Abstract
Obesity and associated diabetes (diabesity) impair kidney mitochondrial dynamics by augmenting fission and diminishing fusion, which results in mitochondrial and renal dysfunction. Based on available evidence, the antioxidant activities of melatonin may improve impaired renal mitochondrial function in obese diabetic animals by restoring the imbalanced dynamics through inhibiting fission and promoting fusion. Male Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally treated either with melatonin (10 mg/kg BW/day) (M-ZDF and M-ZL) or vehicle (C-ZDF and C-ZL) for 17 weeks. Kidney function was evaluated by measurement of total urine volume, proteinuria, creatinine clearance, and assessment of kidney mitochondrial dynamics and function. C-ZDF exhibited impaired dynamics and function of kidney mitochondria in comparison to C-ZL. Melatonin improved nephropathy of ZDF rats and modulated their mitochondrial dynamics by reducing expression of Drp1 fission marker and increasing that of fusion markers, Mfn2 and Opa1. Furthermore, melatonin ameliorated mitochondrial dysfunction by increasing respiratory control index and electron transfer chain complex IV activity. In addition, it lowered mitochondrial oxidative status. Our findings show that melatonin supplementation improves nephropathy likely via modulation of the mitochondrial fission/fusion balance and function in ZDF rats.
Highlights
Mitochondrial morphology is strongly biodynamic and varies quickly in response to cellular stress or to changed metabolic demand [1]
Mitochondrial fission is controlled by dynamin-related protein 1 (Drp1), while mitochondrial fusion involves mitofusin 2 (Mfn2) and optic atrophy protein type 1 (OPA1) [2,3]
Studies in different animal models reveal that mitochondrial impairment is characterized by dynamic imbalance, reduced oxidative phosphorylation (OXPHOS) capacity, mitophagy and creating a mitochondrial prooxidant state, which worsens the renal function in obesity and diabetes
Summary
Mitochondrial morphology is strongly biodynamic and varies quickly in response to cellular stress or to changed metabolic demand [1]. Rodents with genetic mutilation of fusion markers (Mfn and OPA1) suppressed OXPHOS and insulin-stimulated ATP synthesis and caused a dysregulation of glucose homeostasis and insulin signaling, which leads to an impairment of the of obese-related insulin resistance and diabetes [14,15] All these reports emphasize the functions of mitochondrial dynamics in the control of mitochondrial function, glucose metabolism and insulin signaling, and in the progression to diabesity and its nephropathy. The ZDF rat is extensively used as a diabesity model because it recapitulates the pathogenesis and evolution of human type 2 diabetes mellitus (T2DM) It exhibits insulin resistance, and increased meta-inflammatory and prooxidative status, with hyperlipidemia and progressive nephropathy [27,28,29,30,31]. This work determined whether chronic in vivo melatonin treatment alleviates nephropathy induced by diabesity through improvement of kidney mitochondrial dynamics and functions in diabetic obese ZDF rats
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