The Role of Glucagon Receptors in Chronic Kidney Disease: Insights into Pathophysiology, Implications and COVID-19 Considerations


Chronic kidney disease (CKD) stands as a formidable challenge to global health, with a prevalence that reached 9.1% of the global population in 2017. This condition, characterized by the progressive decline of kidney function, culminates in end-stage renal failure, presenting a significant burden due to its associated morbidity and mortality. Risk factors such as diabetes mellitus, hypertension, and recurrent acute kidney injuries heighten the likelihood of CKD development. Notably, patients recovering from COVID-19 are also at an increased risk, underscoring the disease’s complex etiology and the multifaceted threats to renal health.

The pathophysiology of CKD involves a reduction in the renal glomerular filtration rate and evidence of kidney damage, such as proteinuria, alongside a range of pathological changes from fibrosis to microvascular rarefaction. This disease state not only compromises renal function but also significantly elevates the risk of cardiovascular complications, thereby exacerbating the health burden on affected individuals.

Central to the understanding of CKD’s pathogenesis is the role of glucagon receptors (GCGRs) in the kidney. These receptors are predominantly located in the nephron segments, including the thick ascending limb of the loop of Henle, the distal convoluted tubule, the connecting tubule, and the collecting duct. Their presence is also notable in the proximal tubule, Henle’s loop limbs, the glomerulus, and among interstitial immune cells, albeit at lower levels. The segmental regions with higher GCGR abundance are critical for glucagon binding and the subsequent activation of adenylyl cyclase and phospholipase C, which points to a functional GCGR signaling cascade within the kidney.

Despite the extensive analysis of hepatic GCGRs, the renal counterparts have not been as thoroughly explored. The physiological functions of renal GCGRs remain largely elusive, yet studies have demonstrated their impact on various aspects of kidney function. This includes glucagon-induced renal vasodilation, modulation of electrolyte excretion, urea excretion and urine concentration, and alterations in bicarbonate absorption, which collectively suggest a regulatory role in renal and systemic homeostasis.

The exploration of GCGRs extends to their role in renal metabolism, although this area remains less defined compared to their hepatic functions. The relationship between glucagon and renal gluconeogenesis, glucose transport, and the feedback loop involving SGLT2 highlights the complex regulatory mechanisms at play in kidney function.

Human genetic studies further illuminate the association of GCGR gene variants with various diseases and traits, indicating the gene’s influence on renal and hepatic function. In the context of CKD, alterations in kidney GCGR expression have been observed, suggesting a potential linkage between GCGR dysregulation and CKD pathogenesis. This hypothesis gains support from animal models, where reduced renal GCGR expression correlates with disease progression.

Innovative research involving the creation of kidney-specific GCGR knockout (KO) mouse lines has provided valuable insights into the significance of kidney GCGR in maintaining systemic metabolic balance and the development of CKD. These studies underscore the crucial role of renal GCGR downregulation in the pathophysiology of CKD, offering new perspectives for therapeutic strategies aimed at mitigating CKD progression.

This detailed exploration into the role of glucagon receptors in CKD not only enhances our understanding of the disease’s underlying mechanisms but also opens avenues for the development of targeted treatments. The translational implications of these findings are vast, holding the promise of improved outcomes for individuals afflicted with this chronic condition.

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