Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1

Abstract

Background/Aims: Previously we have shown that activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element (ARE) attenuated hyperglycemia-induced damage in podocytes, but the molecular mechanism remains unknown. Methods: Tert-butylhydroquinone (t-BHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression, while nicotinamide and siRNAs were used to regulate sirtuin 1 (Sirt1) activity and expression, respectively. Mitochondrial superoxide, membrane potential and ATP levels were measured to assess changes in mitochondrial function. Nephrin and synaptopodin expression were measured by western blot analysis. Human podocytes and db/db diabetic mice were used in this study. Results: t-BHQ pretreatment of human podocytes exposed to high glucose (HG) alleviated mitochondrial dysfunction, enhanced the expression of Sirt1, nephrin and synaptopodin and lowered BSA permeability compared with podocytes exposed to HG without t-BHQ pretreatment (p< 0.05). Human podocytes exposed to HG had more severe mitochondrial dysfunction, lower expression of Sirt1, synaptopodin and nephrin and higher BSA permeability than podocytes exposed to HG when Nrf2 expression was downregulated by siRNAs (p< 0.05). The protection provided by activation of the Nrf-ARE pathway in podocytes exposed to HG was partially diminished when Sirt1 expression or activity was decreased by siRNAs or inhibitor compared with podocytes exposed to HG and pretreated with t-BHQ (p< 0.05). When nicotinamide and t-BHQ were both administered to db/db mice, we observed higher levels of urinary albumin/creatinine, lower nephrin and synaptopodin expression, more severe mesangial matrix deposition, collagen deposition on pathological slides and mitochondrial structural damage in podocytes compared to db/db mice treated only with t-BHQ. Conclusions: Our findings suggest that crosstalk between Sirt1 and the Nrf2-ARE anti-oxidative pathway forms a positive feedback loop and that protection provided by t-BHQ activation of the Nrf2-ARE pathway in db/db mice is partly dependent on Sirt1.

Increased long noncoding RNA maternally expressed gene 3 contributes to podocyte injury induced by high glucose through regulation of mitochondrial fission

“…5a, b ). Consistent with our previous report 19 , 20 , cultured human podocytes were injured by HG, as demonstrated by lower expression of Nephrin and Synaptopodin (Fig. 5c, e ).…”

Sirt1 inhibits HG-induced endothelial injury: Role of Mff-based mitochondrial fission and F‑actin homeostasis-mediated cellular migration

“…In the present study, the activation of Sirt1 with SRT1720 inhibited EC apoptosis and endothelial dysfunction in diabetes. Previous reports have argued that the protective endothelial effect of Sirt1 is closely associated with the regulation of mitochondrial functions by limiting mitochondrial DNA damage and preventing the activation of mitochondrial damaging MMP-9 (11,43,44). Furthermore, mitochondrial dysfunction caused by mitochondrial fission is reported to be involved in the development of diabetic nephropathy (7,45) and diabetic cardiomyopathy (46).…”

Hydrogen Sulfide Inhibits High Glucose-Induced Neuronal Senescence by Improving Autophagic Flux via Up-regulation of SIRT1

“…In the brain, SIRT1 is mainly expressed in neurons and has numerous biological functions, including regulation differentiation, metabolism, cell survival, and aging (Qadir and Anwar, 2017). It has been reported that SIRT1 activation attenuates hyperglycemia and plays an important mediatory role in treating diabetic complication (Li X. N. et al, 2017; Zhang Q. et al, 2018; Zhang Y. et al, 2018). Furthermore, SIRT1 improves autophagic flux (Zhang et al, 2016; Liu et al, 2017).…”