Introduction
The relationship between systemic hypertension and renal function is well established and bidirectional, with the kidney playing a central role in both the development and progression of elevated blood pressure. The kidney contributes to blood pressure regulation through the renin–angiotensin–aldosterone system (RAAS), modulation of sodium and water balance, and maintenance of extracellular fluid homeostasis. Dysregulation of these mechanisms promotes sustained increases in arterial pressure and contributes to the pathogenesis of hypertension.
Conversely, the kidney represents a major target organ of hypertensive end-organ damage. Chronic elevation of blood pressure leads to progressive structural and functional renal injury, beginning at the level of the renal tubules, which are particularly vulnerable to ischemic damage. Early functional alterations include impaired urinary concentrating ability, manifested clinically as nocturia, reduced urine specific gravity, and decreased urine osmolality. With ongoing ischemic insult, glomerular injury ensues, often presenting as mild proteinuria, which may progress to moderate proteinuria in a subset of hypertensive individuals.
Progressive nephron loss results in a sustained decline in glomerular filtration rate, ultimately culminating in end-stage renal disease (ESRD) in advanced cases. Morphologically, early hypertensive nephropathy is characterized by relatively preserved kidney size, whereas late-stage disease demonstrates reduced renal volume with a finely granular surface. These changes are primarily driven by arteriolosclerosis, leading to chronic ischemia, glomerulosclerosis, tubular atrophy, and interstitial fibrosis.
From a therapeutic perspective, current conventional management strategies are largely directed toward controlling blood pressure and preserving residual nephron function in order to delay progression of renal impairment. However, these interventions do not fully reverse established structural damage.
In this context, herbal medicine has historically been employed in the management of hypertensive nephropathy, with emerging evidence suggesting potential renoprotective effects through multiple mechanisms, including antioxidant, anti-inflammatory, and RAAS-modulating actions. Therefore, systematic exploration of herbal therapeutics and their molecular mechanisms in hypertensive renal injury is of significant clinical and scientific interest. The present review aims to summarize recent experimental and translational research on herbal interventions in hypertensive nephropathy, with a focus on their mechanistic and therapeutic relevance.
Hypertensive nephropathy
Hypertensive nephropathy is a progressive renal disorder most commonly observed in individuals over 50 years of age with a long-standing history of uncontrolled or poorly controlled hypertension.1 It shows a higher prevalence in males compared with females and represents a major cause of chronic kidney disease in the elderly population. The clinical manifestations typically lag behind underlying structural renal damage, with pathological changes often preceding overt symptoms by several years.
In most cases, hypertension persists for more than a decade before early clinical features such as nocturia, mild proteinuria, and impaired urinary concentrating ability become apparent. Functional impairment initially involves distal tubular dysfunction, followed by progressive glomerular involvement as the disease advances.
Pathologically, hypertensive nephropathy begins with vascular injury, particularly affecting renal arterioles, and subsequently progresses to ischemic damage of the renal parenchyma. The earliest vascular changes include hyaline arteriolosclerosis of afferent arterioles and medial thickening of interlobular and arcuate arteries. These alterations are primarily driven by endothelial dysfunction, increased intraluminal pressure, and plasma protein leakage into the vessel wall, resulting in progressive vascular remodeling.
Ongoing injury leads to smooth muscle cell hypertrophy and hyperplasia, along with varying degrees of intimal fibrosis in small and medium-sized renal arteries. These structural changes cause progressive luminal narrowing, increased vascular stiffness, and reduced renal perfusion. As a consequence, chronic ischemia develops within the renal parenchyma, promoting tubular atrophy and interstitial fibrosis.
With continued disease progression, glomerular changes become prominent, characterized initially by ischemic glomerular shrinkage, wrinkling of the capillary basement membrane, and relative preservation of the glomerular lumen in early stages. Over time, these changes contribute to irreversible nephron loss and declining renal function, ultimately progressing toward chronic kidney disease and potentially end-stage renal disease.
Mechanism of herbal medicine in the treatment of hypertensive nephropathy
Suppression of the renin–angiotensin system:
The renin–angiotensin system (RAS) plays a central role in renal hemodynamic regulation and blood pressure control. Angiotensin II (Ang II) promotes vasoconstriction by acting on renal arteriolar smooth muscle and enhancing sympathetic activity, thereby increasing renal vascular resistance. It also stimulates aldosterone-mediated sodium and water retention, contributing to volume expansion and hypertension.
Experimental studies indicate that several herbal compounds modulate the RAS to protect against hypertensive nephropathy. Genipin from Gardenia species attenuates Ang II–TLR/MyD88/MAPK signaling, thereby improving renal function in hypertensive models. Formulations such as Qian Yang Yu Yin granules suppress Ang II activity through epigenetic regulation of nicotinamide N-methyltransferase. Other herbal preparations, including Jiangya Tongluo formula and musk-based formulations, reduce renal Ang II levels and improve vascular protection.
Multiple plant-derived compounds also exhibit RAS-modulating activity. These include flavonoids (e.g., Scutellaria baicalensis), terpenoids (e.g., Poria cocos, Alisma orientale), saponins (e.g., ginseng), and alkaloids (e.g., Uncaria rhynchophylla), many of which inhibit ACE activity or downstream Ang II signaling pathways.
