Title: Soluble GuanylateCyclase (sGC) as a therapeutic target for diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD) and is characterized by a progressive decline in renal function accompanied by mesangial expansion, glomerular basement membrane thickening, and tubulointerstitial damage. Current treatments include glycemic and blood pressure control to delay the progression. Novel drugs including SGLT2i inhibitors,GLP-agonists, and mineralocorticoid receptor antagonists are reported to be effective in treating the disease. Furthermore, endothelial dysfunction is the leading cause for the progression of DN. The nitric oxide-soluble guanylatecyclase-cyclic guanosinemonophosphate (NO-sGC-cGMP) signaling cascade pathway plays a critical role in regulating renal function. Cyclic guanosine monophosphate (cGMP) vasodilates renal vasculature and directly influences renal blood flow, renin secretion, glomerular function, and tubular exchange.We hypothesized that the sGC stimulator Compound 1 is protective against DN at stages in whichNO bioavailability is low or diminished. The effects of renal function were investigated with ansGC stimulator under acute & chronic treatment in a preclinical DN model. The chronic treatment of sGC stimulator alone reduced kidney hypertrophy, significantly slowed the progression ofproteinuria, and reduced urinary albumin and creatinine ratio. In combination with Enalapril, the sGC stimulator significantly decreased the incidence of glomerulosclerosislesions, as observed by the reduction in interstitial fibrosis and in the tubules,interstitial, and glomeruli nephropathy score. Our data strongly suggests that sGC stimulator improves renal function as a monotherapy& exhibits greater benefit in attenuating the progression of the disease with standard of care drug Enalapril, underpinning the importance of the NO-sGC-cGMP pathway in the pathogenesis of DN.