# Role of KLF15 in proximal tubule metabolism

> **NIH VA I01** · NORTHPORT VA MEDICAL CENTER · 2024 · —

## Abstract

Chronic kidney disease (CKD) is a leading risk factor for cardiovascular disease, with a
disproportionate burden on U.S. Veterans. Recent data demonstrates that acute kidney injury (AKI), despite
initial renal recovery, is a major risk factor for CKD. The proximal tubule (PT) is the primary target in AKI due to
its high susceptibility to ischemia and DNA-damaging nephrotoxins such as chemotherapeutic agents.
Damaged PT cells dedifferentiate, and initially undergo cell cycle arrest, predominantly at the G2/M checkpoint.
This cell cycle arrest may allow repair of DNA damage caused by reactive oxygen species secondary to
mitochondrial damage or directly by DNA-damaging toxins. Sustained cell cycle arrest is associated with a
switch to secretion of pro-fibrotic signaling molecules, inducing resident fibroblasts to proliferate and
differentiate to myofibroblasts, beginning the transition to a fibrotic injury. PT cells also undergo metabolic
reprograming, with severe downregulation of fatty acid b-oxidation (FAO), and limited compensation by
anerobic glycolysis. While restoring FAO either by overexpressing Ppara or by using a peroxisome proliferator
activated receptor alpha (PPARa) agonist attenuates AKI and CKD in murine models, this has not translated to
use in clinical AKI, suggesting additional factors are required to mitigate the progression from AKI to CKD.
 Krüppel-Like Factor 15 (KLF15) is a kidney-enriched transcription factor, involved in a diverse range of
cellular processes, including cell differentiation and FAO. In the initial funding period of the VA Merit, we
demonstrated the salutary role of KLF15 in glomerular disease leading to a composition-of-matter IP on KLF15
agonists by the Veterans Affairs. During this initial period, we also identified that KLF15 is highly expressed in
differentiated PT cells, but is significantly reduced in murine models of PT injury. Utilizing a murine model of
PT-specific injury secondary to DNA damage, we observed that PT-specific knockdown of Klf15 exacerbated
AKI as well as CKD. PT-specific knockdown of Klf15 also increased pathways involving cell cycle arrest,
oxidative stress, pro-fibrotic signaling and a decrease in pathways utilizing FA for the generation of acetyl-CoA,
a central metabolic intermediate in macromolecule biosynthesis and energy production. We also observed an
enrichment of genes critical for FA utilization with putative and proximal KLF15- and PPARa-binding sites,
suggesting potential KLF15-PPARa co-operativity in the regulation of FA utilization. In addition, we
demonstrated a significant increase in glycerolipid synthesis pathways and lipid droplet formation in the setting
of suppressed FAO, suggesting a potential compensatory mechanism post-DNA damage. KLF15 expression
was also associated with PPARA expression in human kidney biopsies with and without CKD. In addition,
multivariate regression analysis demonstrated that a decrease in KLF15 expression was independently
associated with...

## Key facts

- **NIH application ID:** 10721356
- **Project number:** 5I01BX003698-06
- **Recipient organization:** NORTHPORT VA MEDICAL CENTER
- **Principal Investigator:** Sandeep K Mallipattu
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721356

## Citation

> US National Institutes of Health, RePORTER application 10721356, Role of KLF15 in proximal tubule metabolism (5I01BX003698-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10721356. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*