# The Role of Hypobromous Acid in Renal Disease

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $355,500

## Abstract

The excessive generation of reactive oxygen species (ROS) significantly contributes to maladaptive
renal inflammation and fibrosis. While most attention has been directed towards superoxide, hydrogen
peroxide (H2O2), and other ROS, our recent work has focused on hypobromous acid (HOBr) as an important
ROS. Animal heme peroxidases produce HOBr using H2O2 and Br- as substrates. HOBr, a chemical cousin of
bleach (HOCl), is a powerful oxidant capable of damaging proteins, lipids, and nucleic acids and typically
promotes tissue injury.
 We recently discovered that an extracellular matrix (ECM) protein known as peroxidasin (Pxdn) also
generates HOBr. Pxdn uses HOBr as an anabolic, reactive intermediate to form novel sulfilimine (S=N) cross-
links in collagen IV, a prominent constituent of basement membranes (BM), such as glomerular BM (GBM). In
Drosophila, we found that loss of Pxdn and sulfilimine cross-links compromised basement membrane and
tissue integrity leading to larval lethality. However, Pxdn knock-out (KO) mice are viable but demonstrate
reduced sulfilimine cross-links and BM strength. Based on this phenotype, we expected that unilateral ureteral
obstruction (UUO) and increased intratubular pressures would lead to greater tubular BM stretch and
mechanical stress on tubular cells in Pxdn KO mice. Consequently, Pxdn KO mice would exhibit increased
renal inflammation and fibrosis. Paradoxically, Pxdn KO mice demonstrated less renal inflammation and
fibrosis with diminished HOBr mediated oxidative damage. Based on these data, we hypothesize that Pxdn
normally uses HOBr to cross-link collagen IV and support tissue integrity, but when dysregulated, Pxdn
generates excessive HOBr leading to oxidative damage and tissue injury.
 To test this hypothesis, in Aim 1, we will determine whether Pxdn loss of function protects against renal
injury that varies in extent of inflammation and localization contrasting glomerular and tubulointerstitial disease.
Aim 2 will examine how HOBr alters renal cell behavior to promote tubulointerstitial fibrosis and inflammation,
including the use of mass spectrometry to identify HOBr mediated oxidative modifications of proteins. In Aim 3,
we will mechanistically address how Pxdn uses HOBr to cross-link collagen IV yet avoid collateral damage to
other biomolecules. Taken together, this proposal aims to define a novel role for HOBr in renal inflammation
and fibrosis. These studies hope to rationalize a strategy to target HOBr to treat chronic kidney disease.

## Key facts

- **NIH application ID:** 10136586
- **Project number:** 5R01DK116964-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Gautam Bhave
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,500
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136586

## Citation

> US National Institutes of Health, RePORTER application 10136586, The Role of Hypobromous Acid in Renal Disease (5R01DK116964-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10136586. Licensed CC0.

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