The Protective Role of Natriuretic Peptide Receptor 2 against High Salt Injury in the Renal Papilla

Mutations in natriuretic peptide receptor 2 ( Npr2 ) gene cause a rare form of short-limbed dwarfism, but its physiologic effects have not been well studied. Human and mouse genetic data suggest that Npr2 in the kidney plays a role in salt homeostasis. Here, we described anatomical changes within renal papilla of Npr2 knockout ( Npr2 −/− ) mice. Dramatic reduction was found in diuresis and albuminuria was evident after administration of 1% NaCl in drinking water in Npr2 −/− and heterozygous ( Npr2 +/− ) mice compared to their wild-type ( Npr2 +/+ ) littermates. There was indication of renal epithelial damage accompanied by high numbers of red blood cells and inflammatory cells (Mac2) and an increase of renal epithelial damage marker (TIM-1) in Npr2 −/− mice. Addition of 1% NaCl tended to increase apoptotic cells (cleaved Caspase 3) in the renal papilla of Npr2 −/− mice. In vitro , genetic silencing of the Npr2 abolished protective effects of C-type natriuretic peptide, a ligand for Npr2, against death of M-1 kidney epithelial cells exposed to 360mM NaCl. Finally, significantly lower levels of expression of the NPR2 protein were detected in renal samples of hypertensive compared to normotensive human subjects. Taken together, these findings suggest that Npr2 is essential to protect renal epithelial cells from high concentrations of salt and prevent kidney injury.