Targeting HDAC6 mitigates diabetic nephropathy through modulation of oxidative stress, inflammatory pathways, and apoptotic signaling.

Histone deacetylase 6 (HDAC6), a key regulator of non-histone protein acetylation and inflammatory signaling, has emerged as a potential therapeutic target in renal diseases. This study investigated the renoprotective effects of selective HDAC6 inhibition in streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats. Male Sprague-Dawley rats injected STZ (60 mg/kg, i.p.) to induce diabetes, followed by treatment with the selective HDAC6 inhibitors tubastatin A (TubA, 30 mg/kg/day, i.p.) or ACY-1215 (30 mg/kg/day, i.p.) for 3 weeks after confirmation of hyperglycemia. Diabetic rats exhibited significant increases in blood glucose, blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total cholesterol, and triglycerides, along with severe renal histopathological alterations. Urinary biomarkers of kidney injury, including kidney injury molecule-1 (KIM-1), selenium-binding protein 1 (SBP1), and neutrophil gelatinase-associated lipocalin (NGAL), were significantly elevated in diabetic rats and were significantly reduced following treatment with HDAC6 inhibitors. Proteomic profiling identified 159 and 167 differentially expressed proteins in the TubA/STZ and ACY-1215/STZ groups, respectively, indicating partial restoration of diabetes-associated molecular dysregulation. Mechanistically, HDAC6 inhibition restored antioxidant defenses, as evidenced by increased expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), Heme oxygenase 1 (HO-1), sirtuin-3 (SIRT3), and MnSOD, reduced oxidative stress markers including advanced glycation end-products (AGEs), malondialdehyde (MDA), and 8-Hydroxy-2-deoxyguanosine (8-OHdG), suppressed Interleukin-1 beta (IL-1β) and Interleukin 6 (IL-6), attenuated apoptosis, and inhibited fibrosis and epithelial-mesenchymal transition by modulating the expression of transforming growth factor β1 (TGF-β1), vimentin, α-smooth muscle actin (α-SMA), and E-cadherin. Collectively, these findings demonstrate that HDAC6 inhibition exerts potent renoprotective effects and represents a promising therapeutic strategy for diabetic nephropathy.