# Role of p66Shc in Regulation of Microvascular Reactivity of Renal Blood Vessels

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $384,100

## Abstract

Renal microvascular injury occurs in a majority of patients with diabetes and hypertension-induced
nephropathy. Thus, the uncovering of the molecular mechanisms of changes in microvascular reactivity of
renal blood vessels is necessary for developing new therapeutic strategies to combat these diseases, which
contribute significantly to escalation of health care. Based on our preliminary data we hypothesize that
overexpression of adaptor protein p66Shc is implicated in the loss of microvascular reactivity during the
progression of both hypertension-induced nephropathy and diabetic nephropathy. We will use genetically
modified Dahl salt sensitive (SS) rats, generated by targeted modification of Shc1 gene, and primary renal
vascular smooth muscle cells (SMC) derived from these rats. p66Shc-dependent regulation of microvascular
reactivity will be studied in rat afferent arterioles and human renal microvessels from deceased donors with
medical history of either diabetes or hypertension-induced nephropathy. Specific Aim 1 will test the hypothesis
that loss of renal microvascular reactivity in hypertension induced nephropathy is caused by p66Shc-
dependent inhibition of Ca2+ influx mediated by TRPC channels and will analyze molecular mechanisms of
TRPC regulation by p66Shc. We will test the role of p66Shc interaction with guanine exchange factor beta-Pix
in regulation of TRPC channels activity and channel subcellular distribution. Using 2-photon imaging we will
study the role of p66Shc in regulation of spontaneous intracellular Ca2+ oscillations in SMC embedded in the
vascular wall of human renal resistance vessels. We will also test compound SHetA2, known to interfere with
p66Shc action, for its ability to prevent p66Shc-induced decline of renal function in hypertension nephropathy.
The restoration of renal vascular function will be evaluated by studying microvascular responses to purinergic
activation and perfused pressure in the control SS rats and SS rats treated with compound SHetA2. We will
also define whether SHetA2 has beneficial effect on vascular function in samples from diseased donors with
and without hypertension. Specific Aim 2 will test the hypothesis that p66Shc regulates arteriolar KATP channel
activity and causes hyperfiltration in diabetic nephropathy. Effect of upregulation of KATP activity, in concert with
impaired Ca2+ influx responses to modulators of myogenic tone, is likely to promote vasodilation of renal
afferent arterioles, causing hyperfiltration. We will study whether p66Shc regulates KATP channels in human
renal microvessels. We will also employ type 1 diabetic rat model of STZ-induced diabetic nephropathy, which
display markers of the disease similar to those observed in human patients. p66Shc-dependent KATP channel
activity will be tested by electrophysiological recording in renal SMC. We will test whether p66Shc stimulates
KATP channel activity via inducing protein-protein interactions with adaptor protein 14-3-3. The p...

## Key facts

- **NIH application ID:** 10198033
- **Project number:** 5R01HL147976-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** ANDREY SOROKIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,100
- **Award type:** 5
- **Project period:** 2019-07-22 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198033

## Citation

> US National Institutes of Health, RePORTER application 10198033, Role of p66Shc in Regulation of Microvascular Reactivity of Renal Blood Vessels (5R01HL147976-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10198033. Licensed CC0.

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