Inhibition of sympathetic overactivity:
Hypertension is strongly associated with increased sympathetic nervous system activity, resulting in elevated catecholamine release, vasoconstriction, and sodium retention in renal tubules. These changes promote vascular remodeling and increased renal vascular resistance.
Herbal medicines demonstrate sympatholytic potential through central and peripheral mechanisms. Chrysanthemum and Scrophularia species reduce sympathetic tone and improve blood pressure control. Astragaloside IV lowers norepinephrine levels, suggesting inhibition of sympathetic activation. Traditional formulations such as Guizhi decoction modulate autonomic balance, while acupuncture-based therapies also contribute to sympathetic regulation.
Antioxidant stress and anti-inflammatory responses:
Oxidative stress and inflammation are key drivers of hypertensive nephropathy. Excess reactive oxygen species (ROS) impair endothelial function, while inflammatory cytokines (TNF-α, IL-6, NF-κB) promote vascular injury, glomerulosclerosis, and renal fibrosis.
Herbal antioxidants significantly attenuate these pathological processes. Salvia miltiorrhiza, Coreopsis tinctoria, and Brazilian red propolis reduce ROS production and improve vascular remodeling. Polyphenols from Apocynum venetum and resveratrol exhibit strong free radical scavenging activity and anti-hypertensive effects.
Additional agents such as paeonol, galangin, and icariin inhibit oxidative and inflammatory signaling pathways, including NADPH oxidase and NF-κB. Formulations like Tongxinluo and Banxia Baizhu Tianma decoction suppress pro-inflammatory cytokines and improve renal function in hypertensive models.
Regulation of vasoactive substances and endothelial protection:
Endothelial dysfunction in hypertension is characterized by reduced nitric oxide (NO) bioavailability and increased endothelin-1 (ET-1), leading to vasoconstriction and vascular remodeling.
Several herbal agents restore endothelial balance by enhancing NO signaling and suppressing ET-1. Cirsium japonicum, Morinda citrifolia, and ginger varieties increase NO production and improve vasodilation. Curcumin and morin modulate endothelial nitric oxide synthase (eNOS) activity and vascular smooth muscle relaxation.
Other compounds, including hydroxysafflor yellow A and tanshinone derivatives, improve endothelial function through calcium signaling and PI3K–Akt–eNOS pathways. Combination therapies (e.g., Astragalus with Salvia miltiorrhiza) further enhance endothelial repair and reduce vascular inflammation.
Improvement of obesity-associated metabolic factors:
Obesity and insulin resistance significantly contribute to hypertensive nephropathy by increasing renal sodium reabsorption, activating RAS, and promoting glomerular hyperfiltration.
Herbal interventions targeting metabolic dysfunction show protective renal effects. Astragaloside IV improves leptin sensitivity and reduces inflammation in high-fat diet models. Ocimum sanctum and Citrus paradisi reduce blood pressure and improve renal function in obesity-related hypertension.
Additional agents such as Coptis chinensis inhibit NLRP3 inflammasome activation, while curcumin protects podocytes via Wnt/β-catenin pathway modulation. Tribulus terrestris and herbal formulations like Mai Tong Fang reduce body weight, lipid accumulation, and renal injury, thereby attenuating obesity-induced hypertensive damage.
Conclusion
Hypertensive nephropathy is a multifactorial renal disorder characterized by progressive renal hemodynamic alterations and vascular remodeling driven by chronic hypertension. Despite advances in modern medicine, current therapeutic strategies largely focus on single-target interventions, which often provide limited efficacy in halting disease progression.
In contrast, herbal medicines demonstrate multi-targeted actions in hypertensive nephropathy, including improvement of renal perfusion, attenuation of vascular remodeling, and delay of renal functional decline. Experimental evidence further suggests that several herbal constituents act simultaneously on multiple pathogenic pathways, highlighting their potential advantage in managing complex renal pathophysiology.
However, clinical evidence supporting herbal interventions in hypertensive nephropathy remains limited. While preclinical studies provide valuable mechanistic insights, they are often restricted to cellular or animal models and lack dynamic evaluation of disease progression in humans. Therefore, basic research should be considered hypothesis-generating rather than definitive, underscoring the need for translational validation.
Future research should prioritize well-designed, large-scale, randomized controlled clinical trials to establish the efficacy, safety, and standardization of herbal therapies. Strengthening clinical evidence will be essential for integrating herbal medicine into evidence-based management of hypertensive nephropathy and expanding its potential applications in related chronic diseases.2
References:
- Wang L, Wang J, Zhang Y, Zhang H. Current perspectives and trends of the research on hypertensive nephropathy: a bibliometric analysis from 2000 to 2023. Ren Fail. 2024;46(1):2310122. doi:10.1080/0886022X.2024.2310122. https://pmc.ncbi.nlm.nih.gov/articles/PMC10863539/
- Dong Z, Dai H, Feng Z, et al. Mechanism of herbal medicine on hypertensive nephropathy (Review). Mol Med Rep. 2021;23(4):234. doi:10.3892/mmr.2021.11873. https://pmc.ncbi.nlm.nih.gov/articles/PMC7893801/