These studies were carried out to determine if there is a difference in Angiotensin II (Ang II)-protein kinase C (PKC) regulation of the Na+:Ca2+ exchanger in cultured mesangial cells from Dahl/Rapp S and R rats. R and S mesangial cells were grown on coverslips, serum starved, and loaded with fura 2 to measure cytosolic calcium concentration ([Ca2+]i). Exchanger activity was assessed by measuring changes in [Ca2+]i) after reducing extracellular Na (Nae) from 150 to 2 mM. This maneuver was specific for the exchanger since the effects of reducing Nae or [Ca2+]i) were inhibited by 24 hr pretreatment with 100 nM of antisense oligonucleotide against the N-terminus transmembrane domain. Either Ang II (10 nM) or PKC activation by 15 min treatment with 100 nM PMA significantly increased *[Ca2+]i) in response to removal of Nae in R but not S mesangial cells. Increase in exchanger activity by either PMA or Ang II was abolished by prior 24 hr exposure to PMA, a maneuver that downregulates PKC activity. In addition, immunofluorescence studies showed that PKC activation translocated the Na+:Ca2+ exchanger to the plasma membrane in R but not S mesangial cells. These data demonstrate that Ang II stimulates Na+:Ca2+ exchange activity via PKC in R mesangial cells. This process involves translocation of the exchanger from the cytoplasm to the plasma membrane and appears to be defective in S mesangial cells.