High‐Fat Diet Causes Mitochondrial Dysfunction and Renal Fibrosis in Minipigs

Abstract

Obesity is a common and complex health problem which has been dramatically increasing in the world. It is also considered as an independent risk factor for chronic kidney disease. Kidney is one of the most energy‐demanding organs in the human body, which has the second highest mitochondrial content and oxygen consumption only next to the heart. The purpose of this study was to investigate the nexus between mitochondrial function and kidney injury by using dietary‐induced obese minipig model.Materials and methodsSix‐month‐old Lee‐Sung minipigs were assigned randomly into 2 groups and fed either a control diet (C) or a high‐fat diet (HFD) for six months, the kidney was collected for the analysis.ResultsCompared with C group, HFD group had heavier body weight, thicker back fat, higher plasma levels of glucose, triacylglycerol and total cholesterol. Furthermore, the biomarkers of kidney injury, including blood creatinine, urine creatinine, urine urea, and urine protein were higher in the HFD group than the C ones. A heavier kidney was observed in the HFD pigs; whereas a smaller ratio of kidney weight to body weight was found in the HFD group than C group, implying a less effective loading in the kidney function of HFD pig. In histologic section of kidney, disarranged structure and more glomerular fibrosis were observed in the HFD pigs. Moreover, HFD caused a decreased antioxidant capacity in the kidney, indicating an oxidative stress. Whether HFD caused the renal injury through mitochondrial mechanisms, we analyzed the ATP generation and found that HFD kidney displayed a lower ATP production than C group did. The mitochondrial‐related genes in kidney were analyzed as well. The mRNA expression of SIRT1, which has a role in variety of mitochondrial processes, including redox homeostasis and mitochondrial biogenesis was downregulated by HFD. PGC1‐1a, a nutritional sensor in the kidney, was inhibited by HFD, suggesting a decrease in mitochondrial biogenesis. UCP2, activated by mitochondrial ROS, was upregulated in HFD group compare with C group. The mRNA expressions of Opa1 and Fis1, markers of mitochondrial dynamics, were downregulated by HFD, suggesting a mitochondrial dysfunction.In conclusion, long term HFD feeding in Lee‐Sung minipigs induced obesity, dyslipidemia and renal injury. Mitochondrial dysfunction might partially contribute to the progression of obesity‐related renal damage.Support or Funding InformationThis study was sponsored by the Ministry of Science and Technology, Taiwan (MOST107‐2313‐B‐002‐049).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.