The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential

Abstract

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy-resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P)H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P)H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation.

Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial

“…Although beneficial effects of GLP1 agonists on diabetic kidney disease have been reported in some animal models [27,28] and prospective observational studies [29,30], there have been so far no randomized control trials except one ongoing study [31] primarily to investigate whether GLP1 agonists could improve albuminuria and long-term change in renal function (glomerular filtration rate) in patients with type 2 diabetes. Visceral obesity is reported to be associated with the progression of albuminuria in patients with type 2 diabetes [32].…”

The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial

“…GLP-1 has been reported to have various renoprotective effects [21][22][23][24][25][26][27][28][29][30][31], but renal expression of GLP-1 is suppressed in T2DM [32]. Sitagliptin elevates downregulated intrarenal GLP-1 expression in the T2DM rat model [32].…”

Risk of chronic kidney disease in type 2 diabetes determined by polymorphisms in NOS3, APOB, KCNJ11, TCF7L2 genes as compound effect of risk genotypes combination

“…Гипергликемия и воспаление яв-ляются ключевыми в патогенезе сосудистых осложнений и поражения почек при СД. Кроме того, нарушение секре-ции ГПП-1 в настоящее время рассматривается не только как фактор развития СД, но и наиболее перспективный предиктор и терапевтический субстрат поражения почек при СД [17]. Ассоциация гена TCF7L2 c ХБП показана на японской популяции [18].…”