Diet-induced obesity in C57BL/6J mice causes increased renal lipid accumulation and glomerulosclerosis via a sterol regulatory element-binding protein-1c-dependent pathway.
Obesity and metabolic syndrome are associated with glomerulosclerosis and proteinuria, but the mechanisms are not known. The purpose of this study was to determine if there is altered renal lipid metabolism and increased expression of sterol regulatory element-binding proteins (SREBPs) in a model of diet-induced obesity. C57BL/6J mice that were fed a high fat, 60 kcal % saturated (lard) fat diet (HFD) developed obesity, hyperglycemia, and hyperinsulinemia compared with those that were fed a low fat, 10 kcal % fat diet (LFD). In contrast, A/J mice were resistant when fed the same diet. C57BL/6J mice with HFD exhibited significantly higher levels of renal SREBP-1 and SREBP-2 expression than those mice with LFD, whereas in A/J mice there were no changes with the same treatment. The increases in SREBP-1 and SREBP-2 expression in C57BL/6J mice resulted in renal accumulation of triglyceride and cholesterol. There were also significant increases in the renal expression of plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF), type IV collagen, and fibronectin, resulting in glomerulosclerosis and proteinuria. To determine a role for SREBPs per se in modulating renal lipid metabolism and glomerulosclerosis we performed studies in SREBP-1c(-/-) mice. In contrast to control mice, in the SREBP-1c(-/-) mice with HFD the accumulation of triglyceride was prevented, as well as the increases in PAI-1, VEGF, type IV collagen, and fibronectin expression. Our results therefore suggest that diet-induced obesity causes increased renal lipid accumulation and glomerulosclerosis in C57BL/6J mice via an SREBP-1c-dependent pathway.
Jiang
Tao
T
Department of Medicine, the University of Colorado Health Sciences Center, Denver, 80262, USA.
Wang
Zhuowei
Z
Proctor
Gregory
G
Moskowitz
Shevie
S
Liebman
Scott E
SE
Rogers
Thomas
T
Lucia
M Scott
MS
Li
Jinping
J
Levi
Moshe
M
D000821:Animal Feed; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology*; D007668:Kidney / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D010477:Perfusion; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D001391:Azo Compounds; D001786:Blood Glucose; D022762:CCAAT-Enhancer-Binding Proteins; D024141:Collagen Type IV; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005353:Fibronectins; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D014280:Triglycerides; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; C011049:oil red O