Histone deacetylase 9 (HDAC9) is associated with increased lysine acetylation levels in diabetic mice kidneys: a potential mechanism underlying renal impairment in type 2 diabetes

Abstract

Diabetic nephropathy is one of the major complications faced by patients with type 2 diabetes (T2DM). It is characterized by fibrosis, mesangial matrix expansion, loss of proper glomerular filtration, and marked renal vascular dysfunction. The mechanism by which diabetic milieu promotes renal dysfunction is not entirely understood. Recent studies have demonstrated that nephropathy in type 1 diabetes is correlated with high levels of renal lysine acetylation. Importantly, histone deacetylase 9 (HDAC9), a class II subclass IIa mammalian HDAC that catalyze the removal of acetyl groups from ɛ‐amino groups of lysine's, has been linked to T2DM complications. Thus, we hypothesize that T2DM increases levels of renal lysine acetylation which is associated with downregulation of HDAC9. To address our hypothesis, male fourteen‐weeks‐old db/db mice, an experimental model of T2DM, and same age‐matched heterozygous nondiabetic (ND) mice (db/m+) were utilized in this current study. As expected, db/db mice exhibited robust increase in body weight (39.8g vs. 19.5g ND, p<0.05, n=7), kidney weight (238.8mg vs. 163.9mg ND, p<0.05, n=6) and blood glucose levels (265 mg/dl vs. 104.5mg/dl ND, p<0.05, n=7). Together these results confirm the diabetic state in the model utilized. Further, to determine whether HDAC9 and lysine acetylation are altered in kidneys from diabetic mice, western blot analysis was performed. Kidneys from diabetic mice exhibited markedly increases in lysine acetylation levels (80% increase vs. ND, p<0.001, n=5), which was correlated with significant reduction in HDAC9 expression (60% reduction vs. ND, p<0.05, n=5), suggesting that decreased HDAC9 may contribute to the elevated levels of lysine acetylation. Of note, no changes in others HDAC class II subclass IIa, including HDAC4, HDAC5 and HDAC7 were found in kidneys from db/db mice. Our results demonstrate that diabetic milieu increases lysine acetylation in kidney and downregulated HDAC9 epigenetic enzyme expression. Thus, targeting HDAC9 may offer novel therapeutic strategies for treating diabetic nephropathy. Studies using overexpression of HDAC9 has been initiated to confirm the role of HDCA9 in the diabetic renal dysfunction.Support or Funding InformationNIH