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 45Ca2+ uptake (reverse mode) and [Ca2+]i elevation (forward mode) in the presence and absence of H2O2 and peroxynitrite. Our results showed that 45Ca2+ uptake in SNCX cells was attenuated at 500 and 750 micromol/L H2O2 (63+/-12% and 25+/-7%, respectively; n=16) and at 50 and 100 micromol/L peroxynitrite (47+/-9% and 22+/-9%, respectively; n=16). In RNCX cells, 45Ca2+ uptake was attenuated at only 750 and 100 micromol/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 micromol/L H2O2 (58+/-5.5 vs 17+/-4.1 nmol/L; n=13) and 100 micromol/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.
Unlap
M Tino
MT
Nephrology Research and Training Center, Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, 35294, USA. unlap@uab.edu
Bates
Elizabeth
E
Williams
Corey
C
Komlosi
Peter
P
Williams
Iantha
I
Kovacs
Gergely
G
Siroky
Brian
B
Bell
P Darwin
PD
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000493:pharmacokinetics; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000378:metabolism*; D013050:Spectrometry, Fluorescence
D005452:Fluoresceins; D017673:Sodium Chloride, Dietary; D019831:Sodium-Calcium Exchanger; D030421:Peroxynitrous Acid; C043829:2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; D006861:Hydrogen Peroxide; D002118:Calcium