Herbal Bioactives Targeting Key Molecular Pathways in Nephrotoxicity: Mechanisms, Biomarkers and Therapeutic Potential

Yashashri Tarale, Sadhana Gautam, Dr. Bhushan Gandhare, Samruddhi Kalunke, Payal Jadhav,

doi:10.5281/zenodo.19271211

Review Paper | Open Access
Volume 04 | Issue 03 | Article Id IJPS/260403295

Herbal Bioactives Targeting Key Molecular Pathways in Nephrotoxicity: Mechanisms, Biomarkers and Therapeutic Potential
Yashashri Tarale* Sadhana Gautam Dr. Bhushan Gandhare Samruddhi Kalunke Payal Jadhav
Department of Pharmacology, VYWS Institute of Pharmaceutical Education and Research, Borgaon (Meghe) Wardha, Maharashtra, India

Abstract

Nephrotoxicity is still a significant clinical concern related to common medications including cisplatin, aminoglycosides, non-steroidal anti-inflammatory medicines, and environmental pollutants. The illness is typified by increasing renal impairment brought on by fibrosis, oxidative stress, inflammation, mitochondrial damage, and apoptosis. There are still few effective nephroprotective treatments with few side effects, despite improvements in supportive care. Because of their multitargeted actions and advantageous safety profiles, herbal bioactive substances have become attractive therapeutic options. This review covers the molecular pathophysiology of nephrotoxicity in detail, emphasizing important signaling pathways such NF-?B activation, MAPK signaling, TGF-? driven fibrosis, apoptotic cascades, and reactive oxygen species (ROS) formation. The main regulator of antioxidant defense, the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway, is highlighted in particular because it is essential for shielding renal tissues from oxidative and inflammatory damage.

Keywords

Herbal Bioactives; Nephrotoxicity; oxidative stress; Nrf2 signaling; NF- kB; Renal Biomarkers; Apoptosis; MAPK; TGF-B; Nephroprotection.

Introduction

Nephrotoxicity:

Renal illness or dysfunction that results directly or indirectly from exposure to medications and industrial or environmental toxins is known as nephrotoxicity.^[1] A change in renal function as measured by blood urea nitrogen (BUN), serum creatinine (sCr)^[2], glomerular filtration rate (GFR), or urine output is one sign of nephrotoxicity; however, nephrotoxicants can cause kidney damage without altering any recognized clinical indicator of renal function. Even when there are no initial changes in the GFR, kidney injury is deined as alterations in the structure or function of the kidney.^[3,4]

Figure No 1: Normal and Disease Kidney

Renal damage may progress to acute kidney injury (AKI) or chronic kidney disease (CKD). Time is a key consideration between acute kidney injury and chronic kidney disease. The terms AKI and CKD represent a relatively newer way to refer to the historical terms of acute renal failure (ARF) and chronic renal failure (CRF). A key difference between AKI and CKD in both of these criteria is the length and rate of time in which renal function is declined, with CKD being defined as lasting longer than 3 months based on structural and functional abnormalities. In contrast to CKD. AKI is a sudden change in renal function and is commonly defined by changes in BUN (azotemia) and serum creatinine. The assessment of AKI is primarily based. The damage to the kidney does not have to be induced by chemicals, thereby distinguishing renal pathology from nephrotoxicity. Further, kidney damage induced by pathological events can be induced by extrinsic events such as hypertension, obesity, sepsis, liver failure, and diabetes.^[5]

Nephrotoxic Drugs:

Drugs cause approximately 20 % of community-and hospital-acquired episodes of acute renal failure.^[6,7,8] Among older adults, the incidence of drug-induced nephrotoxicity may be as high as 66 percent.^[9] Compared with 30 years ago, patients today are older, have a higher incidence of diabetes and cardiovascular disease, take multiple medications, and are exposed to more diagnostic and therapeutic procedures with the potential to harm kidney function.^[10]Although renal impairment is often reversible if the offending drug is discontinued, the condition can be costly and may require multiple interventions, including hospitalization. ^[11]

Epidemic Nephrotoxicity

Nephrotoxicity can also have induced by 'atypical' or 'unconventional' agents, such as environmental agents (metals, minerals & animals), food agents (mushrooms, medicinal traditional herbals, dietary supplement & melamine), drugs, and other products (ethylene glycol). Nephrotoxicity varies according to local background, dependent on different food and cultural customs, as well as to differences in local fauna and flora.^[12]Recent outbreaks of nephrolithiasis and acute kidney injury among children in China have been linked to ingestion of milk-based infant formula contaminated with melamine. The USFDA has twice amended its assessment of melamine toxicity for infants, and concluded that only foods with less than 1 p.p.m. of melamine are safe for infants.^[13]

