actions that has demonstrated protective potential against diabetic nephropathy, though the miRNA-related molecular pathways responsible for this effect have not yet been fully characterized^67,68,69. Hyperglycemia in diabetes activates the aldose reductase enzyme, resulting in excessive intracellular sorbitol accumulation, which promotes the development of complications including neuropathy, retinopathy, and cataract. Celery-derived apigenin can attenuate these effects by suppressing aldose reductase activity and improving metabolic balance⁷⁰

Table 5 Role of Apigenin in Diabetic nephropathy

Rationale for Selecting Flavonoids in Diabetic Nephropathy

Flavonoid	Animal/cell model	Dosage	Target/pathways/ mechanism	Reference
Apigenin	Male wistar rat	50mg/kg	NRF2(nuclear factor erythroid 2 related) pathway	71
	HK-2 Cells	100-200μ (invitro)	NF-E2 related factor 2(nrf2) pathway	72
	Adult rat(male)	25-50 mg/kg	NrF2/HO-1/NF-ΚB	73
	Male albino Wistar rats STZ induced	20mg/kg	MAPK\NF-ΚB\TNF-α and TGF-β1-MAPK Fibronectin pathway	74
	Male wister rat	20mg/kg	MAPK Pathway	75

Compounds such as quercetin, rutin, and catechin—classified as bioflavonoids—have potent antioxidant activity, anti-inflammatory actions, and protective effects on renal function. The growing number of experimental studies supports treatment potential, but most tests are in preclinical or early clinical stages. Furthermore, comprehensive checks specifically addressing their role in diabetic nephropathy (DN) are rare. This is a clear gap in the literature, particularly in the contextualization of their mechanisms and therapeutic meanings. Thus, a focused review of these connections in DN will help integrate existing evidence and stimulate further research into the potential as new additional therapies. flavonoids provide valuable mechanism knowledge through their interactions with several molecular targets involved in the pathogenesis of DN. Their nephroprotective effects are given by several important mechanisms Oxidative stress arises from up regulation of (ROS) and diminished regulation of intrinsic antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase. Suppressing the AGE–RAGE signaling pathway plays a critical role in mitigating chronic inflammation, extracellular matrix deposition, and the progression of diabetic kidney fibrosis. This leads to down regulation, appearance of proinflammatory cytokines, IL-1β TNF-α, IL-6. It plays a part in damaging the glomeruli, enlarging the mesangial area, and causing fibrosis in the kidney’s tubular regions.

Flavonoids exert Reno protective effects in diabetic nephropathy by modulating multiple interconnected signaling pathways. Current directions emphasize complementary and integrative medicine approaches, particularly in addressing chronic lifestyle-related diseases such as diabetes and its associated complications. Flavonoids that are commonly oriented in fruits, vegetables and medicinal plants with this tendency - naturally occurring polyphenolic compounds. Their overall good safety profile and natural source enhance patient acceptance. It is important that the potential roles as supplementary to traditional pharmacological therapies (such as ACE inhibitors, ARB, SGLT2 inhibitors) support increased movement towards personalised and integrated care approaches. Diabetic nephropathy is a multifactorial disease characterized by the complex interactions of oxidative stress, inflammation, endothelial dysfunction and fibrosis. Conventional therapies typically target specific mechanisms (e.g., RAAS inhibition), which might not fully stop or reverse disease progression. In contrast, flavonoids exhibit pleiotropic effects, acting on multiple biological pathways simultaneously that growth of diabetic nephropathy. The ability to target multiple pathways simultaneously makes this therapeutic strategy particularly valuable in treating complex disorders, where conventional monotherapies typically yield only partial benefits.

CONCLUSION:

The bioflavonoids present in Cassia auriculata offer important promise as nephroprotective agents in the management of diabetic nephropathy. Through their effective antioxidant, anti-inflammatory, these naturally occurring compounds effectively target the key pathological mechanisms involved in renal damage. Experimental evidence supports their ability to protect kidney structure and function, making them potential candidates for adjunct or alternative therapy. Given their low toxicity, natural origin, and broad-spectrum therapeutic effects, bioflavonoids from Cassia auriculata hold great potential for future development in nephroprotective treatment strategies. However, further studies including standardization, pharmacokinetic profiling, and clinical validation are essential to translate these findings into safe and effective therapeutic applications. Based on this review we suggest that dual Phyto flavonoids loaded with nano formulation not yet reported against diabetic induced Nephropathy. Hence we are plan to design and characterization studies of dual bioflavonoids loaded nano formulation. Further need lot of molecular mechanism to establish the clinical use of this nano formulation

CONFICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGEMENTS:

The authors would like to thank Neelaveni Thangavel and RVS Educational Trust for their kind support during our studies.

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Received on 20.11.2025      Revised on 08.12.2025

Accepted on 24.12.2025   Published on 12.02.2026

Available online from February 14, 2026

Res.J. Pharmacology and Pharmacodynamics.2026;18(1):94-102.

DOI: 10.52711/2321-5836.2026.00012

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