Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Abstract

Background/Aims: Hyperglycaemia stress-induced renal injury is closely associated with mitochondrial dysfunction through poorly understood mechanisms. The aim of our study is to explore the upstream trigger and the downstream effector driving diabetic nephropathy via modulating mitochondrial homeostasis. Methods: A diabetic nephropathy model was generated in wild-type (WT) mice and MAP Kinase phosphatase 1 transgenic (MKP1-TG) mice using STZ injection. Cell experiments were conducted via high-glucose treatment in the human renal mesangial cell line (HRMC). MKP1 overexpression assay was carried out via adenovirus transfection. Renal function was evaluated via ELISA, western blotting, histopathological staining, and immunofluorescence. Mitochondrial function was determined via mitochondrial potential analysis, ROS detection, ATP measurement, mitochondrial permeability transition pore (mPTP) opening evaluation, and immunofluorescence for mitochondrial pro-apoptotic factors. Loss- and gain-of-function assays for mitochondrial fragmentation were performed using a pharmacological agonist and blocker. Western blotting and the pathway blocker were used to establish the signalling pathway in response to MKP1 overexpression in the presence of hyperglycaemia stress. Results: MKP1 was downregulated in the presence of chronic high-glucose stress in vivo and in vitro. However, MKP1 overexpression improved the metabolic parameters, enhanced glucose control, sustained renal function, attenuated kidney oxidative stress, inhibited the renal inflammation response, alleviated HRMC apoptosis, and repressed tubulointerstitial fibrosis. Molecular investigation found that MKP1 overexpression enhanced the resistance of HRMC to the hyperglycaemic injury by abolishing mitochondrial fragmentation. Hyperglycaemia-triggered mitochondrial fragmentation promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway. Interestingly, MKP1 overexpression strongly abrogated mitochondrial fragmentation and sustained mitochondrial homeostasis via inhibiting the JNK-CaMKII-Fis1 pathway. After re-activation of the JNK-CaMKII-Fis1 pathway, the beneficial effects of MKP1 overexpression on mitochondrial protection disappeared. Conclusion: Taken together, our data identified the protective role played by MKP1 in regulating diabetic renal injury via repressing mitochondrial fragmentation and inactivating the JNK-CaMKII-Fis1 pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy.

Intimate Relations—Mitochondria and Ageing

“…Lack of Fis1 in either nematodes or mammalian cells is associated with only mild fission defects but aberrant morphology [ 375 ]. In a model of diabetic nephropathy, overexpression of MAP kinase Phosphatase 1 was associated with enhanced glucose control, sustained renal function, attenuated kidney oxidative stress and inhibition of the renal inflammation response [ 382 ]. This overexpression also reversed the consequences of the mitochondrial hyperfragmentation seen during hyperglycemia, (decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway).…”

“…This overexpression also reversed the consequences of the mitochondrial hyperfragmentation seen during hyperglycemia, (decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway). These effects were mediated by inhibition of a JNK-CaMKII-Fis1 pathway [ 382 ]. Zhang et al [ 383 ] generated conditional knock-out Fis1 mice to allow for specific Fis1 deletion in adult skeletal muscle.…”

Accelerated Kidney Aging in Diabetes Mellitus

“…OS contributes to aging as a result of causing increased damage to important cellular targets, increasing mutation rates, and inducing growth inhibition [ 34 ]. In diabetic kidneys, the main sources of OS include nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation [ 35 ], mitochondrial dysfunction [ 36 , 37 ], xanthine oxidase pathway abnormality, cyclooxygenase pathway dysregulation, and endothelial nitric oxide synthase uncoupling [ 38 ]. These sources of OS contribute to a range of harmful intracellular events, including DNA damage within the nucleus and mitochondria, and ultimately result in the death of renal intrinsic cells via apoptosis that ER stress and cellular senescence contribute to [ 39 , 40 ].…”

An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome

“…As mentioned above and summarized by Rusciano et al (2019) there is evidence that suggests the important role of CaMKII in many cardiac pathologies involving inflammation due its ability to enhance pro-inflammatory signaling and its responsiveness to inflammation by dysregulating the Ca 2+ balance. In the kidneys, CaMKIIβ expression is associated to aldosterone-induced fibrosis ( Park et al, 2018 ; Zhang et al, 2018 ) and also shows that the increase in mitochondrial fragmentation observed in hyperglycemia stress-mediated renal damage is due to the JNK-CaMKII-Fis1 pathway ( Zhang et al, 2018 ).…”