Histone deacetylase blockade improves renal function and attenuates oxidative stress in rats with cisplatin‐induced acute renal failure

Abstract

Histone deacetylase (HDAC) inhibition has been shown to prevent cytokine induction and to modulate renal disease in rodent models. We tested the hypothesis that HDAC inhibition would improve various renal and oxidative stress parameters in cisplatin (CDDP)‐induced acute renal failure (ARF). 15‐week old male Sprague‐Dawley rats (n=4 per group) were treated with the HDAC inhibitor, valproic acid (VPA; 300 mg/kg, s.c.), or vehicle, for 1 day prior to and 5 days following induction of ARF with a single 6 mg/kg injection of CDDP (or saline vehicle). At the end of 6 days, anesthetized rats underwent acute renal experiments to determine renal blood flow (RBF) and glomerular filtration rate (GFR) using PAH and inulin clearance techniques, respectively. Rats were sacrificed and kidneys removed; renal cortices were isolated for measurement of tissue and mitochondrial free radical levels using electron paramagnetic resonance spectroscopy. Tissue mRNA and protein levels of HDAC and oxidative stress genes were determined using real‐time RT‐PCR and western blot, respectively. No significant changes in mean arterial pressure (MAP) were noted among groups. VPA treatment improved RBF and GFR (p<0.05) and attenuated the higher levels of total tissue and mitochondrial ROS and tissue superoxide in ARF rats. VPA treatment also significantly decreased tissue mRNA and protein expression levels of HDAC and oxidative stress genes, and normalized ATP production and ADP/ATP ratio in rats with ARF. These findings suggest that inhibition of class I HDACs with VPA improves the renal oxidative stress and tissue and mitochondrial injury that accompany CDDP‐induced ARF. Grant support: NIH grant RO1HL080544‐01 for Dr. Joseph Francis.