Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Individuals with type II diabetes (T2DM) and metabolic syndrome (MS) display decreased activity of peroxisome proliferator activated receptor gamma (PPAR¿) and often develop salt-sensitive hypertension (SS HT). PPAR¿ activation by thiazolidinediones (TZDs) lowers blood pressure in T2DM and MS. Moreover, PPAR¿ impairment caused by dominant negative mutations (e.g. P467L) that block PPAR¿ activation by ligands cause severe early onset HT in humans, while selective expression of these mutations in vascular smooth muscle (VSM) recapitulates human HT in mice (S-P467L), suggesting impairment of vascular PPAR¿ is causal. Using S-P467L mice as a model of vascular PPAR¿ impairment, I have provided compelling preliminary data supporting an innovative concept that the detrimental effects of PPAR¿ impairment in VSM may be mediated by enhanced PGE2/E-Prostanoid Receptor 3 (EP3) signaling in pre-glomerular resistance vessels (interlobular artery and afferent arterioles), causing increased renal vascular resistance and blunted renal blood flow during excess salt loading. The blunted renal perfusion is associated with decreased intrarenal nitric oxide (NO) bioavailability and increased sodium retention in S-P467L mice fed a 4% high salt diet. We and others have previously published that vascular PPAR¿ prevents oxidative stress through transcriptional regulation of antioxidant genes. Loss of PPAR¿-mediated antioxidant responses may decrease NO bioavailability in renal microvessels through an imbalance between NO and reactive oxygen species such as superoxide. The goal of this K01 award is to investigate the renal mechanisms of salt sensitivity caused by the impairment of vascular PPAR¿. Aim 1 will test the hypotheses that a) impairment of vascular PPAR¿ blunts renal blood flow by enhancing PGE2/EP3 signaling in renal microvessels, and b) pharmacological inhibition of EP3 decreases renal vascular resistance, improves renal perfusion, and attenuates SS HT during PPAR¿ impairment. Aim 2 will test the hypotheses that a) impaired vascular PPAR¿ results in decreased NOS-mediated NO generation and/or impaired antioxidant defense in the kidney, and b) intrarenal NO deficiency impairs natriuresis and contributes to SS HT during PPAR¿ impairment. Successful completion of the mentored scientist development grant will allow me to acquire necessary skills and expertise to transition to independence in the academia of hypertension research focusing on renal vascular biology, redox biology, and tubular physiology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
