In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 37 ( 2007-09-11), p. 14849-14854
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0702810104
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2007
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
