Low-dose lixisenatide protects against early-onset nephropathy induced in diabetic rats

Aim: Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. This study was performed to investigate the possible protective effect of lixisenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on early diabetic nephropathy induced in diabetic rats and explore the various mechanisms underlie this postulated effect. Main methods: Early DN was induced after 3 weeks in diabetic rats fed with a high-fat diet (HFD) and treated with low dose STZ. One week after induction of diabetes, diabetic rats were administered lixisenatide at two dose levels (1 and 10 nmole/kg/day, ip) or glimepiride (2 mg/kg/day, p.o.) for 2 weeks. Key findings: Lixisenatide, in a low dose regimen, induced a nephroprotective effect evident by significant decreases in serum creatinine and serum urea along with improved renal histology. Low lixisenatide dose showed an antioxidant effect, exhibited by a significant decrease in renal malondialdehyde and total NOx - levels along with a marked rise in total antioxidant capacity. Apart from ameliorating glucose intolerance and insulin resistance, significant down-regulation in renal expressions of iNOS, COX-2, and TGF-B1 were recorded in the diabetic group treated with low dose lixisenatide. Furthermore, low dose lixisenatide was reported to be superior to glimepiride as a nephroprotective. On the contrary, treatment with large dose lixisenatide was founded to be deleterious. Significance: Low-dose lixisenatide treatment was able to protect against early diabetic nephropathy, which might represent a promising approach in the management of diabetes and its renal complication however, further clinical studies are warranted.