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

Abstract

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 Leprdb/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 Leprdb/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.

Unraveling the superiority of (−)‐gallocatechin gallate to (−)‐epigallocatechin‐3‐gallate in protection of diabetic nephropathy of db/db mice

“…Similarly, KIM‐1, a specific and sensitive biomarker for proximal tubular injury, is prominently presents in regenerating renal tubular cells following injury, which indicating tubulointerstitial damage and renal interstitial inflammation in DN (Mori et al., 2021; Suh et al., 2022). In line with previous findings, our study demonstrated significantly higher levels of 24‐h urinary mALB, NGAL, and KIM‐1 in db/db mice compared to the control group (Figure 5d,e), suggesting impaired glomerular filtration and renal tubule injury (Gallo et al., 2016; Liang et al., 2017; Meng et al., 2022). Importantly, our data found that treatment with GCG or EGCG significantly decreased urinary NGAL and KIM‐1 level, and GCG demonstrated more lowing effect that EGCG in db/db mice.…”

Galantamine improves glycemic control and diabetic nephropathy in Leprdb/db mice

“…Our current results showing a reduction of renal p38 MAPK activation by galantamine are consistent with Lim et al who reported that knockout of the p38 MAPK signaling pathway in db/db mice protects against renal dysfunction, albuminuria, renal hypertrophy, loss of podocytes, activation of mesangial cells, and glomerular fibrosis 26 . The finding GTS-21 attenuates p38 MAPK activity and renal apoptosis in db/db mice is consistent with the effects of galantamine on p38 MAPK activity in the current study 22 . Our results also provide evidence galantamine attenuates renal caspase-1 activation by the NLRP3 inflammasome in the db/db model of DN.…”

“…There is evidence that SGLT-2 inhibitors provide an antioxidant mechanism of renoprotection 44 – 46 . However, our laboratory has also shown that α7nAChR activation by GTS-21 reduces apoptosis via regulating cytochrome c , BAX, Bcl-2, and caspase-3 in db/db mice 22 . Our current results showing a reduction of renal p38 MAPK activation by galantamine are consistent with Lim et al who reported that knockout of the p38 MAPK signaling pathway in db/db mice protects against renal dysfunction, albuminuria, renal hypertrophy, loss of podocytes, activation of mesangial cells, and glomerular fibrosis 26 .…”