Mutations in natriuretic peptide receptor 2 (Npr2) gene cause a rare form of short-limbed dwarfism, but its physiological effects have not been well studied. Human and mouse genetic data suggest that Npr2 in the kidney plays a role in salt homeostasis. Herein, we described anatomic 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 with their wild-type (Npr2+/+) littermates. There was indication of renal epithelial damage accompanied by high numbers of red blood cells and inflammatory cells (macrophage surface glycoproteins binding to galectin-3) and an increase of renal epithelial damage marker (T-cell Ig and mucin domain 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 360 mmol/L NaCl. Finally, significantly lower levels of expression of the NPR2 protein were detected in renal samples of hypertensive compared with 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.
Bibliographical noteFunding Information:
Supported in part by the University of Rochester Award 2016 (V.A.K. and M.M.D.) and NIH grants R01 HL134910 (C.Y.) and R01 HL062826 (B.C.B.). We thank Qian Zhou and Kathy Donlon for help with animal handling and histologic processing of mouse kidneys. V.A.K. and B.C.B. conceived and managed the project; G.J.D. B.Q. L.L. D.M.M. S.K.T. and V.A.K. performed experiments; G.J.D. B.Q. D.M.M. and V.A.K. analyzed data; G.J.D. B.Q. and V.A.K. prepared figures; C.N.M. J.C. M.M.D. and C.Y. interpreted results; G.J.D. wrote the manuscript; G.J.D. L.L. D.M.M. C.N.M. J.C. M.M.D. C.Y. B.C.B. and V.A.K. edited and revised the manuscript; and G.J.D. B.Q. L.L. D.M.M. S.K.T. C.N.M. J.C. M.M.D. C.Y. B.C.B. and V.A.K. approved the final version of the manuscript.