Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension

The thiazide-sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and arterial BP. Loss-of-function mutations of NCC cause renal salt wasting with arterial hypotension (Gitelman syndrome). Conversely, mutations in the NCC-regulating WNK kinases or k...

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Bibliographic Details
Published in:Journal of the American Society of Nephrology 2014-03, Vol.25 (3), p.511-522
Main Authors: PICARD, Nicolas, TROMPF, Katja, YANG, Chao-Ling, MILLER, R. Lance, CARREL, Monique, LOFFING-CUENI, Dominique, FENTON, Robert A, ELLISON, David H, LOFFING, Johannes
Format: Article
Language:English
Subjects:
Animals
Anion Transport Proteins - metabolism
Basic Research
Biological and medical sciences
Blood Pressure
Female
Humans
Hypotension - enzymology
Kidney Tubules, Distal - enzymology
Loop of Henle - enzymology
Male
Medical sciences
Mice
Mice, Transgenic
Nephrology. Urinary tract diseases
Phosphorylation
Protein-Serine-Threonine Kinases - metabolism
Proteins - genetics
Proteins - metabolism
Solute Carrier Family 12, Member 1 - metabolism
Solute Carrier Family 12, Member 3 - metabolism
Up-Regulation
Xenopus
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Summary:The thiazide-sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and arterial BP. Loss-of-function mutations of NCC cause renal salt wasting with arterial hypotension (Gitelman syndrome). Conversely, mutations in the NCC-regulating WNK kinases or kelch-like 3 protein cause familial hyperkalemic hypertension. Here, we performed automated sorting of mouse DCTs and microarray analysis for comprehensive identification of novel DCT-enriched gene products, which may potentially regulate DCT and NCC function. This approach identified protein phosphatase 1 inhibitor-1 (I-1) as a DCT-enriched transcript, and immunohistochemistry revealed I-1 expression in mouse and human DCTs and thick ascending limbs. In heterologous expression systems, coexpression of NCC with I-1 increased thiazide-dependent Na(+) uptake, whereas RNAi-mediated knockdown of endogenous I-1 reduced NCC phosphorylation. Likewise, levels of phosphorylated NCC decreased by approximately 50% in I-1 (I-1(-/-)) knockout mice without changes in total NCC expression. The abundance and phosphorylation of other renal sodium-transporting proteins, including NaPi-IIa, NKCC2, and ENaC, did not change, although the abundance of pendrin increased in these mice. The abundance, phosphorylation, and subcellular localization of SPAK were similar in wild-type (WT) and I-1(-/-) mice. Compared with WT mice, I-1(-/-) mice exhibited significantly lower arterial BP but did not display other metabolic features of NCC dysregulation. Thus, I-1 is a DCT-enriched gene product that controls arterial BP, possibly through regulation of NCC activity.
ISSN:1046-6673
1533-3450
DOI:10.1681/asn.2012121202