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1 Laboratory of kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institute, National Institute of Health, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: knep{at}helix.nih.gov.
Escape from aldosterone-induced renal NaCl retention is an important homeostatic mechanism in pathophysiological states in which plasma aldosterone levels are inappropriately elevated, e.g. in primary aldosteronism. Our previous studies have demonstrated that the escape process occurs largely as a result of a marked suppression of the abundance of the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule, but have also demonstrated a paradoxical increase in the protein abundance of the apical Na-H exchanger of the proximal tubule (NHE3). In the present study, we confirmed the increase in NHE3 and also showed that a similar increase in NHE3 protein abundance occurs in escape from angiotensin II-mediated NaCl retention. To investigate the potential role of nitric oxide (NO) in the observed upregulation of NHE3, we repeated the aldosterone escape experiment with a superimposed infusion of a NO synthase inhibitor, L-NAME. L-NAME infusion abolished the increase in NHE3 protein abundance. Furthermore, in a different experiment, NO synthase inhibition uncovered an associated decrease in the abundance of the Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb, not seen with simple aldosterone escape. However, NO synthase inhibition did not block the decrease in NCC abundance normally seen with aldosterone escape. Furthermore, L-NAME infusion in aldosterone-treated rats markedly decreased both NHE3 and NKCC2 protein abundance, without changes in the corresponding mRNA levels. We conclude that NHE3 and NKCC2 protein abundances in kidney are positively regulated by NO and that the increase in NHE3 abundance seen in the aldosterone escape phenomenon is NO-dependent.
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