Arterial smooth muscle cell PKD2 (TRPP1) channels control systemic blood pressure

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), an inherited condition that affects approximately 1 in 800 people, occurs due to mutations in either PKD1 or PKD2 proteins. Although ADPKD is characterized by the formation of kidney cysts, patients suffer from cardiovascular diseases, including hypertension, often with no alteration in renal function. PKD2 is a six transmembrane domain transient receptor potential (TRP) channel that is also termed TRPP1. Recent evidence suggests that PKD2 is expressed in arterial smooth muscle cells, but functional significance is poorly understood. Similarly unclear is the regulation of blood pressure by arterial smooth muscle cell TRP channels. Here, we generated a novel, conditional smooth muscle‐specific PKD2 knockout (PKD2sm−/−) mouse model to investigate the regulation of systemic artery contractility and blood pressure by PKD2. PKD2 channel expression was abolished in arterial smooth muscle cells of PKD2sm−/− mice, whereas PKD1, TRPC6, TRPM4, CaV1.2 or ANO1 proteins were similar to those in PKD2fl/fl controls. Telemetry demonstrated that systemic blood pressure was lower in PKD2sm−/− mice than in PKD2fl/fl controls. Experiments that measured cardiac function, plasma and urine electrolytes, plasma hormones and histological assessment of kidney structure identified no differences in PKD2sm−/− and PKD2fl/fl mice. Vasoconstriction stimulated by phenylephrine (PE), an α1‐adrenergic receptor agonist, and intravascular pressure were both attenuated in resistance‐size systemic arteries from PKD2sm−/− mice, when compared to PKD2fl/fl controls. PE‐induced non‐selective cation current (ICat) activation was smaller in systemic artery smooth muscle cells of PKD2sm−/− mice. Application of patch pressure activated single non‐selective cation channels in systemic artery smooth muscle cells of PKDfl/fl mice that were absent in cells of PKD2sm−/− mice. These data suggest that PE and intravascular pressure stimulate PKD2 channels in systemic artery smooth muscle cells, leading to vasoconstriction and an increase in blood pressure.Support or Funding InformationNIH/NHLBI grants to Jonathan H. Jaggar. American Heart Association grants to Simon Bulley and M. Dennis Leo.