The knock-out of paracingulin attenuates hypertension through modulation of kidney ion transport.

Abstract

Hypertension is a major risk factor for human morbidity and mortality, and the junctional protein paracingulin (CGNL1, JACOP) is required for the development of hypertension in a Dahl salt-sensitive rat model and is linked to human hypertension in genome wide association studies. However, the mechanism through which CGNL1 may regulate hypertension is unknown. Here, we address this question using a mouse model, where hypertension is induced by unilateral nephrectomy and angiotensin II infusion (N+A protocol). Although untreated WT and CGNL1-KO mice showed similar blood pressure, the N+A protocol induced hypertension in WT mice but not in CGNL1-KO mice. We show by immunolocalization and transcriptomic analysis that CGNL1 is expressed throughout the kidney tubules and in the endothelium of blood vessels, but not in smooth muscle. The N+A protocol induced decreased potassium urinary excretion in wild-type (WT), but not in CGNL1-KO mice. Immunoblot analysis shows that the KO of CGNL1 blunted the N+A-induced changes in the expression levels and activation of tubular ion transporters, including the Na/H exchanger 3 (NHE3) and the thiazide-sensitive Na-Cl cotransporter (NCC), and blunted the angiotensin II-dependent changes in the levels and/or activation of AMP-activated protein kinase (AMPK), ERK and myosin light chain. In contrast, myography showed comparable vascular reactivity in thoracic aortas and mesenteric arteries isolated from WT or CGNL1-KO mice. Together, these results suggest the KO of CGNL1 attenuates hypertension by uncoupling angiotensin II signaling in kidney tubule cells, indicating a novel pathway of regulation of signaling by a junctional protein.NEW & NOTEWORTHY The knock-out of paracingulin (CGNL1) prevents the development of hypertension in a unilateral nephrectomy/angiotensin II infusion model (N+A) in mice and this antihypertensive effect likely depends on uncoupling of angiotensin II from stimulation of sodium transporter activity in kidney tubules rather than on alteration of resistance blood vessel contractility.