# Understanding Epithelial Plasticity in Renal Repair after Acute Kidney Injury

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $382,389

## Abstract

Understanding Epithelial Plasticity in Renal Repair after Acute Kidney Injury
Following acute kidney injury (AKI), surviving tubular epithelial cells (TECs) proliferate and regenerate the
injured epithelium leading to kidney function recovery. However, until recently, the intrinsic molecular driver of
epithelial regeneration remained elusive. To this end, we recently identified SOX9 as the molecular driver that
regenerates the injured epithelium. Coupling genetic lineage strategy to tissue-specific, conditional knock-out
methodology, we identified SOX9 as a direct, intrinsic molecular link between repair and formation of the
nephron tubular epithelia. Upon successful regeneration of the epithelia after injury, SOX9 attained baseline
level. However, during progression of ischemic AKI to chronic kidney disease (CKD), distinct, sporadic
persistently injured TECs mounted a strong sustained SOX9 (sSOX9+) with cell proliferation signature thereby
demarcating “unresolved injury/repair cell-type”. These findings raise crucial unanswered questions, including:
(1) does human kidneys activate SOX9 after AKI, (2) how an injured epithelium rapidly mounts a SOX9 pro-
replicative response, (3) how SOX9 drive epithelial regeneration and whether upon activation it dedifferentiates
the injured TECs to its embryonic progenitor-like state to drive repair, and (4) whether sSOX9+ contributes to
the progression of AKI to CKD. To this end, here we further identify (a) SOX9 activation after human AKI, (b) a
nuclear phosphoEGFR:SOX9 pro-replicative axis in both primary mice and human proximal TECs, and (c)
intimate, robust association of sSOX9+ cells with αSMA+ myofibroblasts. The proposed research will test (Aim
1) the hypothesis that injury induced EGFR signaling via nuclear phosphorylated EGFR activates Sox9 and
exerts Sox9-dependent pro-reparative effects, with Sox9 per se being sufficient to drive proliferation; (Aim 2)
will reveal molecular underpinnings of Sox9-orchestrated reparative action whilst determining whether injury-
activated Sox9 dedifferentiates the injured PTECs to a progenitor-like state; (Aim 3) test the hypothesis that
sustained Sox9+ subset demarcating “unresolved injury/repair” cell-type contribute to progression of AKI to
CKD. The proposed research is innovative because using state-of-the-art approaches we will critically
investigate the above heretofore-unexamined molecular and cellular pathways in renal repair. The proposed
research is significant and impactful because (A) our findings akin to our mice studies highlight SOX9
activation within the PTECs after human ischemic AKI and SOX9-based pro-replicative responses in human
primary proximal tubular epithelial cells; and (B) injury-induced epithelial plasticity is a poorly understood
process, and deep, critical insights gained by the proposed research work will advance not only kidney field but
will have direct application to the mechanistic understanding of tissue remodeling in other epitheli...

## Key facts

- **NIH application ID:** 10438573
- **Project number:** 5R01DK118265-05
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Sanjeev Kumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,389
- **Award type:** 5
- **Project period:** 2018-08-21 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438573

## Citation

> US National Institutes of Health, RePORTER application 10438573, Understanding Epithelial Plasticity in Renal Repair after Acute Kidney Injury (5R01DK118265-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10438573. Licensed CC0.

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