Renal expression of parvalbumin is critical for NaCl handling and response to diuretics.
(2007) Proceedings of the National Academy of Sciences of the United States of America — Vol. 104, n° 37, p. 14849-14854 (2007)
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- 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 Ca(2+)-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 thiazide-sensitive 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 Ca(2+) balance and increased bone mineral density. Studies in mouse DCT cells showed that endogenous NCC expression is Ca(2+)-dependent and can be modulated by the levels of PV expression. These results suggest that PV regulates the expression of NCC by modulating intracellular Ca(2+) signaling in response to ATP in DCT cells. They also provide insights into the Ca(2+)-sparing action of thiazides and the pathophysiology of distal tubulopathies.
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Belge, H., Gailly, P., Schwaller, B., Loffing, J., Debaix, H., Riveira-Munoz, E., Beauwens, R., Devogelaer, J.-P., Hoenderop, J. G., Bindels, R. J., & Devuyst, O. (2007). Renal expression of parvalbumin is critical for NaCl handling and response to diuretics. Proceedings of the National Academy of Sciences of the United States of America, 104(37), 14849-14854. https://doi.org/10.1073/pnas.0702810104 (Original work published 2007)