GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, ameliorates diabetic nephropathy in Leprdb/db mice

• Published in: Scientific reports Vol. 12; no. 1; pp. 22360 - 9
• Main Authors: Meng, Qinghe, Tian, Xinghan, Li, Junwei, Pruekprasert, Napat, Dhawan, Ravi, Holz, George G., Cooney, Robert N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-12-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 692/163; 692/163/2743/137; 692/163/2743/137/773; 692/163/2743/393; 692/4022; 692/4022/1585/104; 692/699/1585; 692/699/317; Agonists; Apoptosis; Creatinine; Cytochrome c; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetic nephropathy; Dialysis; End-stage renal disease; HMGB1 protein; Humanities and Social Sciences; Hyperglycemia; Hypertrophy; Inbreeding; Inflammation; Interleukin 6; Kidney diseases; Kidneys; multidisciplinary; Nephropathy; Plasma levels; Science; Science (multidisciplinary); Signal transduction; Vagus nerve
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-27015-y

Diabetic nephropathy (DN) is a serious complicating factor in human type 2 diabetes mellitus (T2DM), and it commonly results in end-stage renal disease (ESRD) that requires kidney dialysis. Here, we report that the α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a novel anti-inflammatory action to ameliorate DN, as studied using an inbred strain of Lepr
db/db
mice in which hyperglycemia and obesity co-exist owing to defective leptin receptor (Lepr) signaling. For this analysis, GTS-21 was administered to 10–12 week-old male and female mice as a 4 mg/kg intraperitoneal injection, twice-a-day, for 8 weeks. Kidney function and injury owing to DN were monitored by determination of plasma levels of BUN, creatinine, KIM-1 and NGAL. Histologic analysis of glomerular hypertrophy and mesangial matrix expansion were also used to assess DN in these mice. Concurrently, renal inflammation was assessed by measuring IL-6 and HMGB1, while also quantifying renal cell apoptosis, and apoptotic signaling pathways. We found that Lepr
db/db
mice exhibited increased markers of BUN, creatinine, NGAL, KIM-1, IL-6, cytochrome C, and HMGB-1. These abnormalities were also accompanied by histologic kidney injury (mesangial matrix expansion and apoptosis). Remarkably, all such pathologies were significantly reduced by GTS-21. Collectively, our results provide new evidence that the α7nAChR agonist GTS-21 has the ability to attenuate diabetes-induced kidney injury. Additional studies are warranted to further investigate the involvement of the vagal cholinergic anti-inflammatory reflex pathway (CAP) in ameliorating diabetic nephropathy.