Na+/Ca2+ exchanger -: Target for oxidative stress in salt-sensitive hypertension

The Na+/Ca2+ exchanger regulates intracellular calcium ([Ca2+](i)), and attenuation of Na+/Ca2+ exchange by oxidative stress might lead to dysregulation of [Ca2+](i). We have shown that the Na+/Ca2+ exchanger differs functionally and at the amino acid level between salt-sensitive and salt-resistant rats. Therefore, the purpose of these studies was to determine how oxidative stress affects the activities of the 2 Na+/Ca2+ exchangers that we cloned from mesangial cells of salt-resistant (RNCX) and salt-sensitive (SNCX) Dahl/Rapp rats. The effects of oxidative stress on exchanger activity were examined in cells expressing RNCX or SNCX by assessing Ca-45(2+) uptake ( reverse mode) and [Ca2+](i) elevation ( forward mode) in the presence and absence of H2O2 and peroxynitrite. Our results showed that Ca-45(2+) uptake in SNCX cells was attenuated at 500 and 750 mumol/L H2O2 ( 63 +/- 12% and 25 +/- 7%, respectively; n = 16) and at 50 and 100 mumol/L peroxynitrite (47 +/- 9% and 22 +/- 9%, respectively; n = 16). In RNCX cells, Ca-45(2+) uptake was attenuated at only 750 and 100 mumol/L H2O2 and peroxynitrite (61 +/- 9% and 63 +/- 6%, respectively; n = 16). In addition, the elevation in [Ca2+](i) was greater in SNCX cells than in RNCX cells in response to 750 mumol/ L H2O2 (58 +/- 5.5 vs 17 +/- 4.1 nmol/L; n = 13) and 100 mumol/L peroxynitrite (33 +/- 5 vs 11 +/- 6 nmol/ L; n = 19). The enhanced impairment of SNCX activity by oxidative stress might contribute to the dysregulation of [Ca2+](i) that is found in this model of salt-sensitive hypertension.