Pathogenic mechanism of drug induced nephrotoxicity

Most drugs found to cause nephrotoxicity by one or more common pathogenic mechanisms. These include altered intraglomerular hemodynamics, tubular cell toxicity, inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy.^[14]Kidney excretes many drugs; it is routinely exposed to high concentrations of drugs or their metabolites or both. Furthermore, the kidney has several features that allow nephrotoxin to accumulate. The proximal renal tubule presents a large area for nephrotoxin binding and transport into the renal epithelium. Reabsorption of the glomerular filtrate progressively increases intra-luminal nephrotoxin concentrations, while specific transport pathways in the kidney may engender site-specific toxicity.^[15]

Table No.1: Drug induced Nephrotoxicity and its mechanism.^[16]

Nephrotoxic drugs	Mechanisms
NSAIDs, Cyclosporine, Tacrolimus, ACE Inhibitors.	Intraglomerular hemodynamics
Antimicrobials, Amphotericin B, Betalactum antibiotics, s Rifampicin, Adefovir, Cidofovir, Contrast dye, Zoledronate.	Tubular cell toxicity
Foscornet, Methotrexate, Triamterene, Ganciclovir.	Crystal nephropathy
Inflammation	Acetaminophen, Aspirin, Acyclovir, Betalactum antibiotics, Quinolones, Rifampicin, Sulfonamides, Cisplatin, Allopurinol, Loops & thiazide diuretics, Chinese medicines.
Rhabdomyolysis	Amitriptyline, Diphenhydramine, Doxylamine, Benzodiazepines, Statins, Methodone
Thrombocytic Microangiopathy	Cyclosporine, Clopidogrel, Mitomycin C, Quinine.

Figure No. 2: Clinical Features of Drug Induced Nephrotoxic.^[17]

Symptoms of Nephrotoxicity

Decrease urine output or oliguria indicating reduced kidney filtration capacity
Fatigue and weakness due to toxin build up and anemia
Fluid retention leading to swelling in legs, ankles, feet
Stomach pain
Inflammation
Swelling
Nocturia
Weakness
Fatigue
Nausea
Vomiting ^[6]

Causes of nephrotoxicity:

Acute tubular necrosis and proximal tubular injury (ATN)

Result of medications' or metabolites' direct harmful effects on proximal tubular cells.
Amphotericin B, cisplatin, iodinated contrast media, aminoglycosides, and antiretrovirals are examples of common agents.
Apoptosis, mitochondrial dysfunction, and oxidative stress are frequently involved in pathogenesis.

Crystal or cast nephropathy, or tubular obstruction

Drugs or their metabolites can precipitate to produce casts or crystals that obstruct tubules. Acyclovir, sulfonamides, methotrexate, indinavir, some antibiotics, and antivirals are examples of common agents.

Inflammatory/ immune-mediated interstitial nephritis

Immunological or inflammatory damage to the renal glomeruli or interstitium brought on by drugs.

Proton pump inhibitors, beta-lactams, NSAIDs, penicillins, rifampin, allopurinol, and diuretics are examples of common agents.

Modified Hemodynamics Within the Glomerular System

Acute kidney damage is caused by drugs that alter glomerular blood flow or produce vasoconstriction.

NSAIDs, ACE inhibitors, ARBs, and calcineurin inhibitors (cyclosporine, tacrolimus) are common medications.

An Overview of Nephrotoxicity

Prevalence in Hospitalized Patients: Depending on the study and criteria applied, drug-induced nephrotoxicity accounts for 8–60% of acute kidney injury (AKI) cases in different patient populations.

Drug-induced nephrotoxicity rates in adults have been shown to range from 14–26% in prospective cohort

Critically ICU and Critically III Patients: The rate of nephrotoxicity among critically sick patients on nephrotoxic medications, such as polymyxins, can reach 34.8% (95% CI, 30.8-38.9%), with severe nephrotoxicity occurring in 12.7% of cases. When comparing ICU patients to non-ICU groups, the rate is significantly greater.

