Hypertension (HTN) affects ~ 30% of adult Americans and is a major risk factor for cardiovascular and renal diseases. Its pathogenesis is complex, with contributions from both genetic and environmental factors. The renin-angiotensin-system (RAS) is a key biological system that regulates arterial pressure (AP). Its major effector molecule is angiotensin II (Ang II) which mediates opposing effects through the signaling of its receptors, AT1R and AT2R. We have identified a transmembrane glycoprotein, collectrin (Tmem27 on chromosome X), a key regulator of AP and modulator of the bioavailability of nitric oxide (NO) and superoxide (O2?_), as a downstream target of Ang II. We published that collectrin is a critical chaperone for the reabsorption of all amino acids (AAs) in the proximal tubules (PT), and for the uptake of the cationic AA L- arginine (L-Arg) in endothelial cells (ECs). We reported that global collectrin knockout (Tmem27Y/-) mice have baseline HTN that is ameliorated by supplementation with L-Arg (a substrate for NO production). Furthermore, they have augmented salt-sensitive hypertension (SSH) that is corrected by TEMPOL, a superoxide dismutase mimetic. Tmem27Y/- mice have impaired cellular L-Arg uptake that is associated with decreased dimerization of endothelial and neuronal NO synthase (eNOS and nNOS, respectively) in renal tissues. These observations, along with their preferential production of O2?_ over NO, suggest that Tmem27Y/- mice have a state of NOS uncoupling. Collectrin is highly expressed in the kidney in the PT, collecting duct (CD), and throughout the vascular endothelium. In a manuscript in press, we show through kidney cross-transplantation (XTP) studies that collectrin in the kidney ameliorates SSH. Importantly, renal expression of collectrin is decreased by Ang II in an AT1R dependent manner, and is independent of hypertension per se. In preliminary data, we found significant association of human TMEM27 single nucleotide polymorphisms (SNPs) with diastolic BP (DBP) in the HyperGEN study. We hypothesize that collectrin is downregulated by Ang II through AT1 receptor signaling, and is a molecular mechanism linking Ang II, NOS uncoupling, and HTN. Accordingly, our objective is to precisely delineate the renal tissue-collectrin-NOS axis through which collectrin regulates AP homeostasis and salt sensitivity; and to determine its influence on AP in human populations that include salt- sensitive (SS)/-resistant (SR) cohorts. We will comprehensively use in vivo and population genetic approaches to: 1A) To test the hypothesis that collectrin is downregulated by AT1 receptor signaling and upregulated through AT2 receptor signaling, and 1B) To test the hypothesis that collectrin in the PT and/or CD maintains NO and O2?_ balance to control sodium balance and therefore AP; 2) To test the hypothesis that deletion of endothelial collectrin decreases renal blood flow, and increases peripheral vascular resistance, AP and SSH; and 3) Determine the association of human TMEM27 gene variants with blood pressure in population based studies and in well characterized salt-sensitive and salt-resistant subjects.
Hypertension is a major risk factor for stroke, heart disease and kidney disease. While the causes of hypertension in most cases are not known, a defect in the balance of nitric oxide (NO) and superoxide (O2?_), important regulators of vascular tone, may be a key initiating event. We have identified collectrin, a modulator of the balance of NO and O2?_, as a key regulator of blood pressure and salt sensitivity. Collectrin is expressed in many tissues. In this proposal, we will use mouse models to define the exact tissue- collectrin axis and mechanism by which collectrin regulates blood pressure and salt sensitivity for potential identification of new targets to treat hypertension. Across species, collectrin is expressed on the X-chromosome where genome wide association studies (GWAS) in humans have largely excluded due to low genotype coverage and a paucity of statistical methods to account for gene dosage in males versus females and random X-inactivation in females. We will determine the influence of collectrin on blood pressure in human populations by looking at genetic variants of the collectrin gene in four different human cohorts.
| Brown, Isola A M; Diederich, Lukas; Good, Miranda E et al. (2018) Vascular Smooth Muscle Remodeling in Conductive and Resistance Arteries in Hypertension. Arterioscler Thromb Vasc Biol 38:1969-1985 |
| Gigliotti, Joseph C; Le, Thu H (2017) Ets in the Kidney-Unraveling the Molecular Mechanism Underlying Renal Damage in Salt-Sensitive Hypertension. J Am Soc Nephrol 28:3131-3133 |
