Obesity has been recognized as a major risk factor for
chronic kidney disease, but the underlying mechanism remains elusive. Here, we investigated the mechanism whereby long-term high-fat diet (HFD) feeding induces renal injury in mice. The C57BL/6 mice fed HFD for 16 weeks developed
obesity, diabetes, and kidney dysfunction manifested by
albuminuria and blood accumulation of BUN and
creatinine. The HFD-fed kidney showed marked glomerular and tubular
injuries, including prominent defects in the glomerular filtration barrier and increased tubular cell apoptosis. Mechanistically, HFD feeding markedly increased
triglyceride and
cholesterol contents in the kidney and activated lipogenic pathways for
cholesterol and
triglyceride synthesis. HFD feeding also increased oxidative stress and induced mitochondrial fission in tubular cells, thereby activating the pro-apoptotic pathway. In HK-2 and mesangial cell cultures, high
glucose,
fatty acid, and TNF-α combination was able to activate the lipogenic pathways, increase oxidative stress, promote mitochondrial fission, and activate the pro-apoptotic pathway, all of which could be attenuated by an inhibitor that depleted
reactive oxygen species. Taken together, these observations suggest that long-term HFD feeding causes kidney injury at least in part as a result of tissue
lipid accumulation, increased oxidative stress, and
mitochondrial dysfunction, which promote excess programmed cell death.