The Role of the Renal Nervous System in Diabetic Nephropathy: New Therapeutic Targets

Yuki Tanaka^*
*Correspondence: Yuki Tanaka, Department of Pediatric Surgery, University of Tokyo, Tokyo, Japan, Email:

Introduction

Diabetic Nephropathy (DN) is a leading cause of End-Stage Renal Disease (ESRD) worldwide and is characterized by progressive kidney dysfunction, albuminuria, and renal fibrosis. Traditionally, the pathogenesis of DN has been attributed to hyperglycemia-induced metabolic changes, including increased oxidative stress, inflammation, and fibrosis. However, emerging evidence suggests that the Renal Nervous System (RNS), specifically the Sympathetic Nervous System (SNS), plays a critical role in the development and progression of diabetic kidney disease. [1] The RNS, which includes both the sympathetic and parasympathetic components, is involved in regulating renal blood flow, glomerular filtration, and sodium homeostasis. In DN, sympathetic overactivation leads to vasoconstriction, increased blood pressure, and exacerbation of renal injury. Additionally, the activation of renal afferent nerves can contribute to renal fibrosis and inflammation. Given the emerging role of the renal nervous system in DN, targeting neural signaling pathways presents a novel therapeutic strategy to modify disease progression and improve patient outcomes. This article explores the role of the renal nervous system in diabetic nephropathy and discusses new therapeutic targets aimed at modulating renal neural activity to treat DN. [2]

Description

The renal nervous system and diabetic nephropathy The renal nervous system regulates a variety of kidney functions, including blood flow, glomerular filtration, tubular reabsorption, and the response to fluid and electrolyte balance. The sympathetic component of the renal nervous system, through the release of norepinephrine and other neuropeptides, exerts a vasoconstrictive effect on the renal vasculature, particularly in the afferent and efferent arterioles. This results in altered Glomerular Filtration Rate (GFR) and increased renal vascular resistance, contributing to the development of hyperfiltration, a hallmark of early diabetic nephropathy. In addition, SNS activation promotes sodium retention and increases blood pressure, both of which exacerbate kidney damage in diabetic patients. Beyond these hemodynamic effects, the sympathetic nervous system also directly influences kidney cells, including podocytes, mesangial cells, and fibroblasts, by activating pro-inflammatory and profibrotic signaling pathways. Additionally, renal afferent nerves play a significant role in transmitting signals that contribute to the development of fibrosis and inflammation in diabetic kidneys. These complex interactions highlight the pivotal role of the renal nervous system in the pathogenesis of diabetic nephropathy. Sympathetic nervous system activation and kidney damage in diabetic nephropathy Chronic sympathetic activation is one of the key factors driving kidney injury in diabetic nephropathy. In DN, excessive sympathetic tone has been linked to increased renal vasoconstriction, elevated blood pressure, and renal ischemia, all of which contribute to kidney dysfunction. Moreover, sustained SNS activation induces a pro-inflammatory and pro-fibrotic environment within the kidney by stimulating the release of cytokines, growth factors, and extracellular matrix components, such as TGF-β and collagen. This not only accelerates renal fibrosis but also promotes endothelial dysfunction, further impairing renal perfusion. Recent studies have also suggested that renal nerve remodeling occurs in DN, which further exacerbates sympathetic overactivity. In particular, the expansion of sympathetic nerve fibers within the kidney and the increased release of neurotransmitters such as norepinephrine and adenosine contribute to glomerular hypertension and glomerulosclerosis. As SNS activation worsens kidney damage, targeting these neural pathways has become an attractive therapeutic strategy for slowing or halting the progression of diabetic nephropathy.

Conclusion

The renal nervous system plays a central role in the development and progression of diabetic nephropathy by regulating renal hemodynamics, promoting inflammation, and driving fibrosis. Sympathetic nervous system overactivation, in particular, has been identified as a key mediator of kidney damage in DN. Understanding the mechanisms through which the renal nervous system contributes to diabetic kidney disease has opened new avenues for therapeutic intervention. Approaches such as renal denervation, neurokinin-1 receptor antagonism, and adrenergic blockade hold promise as strategies to modulate sympathetic activity and slow the progression of DN.

References

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