Project 1 hypothesizes that Dahl salt-sensitive (SS) rats when fed a high salt diet will reabsorb greater than normal amounts of NaCI in the renal medullary thick ascending limb (mTAL) that in turn will stimulate excess production of reactive oxygen species (ROS) and thereby reduce medullary blood flow (MBF). The mTAL of SS rats express greater amounts of Na/K/2CI co-transporter than salt-insensitive control SS.13 rats and it will be determined if they also express greater amounts of isoforms of the Na/H exchanger (NHE) that could account for excess superoxide (O*2~) production. We propose that increased luminal delivery of NaCI together with increases of outer medullary interstitial NaCI concentration may stimulate NAD(P)H oxidase and enhance production of O*2"""""""" and H2O2. It will be determined if greater diffusion of O'2~ and/or H2O2 occurs from mTAL to vasa recta pericytes in the presence of reduced NO bioavailability and whether this leads to a reduction of MBF. These events will be studied using time resolved fluorescence videomicroscopy of medullary tissue strips. Physiological relevance of these observations will be assessed by studies in conscious instrumented rats. Sequential measurements of medullary interstitial O'2~, H202, NO and medullary interstitial [NaCI] will be obtained using implanted microdialysis fibers. Changes of medullary blood flow and arterial pressure will be measured daily in these conscious rats using implanted optical fibers and laser-Doppler techniques together with indwelling arterial catheters before and following an increase in salt (NaCI) intake and the development of hypertension. The project is defined by three specific aims: 1) To determine if exposure of mTAL to increased NaCI by either tubular microperfusion and/or bath superfusion results in greater mTAL production of O*2"""""""" or H2O2 and subsequent constriction of surrounding vasa recta vessels in SS compared to the control SS.13BN rats;2) To explore the cellular mechanisms whereby increased luminal delivery of NaCI to mTAL and increases of interstitial NaCI concentrations enhance 0*2"""""""" production in SS rats;3) To characterize the temporal responses of renal medullary production of O*2"""""""", H2O2, and NO in conscious SS rats to determine if increases in ROS initiate reductions of medullary blood flow following increased NaCI intake.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Medical College of Wisconsin
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Fan, Fan; Roman, Richard J (2017) Effect of Cytochrome P450 Metabolites of Arachidonic Acid in Nephrology. J Am Soc Nephrol 28:2845-2855
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