Abstract
Obesity is associated with perturbations in cellular energy homeostasis and consequential renal injury leading to chronic renal disease (CKD). Myo-inositol oxygenase (MIOX), a tubular enzyme, alters redox balance and subsequent tubular injury in the settings of obesity. Mechanism(s) for such adverse changes remain enigmatic. Conceivably, MIOX accentuates renal injury via reducing expression/activity of metabolic sensors, which perturb mitochondrial dynamics and, if sustained, would ultimately contribute towards CKD. In this brief communication, we utilized MIOX-TG (Transgenic) and MIOXKO mice, and subjected them to high fat diet (HFD) administration. In addition, ob/ob and ob/MIOXKO mice of comparable age were used. Mice fed with HFD had increased MIOX expression and remarkable derangements in tubular injury biomarkers. Decreased expression of p-AMPKα (phospho AMP-activated protein kinase) in the tubules was also observed, and it was accentuated in MIOX-TG mice. Interestingly, ob/ob mice also had decreased p-AMPKα expression, which was restored in ob/MIOXKO mice. Parallel changes were observed in Sirt1/Sirt3 (silent mating type information regulation 2 homolog), and expression of other metabolic sensors, i.e., PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and Yin Yang (YY-1). In vitro experiments with tubular cells subjected to palmitate-BSA and MIOX-siRNA had results in conformity with the in vivo observations. These findings link the biology of metabolic sensors to MIOX expression in impaired cellular energy homeostasis with exacerbation/amelioration of renal injury.
Highlights
Worldwide epidemic prevalence of obesity is well-known, especially in developed countries.According to the estimates of World Health Organization (WHO), by the year 2025 obesity will affect 18% of men and 21% of women worldwide, meaning that health related maladies affecting various organ systems will become major issues necessitating immediate attention and rigorous scientific investigations
Obesity can be regarded as an independent risk factor in the progression of chronic kidney disease (CKD) since it is believed to be associated with glomerular hyperfiltration, aberrant expression of certain adipokines, e.g., leptin and adiponectin, insulin resistance, activation of the renin-angiotensin-aldosterone system (RAAS), increased cellular oxidant stress and synthesis of molecules involved in the process of fibrosis, i.e., extracellular matrix (ECM) proteins [5,6]
RNA isolated from kidneys of different strains of mice was subjected to real-time polymerase chain reaction (PCR)
Summary
According to the estimates of World Health Organization (WHO), by the year 2025 obesity will affect 18% of men and 21% of women worldwide, meaning that health related maladies affecting various organ systems will become major issues necessitating immediate attention and rigorous scientific investigations In this regard, obesity has emerged as one of the major risk factors for the development of chronic renal disease in recent years [1,2]. Obesity has emerged as one of the major risk factors for the development of chronic renal disease in recent years [1,2] Compounding it are other associated factors including hypertension and diabetes, which contribute to the progression of renal injury resulting in the acceleration of chronic kidney disease (CKD) and leading to an end stage renal disorder (ESRD) [3,4,5]. Obesity can be regarded as an independent risk factor in the progression of CKD since it is believed to be associated with glomerular hyperfiltration, aberrant expression of certain adipokines, e.g., leptin and adiponectin, insulin resistance, activation of the renin-angiotensin-aldosterone system (RAAS), increased cellular oxidant stress and synthesis of molecules involved in the process of fibrosis, i.e., extracellular matrix (ECM) proteins [5,6].
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