Obesity is a global epidemic and has been implicated as a risk factor for end-stage renal disease. In this study, we investigated the impact of obesity in the absence of hypertension, on renal lipid accumulation, oxidative stress, mitochondrial function, and endoplasmic reticulum (ER) stress, which could play a major role in the development of obesity-induced renal dysfunction. We compared two genetic mouse models of obesity which we have shown to be normotensive, the leptin-deficient ob/ob mice and a hyperleptinemic melanocortin 4 receptor knockout mice (LoxTB MC4R-/-), to lean wild type (WT) C57BL/6J mice and littermate controls (WT-LoxTB) from LoxTB MC4R-/-breeding colony respectively. We measured urinary albumin excretion, creatinine clearance, renal triglycerides, ATP levels, state-3 mitochondrial respiration, protein carbonylation (a marker of oxidative stress) and C/EBP homologous protein (CHOP) expression (a marker of ER stress) in these mice. Our results indicate that the ob/ob mice and LoxTB MC4R-/-mice exhibit significant albuminuria, increased creatinine clearance (693±61.1 vs. 534±31.5 and 752.3±50.6 vs. 488.9±81.2 μL/min) and renal triglyceride accumulation (8.1±0.8 vs. 4.8±0.2 and 3.9±0.5 vs. 2.2±0.3 mg triglyceride/g tissue) expressed as ob/ob vs. WT and LoxTB MC4R-/- vs. WT-LoxTB respectively. Despite significant decreases in renal ATP levels (6±0.3 vs. 7.9±0.4 and 5±0.2 vs. 8±1.1 pmol/mg) in both obese models, only the LoxTB MC4R-/-mice kidneys showed an impaired state-3 fatty acid oxidation, increased protein carbonylation and 3-fold induction of CHOP protein compared to WT-LoxTB control mice. Taken together, our data suggest that obesity in the absence of hypertension cause only mild renal dysfunction, and unveils the potential involvement of oxidative stress, impaired fatty acid oxidation and ER stress in obesity-induced renal injury associated with MC4R deficiency.


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