AMP-activated protein kinase (AMPK), particularly AMPK-α2 isoform, can attenuate the nephropathic pathogenesis by improving lipid metabolism. The objective of the present study was to define if sulforaphane (SFN) can protect type 2 diabetes (T2D)-induced nephropathy (DN) by activating AMPKα2 and Nrf2-mediated anti-oxidative pathways. AMPKα2 knockout (AMPKα2-KO) mice and their wild type (WT, C57BL/6J) mice were fed high-fat diet (HFD) for 3 months to induce insulin resistance, followed by an i.p. injection of streptozotocin (STZ) to induce hyperglycemia, i.e.:T2D. Control mice were fed normal diet without STZ. T2D and control mice were treated with or without SFN for 3 months and then stop SNF treatment, remained feeding either ND or HFD. These mice were collected 24-hour urine and then sacrificed at 3 and 6 months after diabetes onset to collect kidney’s tissue for pathological examination and molecular assays. Proteinuria was significantly increased in T2D mice at 3 and 6 months, but not in SFN-treated T2D mice. The destruction of kidney structure induced by T2D, including renal fibrosis, lipotoxicity, inflammation, oxidative stress/damage along with significant suppression of AMPK signaling pathways was prevented by SFN in WT diabetic mice. Specifically, T2D-induced, time-dependent from 3 to 6 months, increased accumulation of FN and COL-1, increased expression of TGF-β PAI-1, TNF-α and decreased phosphorylation of AMPKα and its downstream markers (ACC, CPT1-A, Sirt-1, PGC1α, PPARα, and Nrf2). All these pathogenic changes were prevented by SFN in WT diabetic mice, which was more at 6 months compared to 3 months. However, in AMPKα2-KO mice, suggesting that all these are AMPK-dependent. Therefore, the present study suggests that SFN protects against T2D-induced DN via AMPKα2-mediated improvement of lipid metabolisms and up-regulation of Nrf2-mediated anti-oxidative defense system.
Z. Li: None. L. Cai: None. Y. Sun: None.
