# Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2021 · $349,000

## Abstract

Project Summary/Abstract
The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over
20 million Americans have chronic kidney disease. Diabetes Mellitus is the leading risk factor for chronic
kidney disease in the United States. Despite improved glycemic control, individuals with Diabetes Mellitus
continue to develop and progress to diabetic kidney disease (DKD). In DKD, along with endothelial injury and
mesangial expansion, podocyte loss directly contributes to the functional capacity to maintain the renal filtration
barrier. Mitochondrial injury is also uniformly observed in DKD and is accompanied by mitochondrial DNA
damage as well as altered expression of genes involved in mitochondrial biogenesis, function, and
fragmentation. We recently reported the essential role for the zinc-finger transcription factor, Krüppel-like factor
6 (KLF6), in podocyte injury. Specifically, we demonstrated that KLF6 is an early inducible injury response
gene that enhances mitochondrial respiratory complex IV (cytochrome c oxidase, COX) expression, thereby
abrogating the release of cytochrome c and activation of apoptosis in the setting of cell stress. KLF6 maintains
COX assembly by regulating the expression of key transcripts involved in mitochondrial replication,
transcription, and function under cell stress. To date, this is the first study demonstrating a direct regulatory
effect of a zinc-finger transcription factor on mitochondrial function in the podocyte. Our preliminary data also
suggests that podocyte-specific loss of Klf6 (Klf6-/-) accelerated DKD in mice. In addition, we observed a
significant increase in mitochondrial injury with podocyte loss in the diabetic Klf6-/- mice as compared to
diabetic wildtype mice. Furthermore, we observed that modulating the level of KLF6 expression in the podocyte
directly regulated mitochondrial structure, function, genes involved in COX assembly, and apoptosis. Finally,
KLF6 expression was reduced in DKD as compared to healthy control subjects in three independent gene
expression arrays from human kidney biopsies. The objective of this research proposal is to demonstrate
that KLF6 is required to prevent mitochondrial dysfunction and podocyte injury in DKD. The long-term goal of
our project is to identify “druggable” targets in restoring mitochondrial function in podocytes of diabetic kidney.
This proposal will address a current gap in the field by demonstrating that COX assembly is critical to
preventing mitochondrial dysfunction in podocytes of diabetic kidney. The potential impact of this proposed
research is that it will shed new light on the critical role of respiratory complex assembly in improving
mitochondrial function in the podocyte and slowing the rate of DKD progression in the kidney. Finally,
deciphering the mechanism by which KLF6 regulates COX assembly will provide us with a novel pathway to
target in DKD.

## Key facts

- **NIH application ID:** 10151445
- **Project number:** 5R01DK112984-05
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Sandeep K Mallipattu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,000
- **Award type:** 5
- **Project period:** 2017-06-12 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151445

## Citation

> US National Institutes of Health, RePORTER application 10151445, Transcriptional control of mitochondrial function by KLF6 in diabetic kidney disease (5R01DK112984-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10151445. Licensed CC0.

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