Protein phosphatase 1 Inhibitor‐1 deficiency causes hypotension and reduces the phosphorylation of renal NaCl cotransporter (892.18)

Abstract

The thiazide‐sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and blood pressure (BP). Gain‐of‐function in NCC‐regulating kinases or loss‐of‐function of NCC alters BP. The size and location of the DCT has hindered efforts to identify new molecular regulators of this protein. Here, we performed automated sorting of mouse DCTs and microarray analysis for identification of DCT‐enriched gene products, which may regulate NCC. We identified protein phosphatase‐1 inhibitor‐1 (I‐1) as a DCT enriched transcript. Immunolocalisation revealed I‐1 expression in mouse and human DCTs and thick ascending limbs. Coexpression of NCC with I‐1 increased thiazide‐ dependent Na+ uptake, whereas RNAi‐mediated knockdown of I‐1 reduced NCC phosphorylation. Likewise, levels of phosphorylated NCC decreased by approximately 50% in I‐1 knockout mice (I1‐/‐). Compared with WT mice, I1‐/‐ mice had 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.Grant Funding Source: Swiss National Fund