Community-Acquired AKI: The incidence of community-acquired AKI and its outcomes are not well studied, but medications play a significant role, especially with short-term exposures that are often unrecognized. Pediatric Patients: In pediatric hospitals, drug-induced nephrotoxicity is the cause of about 16% of AKI events. Geographical Variation: The highest rates of drug-induced nephrotoxicity are found in South America (39.9%), followed by Europe, Asia, North America, and Africa. Renal Replacement Therapy: Around 20% of nephrotoxic AKI cases require renal replacement therapy, with associated mortality rates exceeding 60% in developing countries. ^[8]

Risk Factors of Nephrotoxicity

Age > 60 years
Underlying renal insufficiency (glomerular filtration rate < 60 mL/min/1.73 m²)
Diabetes mellitus
Heart failure
Sepsis
Intravascular volume depletion (e.g., dehydration, aggressive diuresis)
Exposure to multiple nephrotoxins ^[4]

Pathophysiology of Nephrotoxicity^[7]

Figure No. 3: Pathophysiology of nephrotoxicity^{[ 7]}

Treatment of Nephrotoxicity:

Table No 2: Current Therapies^[ ^9]

Causative Agent / Condition	Nephrotoxicity	Conventional Pharmacological Management
Aminoglycosides (e.g., Gentamicin)	Acute tubular necrosis	Adequate hydration, stop drug, osmotic/loop diuretics to maintain urine flow
Amphotericin B	Tubular toxicity, electrolyte loss	Hydration, potassium & magnesium supplements
Cisplatin	Dose-dependent tubular necrosis	Amifostine (cytoprotective), IV hydration, mannitol diuresis
Radiocontrast media	Contrast-induced nephropathy	N-acetyl cysteine (NAC), IV fluids, sodium bicarbonate
Cyclosporine / Tacrolimus	Vasoconstrictive nephropathy	Calcium channel blockers (diltiazem, verapamil), dose adjustment
Methotrexate (high dose)	Tubular precipitation, crystalluria	IV fluids + Urine alkalization (NaHCO?), leucovorin rescue
Tumor lysis syndrome (hyperuricemia)	Uric acid nephropathy	Allopurinol, Rasburicase, IV hydration
Heavy metals (e.g., Lead, Iron, Mercury)	Tubular necrosis	Chelating agents (Deferoxamine, EDTA, Dimercaprol)
Drug-induced interstitial nephritis (NSAIDs, antibiotics)	Immune-mediated nephritis	Corticosteroids, drug withdrawal
Rhabdomyolysis (myoglobinuria)	Acute tubular necrosis	IV fluids + NaHCO? (urine alkalinization), mannitol diuresis
Severe / Refractory cases	Acute kidney injury	Hemodialysis / Peritoneal dialysis

Sites of Nephrotoxicity:

Proximal tubule injury

Proximal tubule necrosis is a common manifestation of nephrotoxic agents like aminoglycoside antibiotics, cisplatin and heavy metals. Proximal tubule dysfunction without tubule necrosis may also be an important aspect of nephrotoxicity. Histopathological studies in several experimental models of acute renal failure demonstrate early non-lethal dysfunction, such as mitochondrial swelling, blebbing of the endoplasmic reticulum, and sloughing of portions of the plasma membrane, and tubule cell death, intratubule plugging with cellular debris, and interstitial edema develops, leading to a reduction in renal blood flow and a marked decrease in glomerular filtration rate (GFR).^[18]

Renal medullary injury

With a mild nephrotoxic insult to the kidney, impaired urinary concentration, a medullary event, is often the first and sometimes the only apparent injury. Portions of the nephron traveling through the renal medulla are borderline hypoxic as a result of the normally low oxygen tension in the area of the kidney. In addition to their susceptibility to hypoxia, cells of the medullary thick ascending limb are at risk for nephrotoxic injury from polyene antibiotics,^[19,20] cyclosporine and radio contrast agents. Drugs that block sodium reabsorption in the medullary thick ascending limb (e.g.: furosemide, ouabain) diminish cell damage, which suggests that if metabolic demand is reduced during periods of ischemia or nephrotoxic insult, cell necrosis may be avoidable.^[13,14,15]

Intratubular obstruction

Agents that have a low solubility in urine when given in high doses may precipitate within the nephron and obstruct the flow of urine, leading to a reduction of GFR. Such agents should be considered only as relative nephrotoxins, because they may be given safely and precipitation is avoided by maintaining high tubule flow rates and optimizing urine pH.^[13]

