Finerenone ameliorates diabetic kidney disease exacerbated by deletion of natriuretic peptide/guanylyl cyclase-A signaling and dietary high-protein load

Excessive protein intake is one of the main accelerators for chronic kidney disease including diabetic kidney disease (DKD). DKD is known to be a leading cause of end-stage renal disease; however, detailed molecular mechanisms remain unclear. Natriuretic peptides (NPs)/guanylyl cyclase-A (GC-A) signaling has been reported to exert protective effects against aldosterone-induced kidney injury. To investigate the role of NPs/GC-A pathway against DKD progression, we administered streptozotocin to systemic GC-A knockout (KO) mice and endothelial cell-specific GC-A conditional knockout (EC-GC-A cKO) mice, and fed high-protein diet (HPD) for 4 weeks. Furthermore, human glomerular endothelial (GE) cells were transfected with siRNA for GC-A and stimulated with high-protein and high-glucose medium. Systemic GC-A KO mice and EC-GC-A cKO mice with HPD showed increased albuminuria with glomerular enlargement, interstitial fibrosis and upregulation of proinflammatory and profibrotic mRNA expression. In systemic GC-A KO mice with HPD, genes related to renin-angiotensin-aldosterone system, including mineralocorticoid receptor (MR) pathway, were also upregulated, and finerenone administration ameliorated diabetes- and HPD-induced kidney injury. GC-A knockdown enhanced TGFB1 and SERPINE1 mRNA expression in GE cells, and these changes were ameliorated by SGK1 inhibitor. These findings reveal the significance of NPs/GC-A pathway in HPD-induced kidney injury and the effectiveness of MR/SGK1 pathway inhibition.