# Cellular and Molecular Mechanisms of Renal Fibrosis

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $369,000

## Abstract

Project Summary
 Chronic kidney disease is a growing public health problem that affects more than 26 million Americans.
A key pathologic feature of chronic kidney disease is renal fibrosis. Renal fibrosis is characterized by fibroblast
activation and excessive production and deposition of extracellular matrix, which leads to the destruction of
renal parenchyma and progressive loss of kidney function to end-stage renal disease. The current therapeutic
options for this devastating condition are limited and often ineffective. Therefore, a better understanding of the
cellular and molecular mechanisms underlying renal fibrosis is essential for developing effective strategies for
the treatment of fibrotic kidney disorder.
 We have studied the factors initiating and controlling renal fibrosis and have discovered a critical and
obligate role for immune-inflammatory dysregulation in the initiation and development of renal fibrosis. Our
studies have demonstrated that the fibrosis arises from kidney injury is associated with the formation of bone
marrow-derived fibroblasts that accumulate in the kidney. The presence and accumulation of these fibroblasts
from a CD45+ mononuclear precursor population and the development of renal fibrosis are driven by and
dependent upon induction of the chemokine CXCL16 in renal tubular epithelial cells and is prevented by genetic
deletion of CXCL16, or its receptor, CXCR6. Furthermore, the accumulation of myeloid fibroblasts is associated
with striking induction of Th2 cytokines, which activate signal transducer and activator of transcription 6
(STAT6) to stimulate myeloid fibroblast activation and fibrogenesis in the kidney. Activated STAT6 induces
expression of histone H3K27 demethylase, Jumonji domain-containing protein 3 (JMJD3), resulting in histone
H3K27 demethylation and myeloid fibroblast activation. In this renewal application, we plan to examine and
characterize the role of STAT6-JMJD3 signaling in myeloid fibroblast activation to further understand the
cellular and molecular mechanisms of renal fibrosis. Our central hypothesis is that Th2 cytokines activate
STAT6 signaling resulting in JMJD3 induction, histone H3K27 demethylation, myeloid fibroblast activation, and
fibrogenesis. To test our hypothesis, we will pursue the following Specific Aims: Specific Aim 1 is to determine
the role of STAT6 signaling in the activation of bone marrow-derived fibroblasts. Specific Aim 2 is to examine
whether JMJD3 mediates bone marrow-derived fibroblast activation.
 In summary, we plan to utilize molecular, cellular, pharmacological, and genetic approaches to study
the role of STAT6-JMJD3 signaling in myeloid fibroblast activation and development of renal fibrosis. Results
from our studies will provide a new understanding of the cellular and molecular mechanisms of renal fibrosis
and could lead to the development of novel therapeutic strategies for the treatment of chronic kidney disease.

## Key facts

- **NIH application ID:** 9926871
- **Project number:** 5R01DK095835-09
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** YANLIN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,000
- **Award type:** 5
- **Project period:** 2018-10-11 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926871

## Citation

> US National Institutes of Health, RePORTER application 9926871, Cellular and Molecular Mechanisms of Renal Fibrosis (5R01DK095835-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9926871. Licensed CC0.

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