Kidney Cortex Histone Deacetylase Expression and Activity of Male and Female Mice in the Cisplatin Nephrotoxic Model

Abstract

Histone deacetylase enzymes (HDACs) modify transcriptional activity by removing an acetyl group from histone tails, generally resulting in a repression of transcription. Administration of HDAC inhibitors has been shown to reduce inflammation and apoptosis in both cancer and cardiovascular disease models. Cisplatin is a chemotherapy agent; however, due to its accumulation in the kidney, it can be nephrotoxic. Administering cisplatin serves as a model for acute kidney injury in mice. Previous studies with male mice have shown that whole kidney Hdac expression increases 24 and 72 h post a 30 mg/kg cisplatin injection, and inhibiting HDACs may prevent kidney injury. The goals of this study were 1) to determine if in females there is also an increase in Hdac expression following cisplatin treatment, especially in the cortex where cisplatin is known to accumulated in proximal tubules, and 2) to determine if class I HDAC inhibition prevents kidney injury in female mice. We hypothesized that females will receive the same protection from HDAC inhibitors as males. Mice were administered either acetic acid as vehicle or the class I‐selective HDAC inhibitor, MS275, at 20 mg/kg/day, via s.c. osmotic mini pump. Three days later the mice were injected with either saline or cisplatin (15 mg/kg i.p. once), and samples collected 3 days later. Male, vehicle, saline (MVS) injected mice had similar plasma creatinine to male, MS275, saline (MMS) mice (MVS 0.13 ± 0.01 mg/dl, MMS 0.14 ± 0.01 mg/dl) and were significantly lower than male vehicle cisplatin (MVC) and male, MS275, cisplatin (MMC) mice (MMS 0.27 ± 0.07 mg/dl, MMC 0.20 ± 0.05 mg/dl, PMS275= 0.8, Pcisplatin= 0.02, PMxC= 0.6, n=5–7). In females, there were no statistically significant differences among any group (FVS 0.14 ± 0.01, FMS 0.13 ± 0.2, FVC 0.16 ± 0.03, FMC 0.28 ± 0.1 mg/dl, PMS275= 0.4, Pcisplatin= 0.2, PMxC= 0.3, n=4–7). Analysis of qPCR revealed that female mice had higher cortical expression of all Hdacs except Hdac2, and that there was a sex dependent effect of cisplatin on Hdac2, and Hdac5 expression. Immunohistochemistry also confirmed sex‐specific abundance of HDAC2 and HDAC5 in the cortex. In both sexes, cisplatin resulted in kidney injury as assessed by histological analyses, but there was no significant effect of MS275 on the number of dilated tubules, interstitial fibrosis, or loss of proximal tubule brush border. Thus, although there are sex‐dependent differences in cortical kidney HDAC expression and abundance, preventative class I HDAC inhibition did not significantly affect kidney injury, or improve kidney function in our acute nephrotoxic cisplatin model. Future experiments will determine if this is also true at more chronic time points post cisplatin injection, or whether inhibition of other HDAC classes can prevent kidney injury in males or females.Support or Funding InformationSupported by the NIH NIDDK K01DK105038, the UAB‐UCSD O'Brien Center P30 grant (DK 079337), and the UAB Pittman Scholarship to KAH.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.