Renal expression of parvalbumin is critical for NaCl handling and response to diuretics.
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.
Belge
Hendrica
H
Department of Nephrology, Université Catholique de Louvain Medical School, B-1200 Brussels, Belgium.
Gailly
Philippe
P
Schwaller
Beat
B
Loffing
Johannes
J
Debaix
Huguette
H
Riveira-Munoz
Eva
E
Beauwens
Renaud
R
Devogelaer
Jean-Pierre
JP
Hoenderop
Joost G
JG
Bindels
René J
RJ
Devuyst
Olivier
O
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D015519:Bone Density; D002118:Calcium / Q000032:analysis / Q000652:urine; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004231:Diuresis; D004232:Diuretics / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007686:Kidney Tubules, Distal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010320:Parvalbumins / Q000097:blood / Q000378:metabolism* / Q000652:urine; D011188:Potassium / Q000652:urine; D012964:Sodium / Q000378:metabolism* / Q000652:urine; D049993:Sodium Chloride Symporter Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D049992:Sodium Chloride Symporters / Q000502:physiology; D049971:Thiazides / Q000494:pharmacology