(Pro)renin receptor (PRR), a new component of renin-angiotensin system (RAS), has emerged as a new regulator of collecting duct function. The present study was designed to investigate the role of PRR in high salt-induced apoptosis in cultured mouse inner medullary collecting duct cells, mIMCD-K2 cells. Exposure to high NaCl at 550 mOsm/kg H₂O increased PRR protein abundance so did mannitol, sodium gluconate or choline chloride. This was accompanied with upregulation of phosphorylated NF-B p65 protein abundance. NF-B inhibition with either QNZ, CAPE, or siRNA-mediated silencing of NF-B p65 attenuated high NaCl-induced PRR upregulation. Exposure to high salt for 24 hours induced apoptosis as assessed by immunoblotting analysis of cleaved caspase-3 and flow cytometry analysis of the number of apoptotic cells. High NaCl-induced apoptosis was attenuated by a PRR decoy inhibitor PRO20 or siRNA-mediated silencing of NF-B p65. In conclusion, PRR expression is induced by high NaCl through NF-B and contributes to cell apoptosis under this circumstance.