Distal tubular dysfunction

Hyperkalemia is produced by several agents that interfere with the renin-angiotensin aldosterone-axis, These abnormalities include impaired production of renin, reduced production of aldosterone and tubular insensitivity to the action of aldosterone", Renal tubular acidosis is caused by agents that interfere with hydrogen ion (H) secretion by distal tubule cells. Hyperkalemia can result from enhanced excretion of potassium by agents that cause renal tubular acidosis. Nephrogenic diabetes insipidus results from blockade of the effects of antidiuretic hormone on collecting tubule cells.^[18]

RENAL BIOMARKERS

Biochemical markers play an important role in accurate diagnosis and also for assessing risk and adopting therapy that improves clinical outcome. According to the NIH working group, biomarker is a characteristic that is objectively measured as an indicator of normal biological processes, pathogenic processes, or a pharmacological response to a therapeutic intervention^{. [16]}

Ideal features of biomarkers used to detect drug-induced nephrotoxicity ^[20]

Identifies kidney injury early (well before the renal reserve is dissipated and levels of serum creatinine increase)
Reflects the degree of toxicity, in order to characterize dose dependencies
Displays similar reliability across multiple species, including humans Localizes site of kidney injury
Tracks progression of injury and recovery from damage
Is well characterized with respect to limitations of its capacities is accessible in readily available body fluids or tissues

Existing biomarkers for detecting kidney injury^[21]

The current biomarkers, serum creatinine (SCr) and blood urea nitrogen (BUN), to monitor renal safety are late and insensitive and show limited specificity with the serious consequences that AKI cannot be prevented or managed with appropriate tools.

Second-generation biomarkers for acute kidney injury in the past decade, several efforts have been undertaken to identify better and earlier markers of nephrotoxicity using genomics and proteomics approaches. Those new markers are more sensitive and can detect damage earlier than BUN and creatinine levels.

List of Biomarkers of nephrotoxicity:

Table No 3: List of Biomarkers of Nephrotoxicity^{[ 22]}

Urinary protein with enzyme activity

Filtered low molecular proteins

Heart -type fatty acid binding protein

Liver type fatty acid binding protein

Alanine amino peptidase

α-Glutathione-S-tranferase

γ-Glutamyl trans peptidase

?- Glutathione-S-transferase

N-Acetyl-β-Dglucosaminidase

α 1 -Microglobulin

β 2- Microglobulin

Cystatin-C

Retinol binding protein

Interleukin-18

Kidney injury molecule-1

Micro albumin

Neutrophil gelatinase associated lipocalin

Management of Nephrotoxicity:

Most patients with ARF recover with conservative management which includes ^[23]

Fluid monitoring
Protein restriction
Drug adjustments
Dietary or potassium control
Dialysis (usually temporary)

Main metabolic abnormalities in patients with renal failure ^[24]

Anorexia – reduced oral nutrient intake
Gastrointestinal consequences of uraemia
Restrictive diets
Uremic toxicity – inadequate dialysis prescription
Metabolic acidosis
Endocrine factors (PTH, insulin resistance etc.)
Peripheral insulin resistance
Impairment of lipolysis
Low grade inflammatory state _activation of protein catabolism
Augmented catabolic response to intercurrent disease
Metabolic acidosis
Hyperparathyroidism’s,
uremic bone disease
Impairment of vitamin D3 activation

Conservative management

Fluid balance:

Adequate hydration is important to maintain renal perfusion and avoid drug-induced renal impairment. Whenever possible, volume status should be assessed and corrected, if necessary, before initiation of nephrotoxic agents. This is particularly true when prescribing medications such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and NSAIDs, which induce alterations in renal hemodynamics in patients who are significantly volume depleted. ^[25]

Nutrition:

Nutrition is an important consideration in ARF Adequate energy must be provided in order to promote anabolism and prevent catabolism, which potentiates hyperkalemia, hyperphosphatemia and acidosis. The purpose of nutritional management is to prevent or treat malnutrition, to reduce accumulation of waste products, potassium and phosphorus, and to prevent complications of uremia^[26]

Table No. 4: Vitamin supplementation in acute renal failure ^[27]

Vitamins	Dose
Vitamin k	4mg/wk
Vitamin E	10ui/d
Thiamine Hcl(B1)	2mg/dl
Vitamin E	10ui/d
Riboflavin (B2)	2mg/d
Pantothenic acid	10mg/d
Ascorbic acid (C)	70-100mg/d
Biotin	200mg/d
Folic acid	1mg/d
Vitamin B₁₂	4ug/d
Folic acid	1mg/d
Vitamin B₁₂	4ug/d

Renal replacement therapy

Renal replacement therapy is indicated in a patient with ARF when kidney function is so poor that life is at risk. The common types of renal replacement therapy include ^[23]

Hemodialysis
Hemofiltration
Haemodiafiltration
Peritoneal dialysis.

