# LRRC8 anion channels, superoxide and RhoA in diabetic erectile dysfunction

> **NIH NIH R01** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2022 · $692,954

## Abstract

PROJECT SUMMARY
 Erectile dysfunction (ED) is one of the most prevalent and impactful complications of diabetes mellitus
(DM). The combination of diabetes and sexual dysfunction affects family planning and overall quality of life, and
ED is now considered an early marker for cardiovascular diseases and consequently could predate the
development of a life-threatening condition. Hyperglycemia, hyperlipidemia and inflammation are all associated
with DM and induce the generation of vascular reactive oxygen species (ROS). Nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase (Nox) is the main source of ROS in the vasculature and ROS activate
intracellular signaling pathways that induce constriction of the penile vasculature. In vascular smooth muscle
cells (VSMCs), this signaling cascade begins with extracellular superoxide (O2-•) production by Nox1 at the
plasma membrane. Extracellular O2-• from Nox1 can alter vascular tone by inactivating endothelium-derived
nitric oxide (NO). But O2-• also triggers activation of RhoA/Rho-kinase signaling to cause constriction of the
penile vasculature. In diabetes, activation of RhoA/Rho-kinase signaling is exaggerated leading to ED.
 We have demonstrated functional and structural inter-dependence between Nox1 and volume-regulated
anion channels (VRACs) composed of leucine-rich repeat-containing 8 (LRRC8) family proteins. LRRC8A is
required for all VRACs and combines with one of four closely related LRRC8 isoforms (LRRC8B through E) to
produce channels with unique biophysical properties. We speculate and provide preliminary data that VRACs
provide O2-• access to the cytoplasm. Our preliminary data demonstrate that LRRC8 knockout (KO) or channel
inhibition enhances dilator function (or reduces constriction) in control blood vessels and null mice are protected
against impairment of vasodilation by TNFα in vitro and angiotensin II (AngII) in vivo.
 This proposal will provide a structural framework to understand how extracellular O2-• produces
intracellular signals that lead to contraction of the penile vasculature. We hypothesize that in diabetes, erectile
dysfunction is partly due to the entry of extracellular O2-• from Nox1 via LRRC8 anion channels to activate
RhoA/Rho-kinase resulting in vascular contraction. Three aims address this central hypothesis: 1) to test
the hypothesis that in diabetes, ED is caused by excess Nox1 and LRRC8A-dependent production of
extracellular O2-• which then enters VSMCs via LRRC8A anion channels, activates RhoA/Rho kinase and
increases vascular tone; 2) to test the hypothesis that diabetic mice that lack the LRRC8 channel in the
vasculature will not develop ED; and 3) to test the hypothesis that drugs that selectively inhibit LRRC8 channels
will be novel therapeutic agents for the treatment of ED in diabetes. This work will provide a comprehensive
approach to understanding the role of LRRC8/VRACs, O2-• and RhoA in the etiology and development of ED in
diabetic males and provide a...

## Key facts

- **NIH application ID:** 10423046
- **Project number:** 1R01DK132948-01
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** FRED S LAMB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $692,954
- **Award type:** 1
- **Project period:** 2022-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10423046

## Citation

> US National Institutes of Health, RePORTER application 10423046, LRRC8 anion channels, superoxide and RhoA in diabetic erectile dysfunction (1R01DK132948-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10423046. Licensed CC0.

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