Protein phosphatase 1 inhibitor-1 deficiency reduces phosphorylation of renal NaCl cotransporter and causes arterial hypotension

J Am Soc Nephrol. 2014 Mar;25(3):511-22. doi: 10.1681/ASN.2012121202. Epub 2013 Nov 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anion Transport Proteins / metabolism
  • Blood Pressure
  • Female
  • Humans
  • Hypotension / enzymology*
  • Kidney Tubules, Distal / enzymology*
  • Loop of Henle / enzymology
  • Male
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Solute Carrier Family 12, Member 1 / metabolism
  • Solute Carrier Family 12, Member 3 / metabolism*
  • Sulfate Transporters
  • Up-Regulation
  • Xenopus


  • Anion Transport Proteins
  • Proteins
  • Slc26a4 protein, mouse
  • Solute Carrier Family 12, Member 1
  • Solute Carrier Family 12, Member 3
  • Sulfate Transporters
  • phosphoprotein phosphatase inhibitor 1
  • Stk39 protein, mouse
  • Protein Serine-Threonine Kinases