title: Regulation of Renal Hemodynamics and Function by RGS2.
abstract: Regulator of G protein signaling 2 (RGS2) controls G protein coupled receptor (GPCR) signaling by acting as a GTPase-activating protein for heterotrimeric G proteins. Certain Rgs2 gene mutations have been linked to human hypertension. Renal RGS2 deficiency is sufficient to cause hypertension in mice; however, the pathological mechanisms are unknown. Here we determined how the loss of RGS2 affects renal function. We examined renal hemodynamics and tubular function by monitoring renal blood flow (RBF), glomerular filtration rate (GFR), epithelial sodium channel (ENaC) expression and localization, and pressure natriuresis in wild type (WT) and RGS2 null (RGS2-/-) mice. Pressure natriuresis was determined by stepwise increases in renal perfusion pressure (RPP) and blood flow, or by systemic blockade of nitric oxide synthase with L-NG-Nitroarginine methyl ester (L-NAME). Baseline GFR was markedly decreased in RGS2-/- mice compared to WT controls (5.0 ± 0.8 vs. 2.5 ± 0.1 μl/min/g body weight, p<0.01). RBF was reduced (35.4 ± 3.6 vs. 29.1 ± 2.1 μl/min/g body weight, p=0.08) while renal vascular resistance (RVR; 2.1 ± 0.2 vs. 3.0 ± 0.2 mmHg/μl/min/g body weight, p<0.01) was elevated in RGS2-/- compared to WT mice. RGS2 deficiency caused decreased sensitivity and magnitude of changes in RVR and RBF after a step increase in RPP. The acute pressure-natriuresis curve was shifted rightward in RGS2-/- relative to WT mice. Sodium excretion rate following increased RPP by L-NAME was markedly decreased in RGS2-/- mice and accompanied by increased translocation of ENaC to the luminal wall. We conclude that RGS2 deficiency impairs renal function and autoregulation by increasing renal vascular resistance and reducing renal blood flow. These changes impair renal sodium handling by favoring sodium retention. The findings provide a new line of evidence for renal dysfunction as a primary cause of hypertension.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, 19102, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Osei-Owusu
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, 19102, United States of America.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Owens
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, 19102, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Jie
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, 19102, United States of America.
authors.forename: Janaina S
authors.initials: JS
authors.lastname: Reis
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University, Philadelphia, Pennsylvania, 19140, United States of America.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Forrester
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University, Philadelphia, Pennsylvania, 19140, United States of America.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University, Philadelphia, Pennsylvania, 19140, United States of America.
authors.forename: Satoru
authors.initials: S
authors.lastname: Eguchi
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, 19102, United States of America.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Singh
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, 63110, United States of America.
authors.forename: Kendall J
authors.initials: KJ
authors.lastname: Blumer
mesh_terms: D000818:Animals; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009318:Natriuresis / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D012079:Renal Circulation / Q000502:physiology*
chemical_list: D053503:Epithelial Sodium Channels; D020710:RGS Proteins; C105345:Rgs2 protein, mouse; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester