HDAC6 is involved in diabetic nephropathy by regulating TGFβ/Smads and NF-κB signaling pathways.

Histone deacetylase 6 (HDAC6), a cytoplasmic member of the histone deacetylase family, plays an incompletely understood role in diabetic nephropathy (DN). While the TGF-β/Smads and NF-κB signaling pathways are established mediators of renal fibrosis and inflammation respectively, the potential regulatory effect of HDAC6 on these pathways in DN remains to be elucidated. Notably, Smad7 has been documented as a negative regulator of both TGF-β/Smads and NF-κB signaling pathways. This study utilized high glucose to establish a diabetic cell model and employed a high-fat diet combined with STZ injection to create a diabetic animal model to explore HDAC6's role in DN and its potential mechanism. Our research indicates that HDAC6 is upregulated in DN, and inhibiting HDAC6 activity with ACY1215 or downregulating HDAC6 expression with siRNA can suppress the TGF-β/Smads and NF-κB signaling pathways, thereby reducing renal fibrosis and inflammation. Moreover, further studies have shown that lentivirus-mediated overexpression of HDAC6 results in increased expression of FN and p-Smad2/3, decreased expression of Smad7 compared to their respective controls. ACY1215, an HDAC6 inhibitor, could alleviate DN by suppression of both the TGF-β/Smads and NF-κB signaling pathways. To sum up, this study reveals that HDAC6 is involved in the pathogenesis and progression of DN. Mechanistically, HDAC6 may participate in DN by regulating the TGF-β/Smads and NF-κB signaling pathways through Smad7.