Abstract
Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARα expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-estrogen-related receptor (ERR)-1α-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1α-ERR-1α, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1α-ERR-1α-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy.
Highlights
Diabetic nephropathy an important and serious complication of diabetes is the most common and most rapidly growing cause of end-stage renal disease creating an enormous expense associated with renal replacement therapy [1]
This study demonstrates that diabetic nephropathy is associated with an increase in renal lipid accumulation, apoptotic renal injury and oxidative stress which are related to a decreased level of Peroxisome proliferator-activated receptor-a (PPARa) expression in diabetic mice
These changes lead to the inactivation of AMPK-PGC-1a-estrogen-related receptor (ERR)-1a signaling and the deregulation of their target molecules, sterol regulatory element-binding protein (SREBP)-1, carbohydrate regulatory element-binding protein (ChREBP)-1 and PI3KAkt-FoxO3a, which subsequently result in an increase in oxidative stress in the kidney
Summary
Diabetic nephropathy an important and serious complication of diabetes is the most common and most rapidly growing cause of end-stage renal disease creating an enormous expense associated with renal replacement therapy [1]. Several investigators have shown accumulation of lipids in the kidneys of diabetic humans and experimental models, and have proposed that lipotoxicity and oxidative stress may play an important role in the pathogenesis of diabetic kidney disease, the underlying molecular mechanisms remain elusive [4,5,6]. Peroxisome proliferator-activated receptor-a (PPARa) is a member of the nuclear hormone receptor superfamily of ligandactivated transcription factors and plays an important role in lipid metabolism [7] as well as sustaining the balance between energy production and utilization in tissues with a high oxidative capacity, such as the liver, kidney and heart [8]. The increased activity of sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate regulatory element binding protein-1 (ChREBP-1) and decreased activity of phosphorylated acetyl-CoA carboxylase (pACC) most likely play a role in increased free fatty acid (FFA) synthesis and accumulation of triglycerides (TG) in diabetic kidney disease and PPARa activation can suppress the SREBP pathway through the reduction of liver X receptor (LXR)/retinoid X receptor (RXR) formation in the liver [16]
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