Melatonin Improves Mitochondrial Dynamics and Function in the Kidney of Zücker Diabetic Fatty Rats

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.

Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat

“…Given our previous findings of improved renal dysfunction outcomes with melatonin supplementation [ 36 ], we next examined whether melatonin can prevent renal structural damage. Compared with renal tissues from C–ZL rats, C–ZDF rats exhibited an early FSGS with glomerular hypertrophy, mesangial expansion, segmental mesangial hypercellularity, and capillary collapse (endocapillary) ( Figure 3 c).…”

“…The effectiveness of melatonin to reduce kidney injury and dysfunction caused by various pathological conditions, such as obesity and diabetes, has been widely investigated, and various mechanisms have been reported to underlie its beneficial effects, including anti-oxidative stress, anti-inflammatory, and anti-apoptotic mechanisms [ 16 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Our group has recently shown that melatonin improved outcomes of renal dysfunction through the modulation of mitochondrial dynamics and function in an animal model of diabesity-induced kidney injury [ 36 ]. This mechanism could not rule out the possibility that melatonin may also depend on ER stress response and its downstream signaling mechanism to limit kidney damage under conditions of obesity and associated diabetes, given that melatonin has been shown to be effective in modulating ER stress response and UPR activation in different pathological situations [ 37 , 38 , 39 ].…”

“…ZDF is an excellent animal model of human obesity-induced type 2 diabetes, recapitulating pathological features similar to that seen in human, including progressive insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, hyperlipidemia, moderate hypertension, and progressive renal injury. The ZDF rats spontaneously develop proteinuria and focal segmental glomerulosclerosis (FSGS) by 14 to 20 weeks, which ultimately lead to renal insufficiency by 22 weeks of age [ 36 , 42 , 43 , 44 , 45 , 46 ]. Our findings provide new insight into the beneficial effect of melatonin supplementation on ER stress-induced kidney damage under diabesity conditions.…”

NADH/NAD+ Redox Imbalance and Diabetic Kidney Disease

“…Indeed, dynamin-related protein 1 (Drp1), well known for its role in regulating mitochondrial fission, has been shown to be upregulated to cause mitochondrial fragmentation in DKD [ 127 , 128 , 129 ]. Conversely, mitochondrial fusion regulating proteins such as optic atrophy-1 (opa1) and mitochondrial fusion proteins, in particular, mitochondrial fusion protein 2 (Mfn2), have been shown to be down regulated to impair mitochondrial fusion in DKD [ 130 , 131 , 132 ]. This disruption of mitochondrial homeostasis is linked with redox imbalance and oxidative stress accompanied with impairment of mitochondrial membrane potential and release of apoptosis stimulating factors such as cytochrome c and apoptosis inducing factor (AIF) [ 133 , 134 , 135 , 136 ].…”

Mitochondria, Oxidative Stress, cAMP Signalling and Apoptosis: A Crossroads in Lymphocytes of Multiple Sclerosis, a Possible Role of Nutraceutics

“…Indeed, in several cell types, melatonin has been found to increase the activities of respiratory chain complexes I and IV, stimulate oxidative phosphorylation, and promote a rise in ATP level [ 187 ]. Furthermore, melatonin improves mitochondrial dynamics by reducing DRP1 expression and increasing that of fusion proteins, Mfn2 and OPA1 [ 188 ].…”