Advisor(s)

Kelly Hyndman
Subhashini Bolisetty

Committee Member(s)

James George
Jennifer Pollock
Timmy Lee

Document Type

Dissertation

Date of Award

6-18-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Joint Health Sciences

Abstract

Acute kidney injury (AKI) is increasingly recognized as a major contributor to the development of chronic kidney disease (CKD) through maladaptive repair and interstitial fibrosis. Epigenetic regulation has emerged as a critical factor of kidney injury responses, however the injury-specific and cell-type specific roles of histone deacetylases (HDACs) remain poorly defined. This dissertation investigates the regulation and functional significance of HDACs in kidney injury, with a particular focus on fibroblast HDAC1 as a mediator of interstitial fibrosis development following AKI. In my cisplatin-induced AKI model, a single dose of cisplatin caused a significant decline in kidney function in both male and female mice. However, there were minimal changes in HDAC expression, abundance, localization, or activity across sexes and treatment groups. Furthermore, inhibition with a class I HDAC inhibitor did not improve kidney function or reduce injury following cisplatin administration. These findings contrast with previous studies, which may be explained by differences in injury severity. Variations in the severity of cisplatin-induced AKI could differentially alter HDAC isoform expression and activity, thereby influencing the therapeutic response to HDAC inhibition. In our studies using the ischemia-reperfusion injury (IRI) model of AKI, we previously demonstrated that HDAC1 expression is significantly increased in the renal interstitium following injury. Because fibroblasts are a major component of the interstitium and a primary source of myofibroblasts, I investigated the specific role of HDAC1 in fibroblasts. My findings indicate that fibroblast HDAC1 is pro-fibrotic, and its activation promotes the development of kidney interstitial fibrosis. Preventative inhibition of fibroblast HDAC1 attenuated fibrosis following IRI. However, therapeutic inhibition initiated after IRI did not prevent the progression of established fibrosis. These findings suggest that HDAC1 plays a critical role during the early stages of interstitial fibrosis development, whereas once fibrosis is established, HDAC1 inhibition alone is insufficient to halt disease progression. In summary, my work shows that HDAC regulation in AKI is injury-specific and cell-type dependent. While cisplatin-induced AKI did not significantly respond to class I HDAC inhibition, ischemia-reperfusion injury AKI identified fibroblast HDAC1 as a key driver in the early development of interstitial fibrosis.

Keywords

Acute kidney injury;cisplatin induced nephrotoxicity;fibroblasts;histone deacetylase 1;ischemia reperfusion injury;renal fibrosis

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