# The role of lysyl oxidase like-2 in chronic kidney disease

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $523,420

## Abstract

Chronic kidney disease (CKD) is a world-wide problem that results from the damage of renal structures
progressing to the complete loss of kidney function also known as end-stage renal disease (ESRD).
Estimations indicate that more than 15% of adults in United States have CKD. There is no cure for ESRD and
current therapies include hemodialysis and kidney transplant which are expensive and place a significant
burden on the quality of life. Fibrosis is central to the pathologic manifestations associated with the progression
of CKD to ESRD. Kidney function declines progressively as results from the accumulation of insoluble collagen
and other ECM proteins in the renal parenchyma. Pharmacological blockade of the renin-angiotensin system
slows down renal function decline, but it does not necessarily stop fibrosis progression, manifesting the urgent
need for new antifibrotic therapies. Lysyl oxidase like-2 (LOXL2) has emerged as an attractive pharmaceutical
target in renal fibrosis because it is an ECM-remodeling enzyme that crosslinks collagen regulating its
deposition and degradation. However, the cellular and molecular mechanism by which LOXL2 contributes to
kidney fibrosis and CKD progression are not well understood.
 In this proposal, we show that LOXL2 is upregulated in human kidney biopsies and experimental mouse
models of kidney disease. Our pilot studies showed that inhibition of LOXL2 significantly ameliorated kidney
function decline and renal fibrosis in diabetic mice. In vitro studies exploring molecular mechanism of LOXL2
expression suggest that profibrotic transforming growth factor beta (TGF-) and hypoxia are key regulators in
the glomerulus and tubulointerstitium, respectively. Moreover, we show that extracellular LOXL2 directly
activates renal cortical fibroblasts, suggesting a novel pathogenic function of LOXL2 that may further contribute
to renal fibrosis. Based on these findings, we hypothesize that LOXL2 contributes to the pathogenesis of CKD
both by promoting collagen crosslinking and by activating renal fibroblasts. We will test this hypothesis by 1)
using genetic and pharmacological approaches combined with injury mouse models of CKD, 2) exploring
cellular and molecular mechanism in in vitro systems, and 3) using state of the art mass spectrometry
technologies to elucidate biochemical changes of collagen in renal fibrosis. Thus, in this project we propose 3
specific aims: to determine the biochemical mechanism of LOXL2-catalyzed collagen crosslinking (Aim 1); to
determine the pathogenic role of LOXL2 in glomerulosclerosis (Aim 2) and tubulointerstitial fibrosis (Aim 3).
The knowledge gained from these studies will not only serve as a foundation to better understand the role of
LOXL2 in renal fibrosis, but also contribute to the development of novel, effective therapies to stop the
progression of CKD.

## Key facts

- **NIH application ID:** 10134320
- **Project number:** 5R01DK099467-09
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Roberto Marcelo Vanacore
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $523,420
- **Award type:** 5
- **Project period:** 2013-09-20 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134320

## Citation

> US National Institutes of Health, RePORTER application 10134320, The role of lysyl oxidase like-2 in chronic kidney disease (5R01DK099467-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134320. Licensed CC0.

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