Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice

Abstract

Aims/hypothesis Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor (PPAR)γ co-activator 1α (PGC-1α), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes. Methods Four groups of male C57BLKS/J db/m and db/db mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks. Results The db/db mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1-PGC-1α signalling and of the key downstream effectors, the PPARα-oestrogen-related receptor (ERR)-1α-sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/ lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling and the downstream effectors, PPARα-ERR-1α-SREBP1. Conclusions/interpretation The results suggest that resveratrol prevents diabetic nephropathy in db/db mice by the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

“…The mice were then killed and the kidneys were rapidly dissected and stored in buffered formalin (10%) for subsequent immunohistochemical analysis. Clinical variables in plasma and urine were determined as previously described [26].…”

Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1α and SOD1

“…The activation of AMPK using pharmacological ligands has been demonstrated to induce anti-inflammatory and immunosuppressive effects in a variety of cell types, and thus is potentially useful in the treatment of various diseases (7,8,16,17). A study has shown that activation of the AMPK signaling pathway by 5-aminoimidazole-4-carbox amide-1-β-D-ribofuranoside and berberine ameliorates the LPS-induced mice model of ALI (11).…”

“…The induction of PGC-1α has been shown to confer protective against oxidative stress with AMPK activation in non-pulmonary systems (16,18). Therefore, it is worthwhile to examine the expression level of PGC-1α in LPS-induced ALI.…”

Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model

“…Because AMP-activated protein kinase (AMPK) has been reported to have anti-inflammatory and antioxidative stress properties in a variety of cell types, 17,[20][21][22][23][24] we investigated the effects of Fstl1 on the AMPK signaling pathway in mesangial cells. Treatment with FSTL1 protein, at 250 ng/ml, increased the phosphorylation levels of AMPK and its downstream target acetyl-CoA carboxylase (ACC) in human mesangial cells in a time-dependent manner ( Figure 5A).…”