Common indications for dialysis in acute renal failure.^[26]

Hyperkalemia
Severe metabolic acidosis
Hyperphosphatemia/hypocalcemia
To make space for nutrition and drug administration
Failure to improve with conservative management

Specific Prevention Strategies for Selected Agents ^[14]

Table No.5: Drugs associated with tubular cell toxicity

Medications

Prevention Strategies

Aminoglycosides

Amphotericin B

Contrast dye

Use extended-interval dosing, administer during active period of day, limit duration of therapy, monitor serum drug levels and renal function 2-3 times /week, maintain trough levels ≤1mcg/ml.

Saline hydration before and after dose administration, consider administering as a continuous infusion over 24hours, use liposomal formulation, limit duration of therapy.

Use low-osmolar contrast in the lowest dose possible and avoid multiple procedures in 24 to 48 hours, 0.9% saline or sodium bicarbonate (154mEq/L) infusion before and after procedure, with hold NSAIDs and diuretics at least 24 hours before and after procedure, monitor renal function 24 to 48 hours post-procedure, consider acetyl cysteine pre-procedure

Table No.6: Drugs associated with chronic interstitial nephropathy

Medications

Prevention Strategies

Acetaminophen, aspirin, NSAIDs

Lithium

Avoid long-term use, particularly of more than

one analgesic, use alternate agents in patients with chronic pain. Maintain drug levels within the therapeutic range, avoid volume depletion.

Maintain drug levels within the therapeutic range, avoid volume depletion

Table No.7: Drugs associated with crystal nephropathy

Medications

Prevention Strategies

Acyclovir, methotrexate,

sulfa antibiotics, triamterene

Discontinue or reduce ensure adequate hydration, establish high urine flow. Administer orally

Role of antioxidants in the prevention of drug nephrotoxicity:

Reactive oxygen species play a significant role in the pathogenesis of many chronic diseases such as diabetes mellitus, cancer, chronic renal failure etc. The primary event leading to renal failure is a free radical mediated injury to the endothelial cells in the outer medulla.²⁸Antioxidants are first line defense against free radical damage and are critical for maintaining optimum health and well-being. The administration of various natural or synthetic antioxidants has been shown to be of benefit in prevention and attenuation of renal scaring in numerous animal models of kidney diseases. These include vitamins, N-acetyl cysteine, lipoic acid, melatonin, dietary flavonoids and phytoestrogens, and many others. Supplementation of antioxidant vitamin C and vitamin E (500mg/day during 6 months) corrects plasma antioxidant status and attenuating the cardiovascular disease that accompanies kidney failure.^[29]

Administration of superoxide dismutase provides a marked protection against gentamicin induced impairment of renal function.^[30]

Nrf2 in Nephrotoxicity Caused by :

1) Arsenic:

The main way that arsenic, a hazardous heavy metal, causes nephrotoxicity is by producing too many reactive oxygen species (ROS), which causes oxidative stress and damages renal tissue.^[31]

2) Diallyl Trisulfide, or Allitridin:

Garlic contains an organosulfur molecule called Allitridin, which activates the PI3K/Akt signaling pathway to produce nephroprotective effects. Akt activation facilitates Nrf2's nuclear translocation by encouraging its separation from its cytoplasmic inhibitor Keap1.

Activated Nrf2 increases the transcription of cytoprotective genes, such as the following, via binding to the antioxidant response element (ARE):

HO-1, or heme oxygenase-1, Synthesis of glutamylcysteine (GCS),SOD, or superoxide dismutase Furthermore, DATS inhibits NF-κB activation, which lowers inflammatory signals and increases kidney cell survival in the face of oxidative damage brought on by arsenic.^[32]

3) Sulforaphane

Cruciferous vegetables include sulforaphane, an isothiocyanate chemical that promotes Nrf2 nuclear translocation and ARE-mediated gene expression via activating the PI3K/Akt–Nrf2 pathway.

