# KLF2 is a novel endoprotective target for DKD

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $740,566

## Abstract

Summary
Patients with diabetic kidney disease (DKD) frequently develop cardiovascular disease (CVD), and vascular
complications and endothelial cell injury is a common pathological event for both DKD and CVD. Therefore, the
development of novel treatments with dual cardio-renal protection is urgently needed. Krüppel-like factors
(KLFs) are a subfamily of 17 DNA-binding transcriptional regulators. Through unbiased screening, we identified
KLF2 as a highly regulated gene in the diabetic kidney. KLF2 is known to mediate flow-dependent phenotype
in endothelial cells, and confers endoprotective effects by inhibition of pro-inflammatory pathways, thrombotic
activation, and uncontrolled angiogenesis. Due to these endo-protective effects, KLF2 has been shown to be
protective in CVD. Over the last several years, we have generated interesting data to support the critical role of
KLF2 in protecting GEC injury in DKD. We find: 1) KLF2 expression is regulated by many factors in GECs such
as glomerular hyperfiltration, high glucose, TGF-α, sex hormone, and SGLT2i. 2) KLF2 expression is reduced
in GECs of human diabetic kidneys and reduction of KLF2 expression is associated with the progression of
human DKD. Two missense mutations of hKLF2 gene were found to be associated with ESKD. 3) KLF2 has
anti-inflammatory effects and regulates eNOS expression in GECs. 4) Endothelial cell-specific KLF2 KO mice
with diabetes develop more severe GEC injury and DKD, while endothelial cell-specific overexpression of KLF2
has protective effects in DKD mice. 5) KO of KLF2 in endothelial cells also aggravates proteinuria and renal
dysfunction in the mice with unilateral nephrectomy. Based on these preliminary data, we hypothesized that
KLF2 has a major protective role against GEC injury in DKD and KLF2 could be an attractive drug target for
treatment of DKD. To further test this hypothesis, we propose the following three aims: Aim 1: Determine how
KLF2 is regulated in diabetic conditions. Aim 2: Determine how KLF2 protects against GEC injury and
progression of DKD. Aim 3: Determine whether KLF2 agonists could be developed as a novel drug for the
treatment of DKD. These studies will help us to further explore the mechanisms of the endo-protective role of
KLF2, validate KLF2 as a potential drug target, and develop KLF2 agonists as a potential treatment for DKD.
We believe that KLF2 agonists could be eventually developed as a novel drug for cardio-renal protection in
diabetic patients with CKD/CVD.

## Key facts

- **NIH application ID:** 11021561
- **Project number:** 1R01DK141510-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Bhaskar Chandra Das
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $740,566
- **Award type:** 1
- **Project period:** 2024-09-20 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11021561

## Citation

> US National Institutes of Health, RePORTER application 11021561, KLF2 is a novel endoprotective target for DKD (1R01DK141510-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11021561. Licensed CC0.

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