The integrating theme and unifying hypothesis of this PPG centers on the concept that H202 production in the renal outer medulla (CM) plays a dominant role in the development of salt-sensitive hypertension. Studies in this PPG will use Dahl salt-sensitive (SS) rats to examine physiological mechanisms and molecular pathways underlying salt-sensitive hypertension; it does not focus on the generic aspects of this disease. This rat model recapitulates many aspects of human salt-sensitive hypertension and demonstrates disease phenotypes which are very similar to those observed in African Americans. Project 1 explores the role of the medullary thick ascending limb (mTAL) and tests the hypothesis that increased salt intake leads to greater mTAL NaCI delivery resulting in excess production of H202 in SS rats as amplified by a greater expression of the p67phox subunit of NADPH oxidase. It is proposed that this results in greater H202 diffusion into the interstitial space thereby constricting vasa recta and reducing medullary perfusion. Project 2 hypothesizes that the initials rise of arterial pressure following an increase in salt intake leads to the infiltration of T-cells in the kidney which exaggerates salt-sensitive hypertension and renal disease by increasing H202 and cytokines. The resulting T-lymphocyte infiltration into the kidney, we propose, is importanfiy influenced by Sh2b3, a gene recently identified by GWAS to be associated with human hypertension. Project 3 hypothesizes that a newly discovered pathway of H202 production related to cellular metabolism contributes importantly to the development and maintenance of hypertension in SS rats. Specifically, fumarase insufficiency in SS rats results in an increase of fumaric acid and glycolytic activity which stimulates H202 production and contributes to the salt-induced hypertension. These conceptually unique hypotheses combined with novel technological tools will advance our understanding of the molecular and physiological mechanisms underlying salt-sensitive hypertension that remain largely unclear. This highly integrated and collaborative program of three projects is supported by an Administrative Core A, the Biochemistry/Microscopy Core B, and Genetic Model Tracking and Monitoring Core C.
| Mattson, David L (2018) Heat stress nephropathy and hyperuricemia. Am J Physiol Renal Physiol 315:F757-F758 |
| Abais-Battad, Justine M; Lund, Hayley; Fehrenbach, Daniel J et al. (2018) Rag1-null Dahl SS rats reveal that adaptive immune mechanisms exacerbate high protein-induced hypertension and renal injury. Am J Physiol Regul Integr Comp Physiol 315:R28-R35 |
| Bukowy, John D; Dayton, Alex; Cloutier, Dustin et al. (2018) Do computers dream of electric glomeruli? Kidney Int 94:635 |
| Spires, Denisha; Ilatovskaya, Daria V; Levchenko, Vladislav et al. (2018) Protective role of Trpc6 knockout in the progression of diabetic kidney disease. Am J Physiol Renal Physiol 315:F1091-F1097 |
| Bukowy, John D; Dayton, Alex; Cloutier, Dustin et al. (2018) Region-Based Convolutional Neural Nets for Localization of Glomeruli in Trichrome-Stained Whole Kidney Sections. J Am Soc Nephrol 29:2081-2088 |
| Regal, Jean F; Laule, Connor F; McCutcheon, Luke et al. (2018) The complement system in hypertension and renal damage in the Dahl SS rat. Physiol Rep 6:e13655 |
| Abais-Battad, Justine M; Lund, Hayley; Fehrenbach, Daniel J et al. (2018) Parental Dietary Protein Source and the Role of CMKLR1 in Determining the Severity of Dahl Salt-Sensitive Hypertension. Hypertension :HYPERTENSIONAHA11811994 |
| Williams, Anna Marie; Liu, Yong; Regner, Kevin R et al. (2018) Artificial intelligence, physiological genomics, and precision medicine. Physiol Genomics 50:237-243 |
| Palygin, Oleg; Miller, Bradley S; Nishijima, Yoshinori et al. (2018) Endothelin receptor A and p66Shc regulate spontaneous Ca2+ oscillations in smooth muscle cells controlling renal arterial spontaneous motion. FASEB J :fj201800776RR |
| Wade, Brittany; Petrova, Galina; Mattson, David L (2018) Role of immune factors in angiotensin II-induced hypertension and renal damage in Dahl salt-sensitive rats. Am J Physiol Regul Integr Comp Physiol 314:R323-R333 |
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