As a result, more phase II detoxifying and antioxidant enzymes are produced, including: HO-1,Glutathione (GSH), SOD, The enzyme catalase (CAT) GPx or glutathione peroxidase ,GST, or glutathione S-transferase. Additionally, sulforaphane lowers oxidative stress indicators such as: Reactive compounds of thiobarbituric acid (TBARS) LOOH, or lipid hydro peroxides, Carbonyl content of proteins (PCC).[33]

4) Atrazine

Atrazine is a triazine herbicide that builds up in renal tissue and causes nephrotoxicity mainly by damaging cells and causing oxidative stress.^[34]

Lycopene

Lycopene activates the AMPK–Nrf2 signaling pathway, which results in nephroprotective benefits.

Nrf2 is phosphorylated by AMPK.
encourages Nrf2's nuclear translocation
increases the expression of downstream antioxidant genes^[35]

5) Cadmium

antioxidant qualities, carnosic acid finds application in the food, health, and cosmetics sectors cadmium is a heavy metal that pollutes the environment. Chronic kidney disease primarily affects the kidney. exposure because cadmium binds to metallothionein and accumulates in the kidneys after being preferentially absorbed by receptor-mediated endocytosis. Cadmium enters the cytosol when lysosomal enzymes break down the cadmium–metallothionein complex, which causes ROS to be released, cellular damage, and renal tissue apoptosis^.[36]

Common sage (Salvia officinalis) and rosemary (Rosmarinus officinalis) both contain carnosic acid (salvin), a benzenediol abietane diterpene. ^[37]

6) Lead

Lead has numerous industrial uses but, unfortunately, it also is a nondegradable environmental pollutant. Lead poisoning has many complications for various organs, especially the brain, blood, and kidneys, which can present with clinical symptoms such as abdominal pain, vomiting, joint and back pain, decreased learning ability, and anemia ^[38]

7) Oxalate of sodium

It is possible for sodium oxalate to cause mesenchymal–epithelial transition. disorder (EMT), a condition in which cell-cell adhesion and polarity are lost in epithelial cells. EMT appears to play a role in the pathogenesis of end-stage renal disease (ESRD) and renal fibrogenesis [39]

The ester of epigallocatechin and gallic acid is called epigallocatechin gallate (epigallocatechin-3-gallate, or EGCG). Camellia synesis, or green tea, is the most prevalent source. One of the many uses for EGCG that have been suggested is the inhibition of oxalate-induced EMT in Madin-Darby canine kidney (MDCK) cells through Nrf2 pathway activation.^[40]

8) Paraquat

Paraquat (N,N′-dimethyl-4,4′-bipyridinium dichloride) is also known as viologen, a family of redox-active heterocyclic compounds of similar structure. This herbicide is toxic to humans and animals due to its redox activity, which produces superoxide anions.⁴⁰Paraquat has been linked to the development of pulmonary fibrosis, Parkinson's disease, and renal and hepatic failure through involving mitochondria and excessive production of ROS.⁴¹

9) Titanium Dioxide

Anatase, ilmenite, and rutile are the natural sources of titanium dioxide, the oxide of titanium. Plastics, food, and cosmetics all use TiO2 in the form of nanoparticles. It has the capacity to harmful effects on health since it can build up in the kidneys and result in necrosis and cellular damage. TiO2 induces oxidative stress through a direct chemical reaction as well as by inducing an inflammatory response that ultimately results in DNA damage and damage to cell membranes and other organelles like mitochondria. ⁴²

DISCUSSION

A complex degenerative condition, nephrotoxicity is mainly caused by oxidative stress, inflammation, apoptosis, mitochondrial malfunction, and progressive fibrosis. Excessive reactive oxygen species (ROS) production, which upsets cellular redox equilibrium and triggers pro-inflammatory pathways like NF-κB and MAPK activation, is a major factor in drug- and toxin-induced kidney damage. Chronic renal dysfunction is exacerbated by persistent oxidative and inflammatory insults that further promote TGF-β-mediated fibrotic remodeling.
By boosting natural antioxidant defense systems, the Nrf2 signaling pathway is one of the molecular regulators that performs a crucial protective role. By promoting the transcription of cytoprotective enzymes like HO-1, NQO1, and superoxide dismutase, Nrf2 activation reduces oxidative damage and inhibits inflammatory cascades. As a result, targeting Nrf2 has become a viable treatment approach for nephrotoxicity.

CONCLUSION

Herbal bioactive substances modulate important molecular pathways, especially by activating the Nrf2 antioxidant defense system, providing a multitargeted treatment approach against nephrotoxicity. Despite encouraging preclinical data, well-planned clinical trials pharmacokinetic analyses are necessary to convert these results into evidence-based nephroprotective treatments.

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