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Renal expression of parvalbumin is critical for NaCl handling and response to diuretics

par Belge, Hendrica;Gailly, Philippe;Schwaller, Beat;Loffing, Johannes;Debaix, Huguette;Riveira-Munoz, Eva;Beauwens, Renaud ;Devogelaer, J.-P.;Hoenderop, Joost J.G.;Bindels, René R.J.;Devuyst, Olivier
Référence Proceedings of the National Academy of Sciences of the United States of America, 104, 37, page (14849-14854)
Publication Publié, 2007-09

Article révisé par les pairs

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Résumé :

The distal convoluted tubule (DCT) plays an essential role in the reabsorption of NaCl by the kidney, a process that can be inhibited by thiazide diuretics. Parvalbumin (PV), a Ca2+-binding protein that plays a role in muscle fibers and neurons, is selectively expressed in the DCT, where its role remains unknown. We therefore investigated the renal phenotype of PV knockout mice (Pvalb-/-) vs. wild-type (Pvalb+/+) littermates. PV colocalized with the thiazidesensitive Na+-Cl - cotransporter (NCC) in the early DCT. The Pvalb-/- mice showed increased diuresis and kaliuresis at baseline with higher aldosterone levels and lower lithium clearance. Acute furosemide administration increased diuresis and natriuresis/kaliuresis, but, surprisingly, did not increase calciuria in Pvalb-/- mice. NaCl supplementation of Pvalb -/- mice increased calciuria at baseline and after furosemide. The Pvalb-/- mice showed no significant diuretic response to hydrochlorothiazide, but an accentuated hypocalciuria. A decreased expression of NCC was detected in the early DCT of Pvalb-/- kidneys in the absence of ultrastructural and apoptotic changes. The PV-deficient mice had a positive Ca2+ balance and increased bone mineral density. Studies in mouse DCT cells showed that endogenous NCC expression is Ca2+-dependent and can be modulated by the levels of PV expression. These results suggest that PV regulates the expression of NCC by modulating intracellular Ca2+ signaling in response to ATP in DCT cells. They also provide insights into the Ca2+-sparing action of thiazides and the pathophysiology of distal tubulopathies. © 2007 by The National Academy of Sciences of the USA.