The tone of the renal afferent arteriole (Aff) increases with perfusion pressure (PP) to protect the kidneys from damage (barotrauma). The normal myogenic response (MR) of the Aff was accompanied by generation of superoxide anion (02')- MRs and ROS signals were reduced by deletion of p47''*'?''or addition of pegalated (PEG) superoxide dismutase (SOD) but were unaffected by PEG-catalase or knockout of nitric oxide synthase (NOS-3) relating normal Aff MRs to stretch-induced O2"""""""" from NADPH oxidase rather than to H2O2. However, incubation of Affs with H2O2 (from 1 to 30 IJM) caused dose-dependent blunting of MRs. Thus ROS in Affs can have opposite MR effects. Normotensive high salt (HS) mice with surgical reduction in renal mass (RRM, 5/6 nephrectomy) will model chronic kidney disease (CKD) and angiotensin II slow pressor infusion (Ang) will model hypertension. The MRs from these two were severely impaired, despite increased ROS in the kidneys and the Affs. However, the culprit ROS was apparently H2O2 since defective MRs were corrected by PEG-catalase but were unaffected by PEG-SOD, and were preserved in RRM mice drinking tempol for 3 months which normalized the increased excretion of H2O2 and Aff ROS.This proposal will investigate the hypothesis that ROS have opposite effects on MRs: short-term 02'enhances normal MRs by increasing VSMC Ca^""""""""^ entry mechanisms and Ca^""""""""^ sensitivity while prolonged H2O2 in models of oxidative stress impair MRs by downregulation of voltage operated calcium channels, PKC^ and transient receptor potential canonical 6 channels, whose mRNAs were downregulated in a ROS-dependent manner in Affs from RPM mice. It will study short- vs. long- term effects of 02""""""""vs. H2O2 on normal MRs (Aim 1) and blunted MRs in mice with RRM or Ang infusion (Aim 2). Gene analysis of individual Affs by gene array, confirmed by RNAseq and RT-PCR will select ROS-dependent candidate pathways. MRs will be recorded directly from perfused Affs during step increases in PD. Fluorescence methods will quantitate ROS subtypes, intracellular Ca^""""""""^ and membrane potential. Use of knockout or VSMC transgenic models combined with transfection or silencing of candidate genes will test directly their roles in PP-induced MRs, ROS generation and Ca^""""""""^ entry and signaling. This project is focused on the roles of ROS in regulating the MR. Results should provide novel treatment targeted for patients with hypertension or CKD. It is integrated with the animal core where whole kidney MRs will be studied and the biomarkers core where genes and protein responses will be assessed.

Public Health Relevance

(See Instructions): An increase in the tone of the afferent arteriole of the kidney resets the blood pressure that the kidney regulates and thereby can lead to hypertension, whereas a breakdown in tone allows transmission of hypertensive pressure into the kidney and worsens chronic kidney disease. This project will study how oxidative stress regulates afferent arteriolar tone in animal models of hypertension or chronic kidney diseases which are major causes of cardiovascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1)
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Georgetown University
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