# Mechanisms of Synergistic Interactions of Hypertension and Diabetes in Promoting Kidney Injury

> **NIH NIH R00** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $249,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Diabetes mellitus has increased dramatically in the U.S. during the last several decades and has rapidly
become a major challenge to our healthcare system. Many patients with diabetes are also hypertensive (HT),
which substantially increases the risk for progression of diabetic nephropathy to end-stage renal disease
(ESRD). Clinical and experimental studies indicate that antihypertensive treatment only slows the progression
of nephropathy to ESRD rather than halting it. Therefore, there is an urgent need to reveal the mechanisms
responsible for diabetic-HT nephropathy and to identify new therapeutic targets. Preliminary studies in a type II
diabetic animal model indicate that even a moderate increase in BP, when superimposed on moderate
diabetes, greatly enhances renal injury as reflected by significantly increased proteinuria and rapid decline in
GFR. In addition, inhibition of endoplasmic reticulum (ER) stress and scavenging of reactive oxygen species
(ROS) from mitochondria (MT) have renal protective effects, suggesting that ER stress and MT dysfunction
may be key factors in contributing to the synergistic effects of HT plus diabetes. There is also evidence that
mechanically sensitive transient receptor potential cation channels, subfamily C, member 6 (TRPC6) may have
an important role in the development of glomerular injury in diabetic nephropathy. Therefore, it hypothesizes
that coexistence of HT and diabetes in type II diabetes synergistically amplifies oxidative stress and cellular
injury in podocytes and endothelium of glomeruli. This synergistic effect is mediated by HT-induced mechanical
stretch which activates TRPC channels and is amplified by the interaction of ER stress, mitochondrial
dysfunction and impaired Ca2+ homeostasis. During the mentored phase, the molecular mechanisms by which
mechanical forces induced by hypertension interact with diabetes to promote renal injury will be determined
using in vitro and in vivo models. Synergistic effects of HT and diabetes on molecular pathways of ER stress,
mitochondrial dysfunction and TRPC6 activation in glomerular capillary endothelial cells and podocytes will be
evaluated as well. During the independent phase, the renal protective effect of TRPC6 deficiency in diabetic-
HT kidney injury will be examined using novel genetically engineered animal models. Results from this study
will provide novel information on the role of TRPC6 channels in mediating diabetic-HT nephropathy. Overall,
this project will facilitate applicant's continued technical, intellectual, and professional training, and will assist
the applicant in establishing an independent research laboratory at an academic research institution.

## Key facts

- **NIH application ID:** 9983699
- **Project number:** 5R00DK113280-04
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** Zhen Wang
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983699

## Citation

> US National Institutes of Health, RePORTER application 9983699, Mechanisms of Synergistic Interactions of Hypertension and Diabetes in Promoting Kidney Injury (5R00DK113280-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9983699. Licensed CC0.

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