# Axl receptor tyrosine kinase, a potential therapeutic target in glomerulonephritis

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $235,640

## Abstract

Nephritis is a serious complication of lupus and can progress to end-stage kidney failure in patients with
active disease. The experiments in this proposal will attempt to increase our understanding the role of Axl
receptor tyrosine kinase in regulating kidney inflammation and pathogenesis. Our preliminary data demonstrate
that Axl contributes to anti-glomerular base membrane (GBM) antibody-induced nephritis by promoting
glomerular mesangial cell survival and proliferation. We have shown that Axl-deficient mice are protected
against anti-GBM nephritis and that treatment of mice with R428, a specific small molecule inhibitor of Axl
signaling, decreases proteinuria and increases survival in mice with this disease. Based on these observations,
we will now investigate the regulation of Axl expression by renal mesangial cells, identify the mechanisms by
which Axl signaling promotes the pathogenesis of glomerulonephritis, and determine whether treatment with
R428 has a general ability to suppress glomerular disease in mouse models of lupus nephritis. Our studies will
be guided by three hypotheses: (1) Axl expression by renal mesangial and tubular cells is upregulated by
inflammatory cytokines that act through at least 2 mechanisms: (a) transcription factor binding of the Axl 5'-
UTRs; and (b) IL-6 activation of Stat3, which increases Axl transcription by decreasing expression of miR-34a.
(2) Axl signaling promotes glomerular disease by acting alone or synergistically with MER and EGFR to
increase renal mesangial and tubular survival and proliferation through the PI3K/Akt/mTOR pathway. (3) Axl
inhibition by R428 will suppress spontaneous and induced murine glomerular disease. These hypotheses will
be tested through three specific aims:
 1. Will identify the mechanisms that regulate Axl expression in the inflamed kidney. We will investigate
two pathways leading to Axl expression in the kidney: 1) Increased IL-6 in the inflamed kidney leads to STAT3
activation, which increases Axl transcription by inhibiting miR34a expression; 2) Axl transcription in the kidney
is driven by multiple transcription factors.
 2. Will identify the signaling mechanisms by which Axl promotes glomerulonephritis. We will test the
hypotheses that: 1) Axl-induced activation of the PI3K and mTOR signaling pathways promotes the survival
and proliferation of mesangial/tubule cells, respectively. 2) Axl synergistically interacts with Mer or the EGFR
pathway to activate target cells and stimulate cytokine secretion.
 3. Will determine the ability of R428 to suppress the development of glomerulonephritis and treat
established glomerulonephritis. We will determine whether R428 can inhibit disease progression prior to and
after disease onset in inducible and spontaneous models of nephritis.
!

## Key facts

- **NIH application ID:** 9901516
- **Project number:** 5R01DK116789-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Wen-Hai Shao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $235,640
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901516

## Citation

> US National Institutes of Health, RePORTER application 9901516, Axl receptor tyrosine kinase, a potential therapeutic target in glomerulonephritis (5R01DK116789-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9901516. Licensed CC0.

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