Podocyte specific knockout ( KO ) of the natriuretic peptide clearance receptor ( NPRC ) attenuates diabetic kidney disease ( DKD )

Glomerular podocytes play a key role in the pathogenesis of diabetic kidney disease (DKD). Recent studies suggest that natriuretic peptides (NPs) are podocyte protective. The beneficial effects of NPs are inhibited by the removal of NPs from the circulation by the NP clearance receptor (NPRC). To determine if inhibiting NP clearance by NPRC ameliorated DKD, we deleted NPRC specifically in glomerular podocytes in a mouse model of type 1 diabetes (Akita mice). We found that diabetes induced a significant increase in albuminuria in WT Akita mice, which was significantly reduced by knockout (KO) of NPRC. Histologic damage was mild in both WT and KO Akita mice and limited to a modest increase in mesangial matrix in both groups. In contrast, expression of the fibrotic markers fibronectin and collagen 1 was significantly increased in isolated glomerular preparations, and expression of both fibrotic markers was significantly improved by podocyte-specific KO of NPRC. Taken together, these data suggest that inhibiting NP clearance by glomerular podocytes has beneficial effects in a mouse model of early-stage DKD.