# Novel Mechanisms Regulating Renal Perfusion and Kidney Redox Biology: Role in Salt Sensitive Hypertension

> **NIH NIH K01** · UNIVERSITY OF ROCHESTER · 2022 · $153,846

## Abstract

PROJECT SUMMARY
Individuals with type II diabetes (T2DM) and metabolic syndrome (MS) display decreased activity of peroxisome
proliferator activated receptor gamma (PPARγ) and often develop salt-sensitive hypertension (SS HT). PPARγ
activation by thiazolidinediones (TZDs) lowers blood pressure in T2DM and MS. Moreover, PPARγ impairment
caused by dominant negative mutations (e.g. P467L) that block PPARγ 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 PPARγ is causal. Using S-P467L
mice as a model of vascular PPARγ impairment, I have provided compelling preliminary data supporting an
innovative concept that the detrimental effects of PPARγ 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 PPARγ prevents oxidative stress through transcriptional regulation of antioxidant genes. Loss of
PPARγ-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 PPARγ. Aim 1 will test
the hypotheses that a) impairment of vascular PPARγ 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 PPARγ impairment. Aim 2 will test the hypotheses that a) impaired
vascular PPARγ 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 PPARγ 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.

## Key facts

- **NIH application ID:** 10582079
- **Project number:** 7K01DK126792-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Jing O. Wu
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $153,846
- **Award type:** 7
- **Project period:** 2021-01-06 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582079

## Citation

> US National Institutes of Health, RePORTER application 10582079, Novel Mechanisms Regulating Renal Perfusion and Kidney Redox Biology: Role in Salt Sensitive Hypertension (7K01DK126792-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10582079. Licensed CC0.

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