Inflammatory Stress Exacerbated Mesangial Foam Cell Formation and Renal Injury via Disrupting Cellular Cholesterol Homeostasis.
Inflammation and lipids play significant roles in the progression of chronic kidney disease. This study was designed to investigate whether inflammation disrupts cellular cholesterol homeostasis and causes the lipid nephrotoxicity in vitro and in vivo, and explored its underlying mechanisms. Inflammatory stress was induced by cytokines (interleukin-1β (IL-1β); tumor necrosis factor α (TNF-α)) to human mesangial cells (HMCs) in vitro and by subcutaneous casein injection in C57BL/6J mice in vivo. The data showed that inflammatory stress exacerbated renal cholesterol ester accumulation in vitro and in vivo. Inflammation increased cellular cholesterol uptake and synthesis via upregulating the expression of low-density lipoprotein receptor (LDLr) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoA-R), while it decreased cholesterol efflux via downregulating the expression of liver X receptor alpha and ATP-binding cassette transporter A1. The increased lipid accumulation by inflammatory stress induced reactive oxygen species (ROS) and increased levels of endoplasmic reticulum (ER) stress markers (inositol-requiring protein 1 and activating transcription factor 6) in HMCs and kidneys of C57BL/6J mice. This study implied that inflammation promoted renal lipid accumulation and foam cell formation by disrupting cellular cholesterol homeostasis. Increased intracellular lipids under inflammatory stress caused oxidative stress and ER stress in vitro and in vivo which may contribute to renal injury and progression of chronic kidney disease.
Centre for Lipid Research, Key Laboratory of Metabolism on Lipid and Glucose, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
Shan
S
Zhong
Lei
L
Zhao
Qing
Q
Li
Ping
P
Yang
Zac
Z
Varghese
John F
JF
Moorhead
Yaxi
Y
Chen
Xiong Z
XZ
Ruan
D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002364:Caseins / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis; D007249:Inflammation / Q000473:pathology*; D053583:Interleukin-1beta / Q000494:pharmacology; D007668:Kidney / Q000473:pathology*; D050356:Lipid Metabolism / Q000502:physiology*; D000071518:Liver X Receptors; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011973:Receptors, LDL / Q000096:biosynthesis; D051436:Renal Insufficiency, Chronic / Q000473:pathology*; D000685:Serum Amyloid A Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D064286:ATP Binding Cassette Transporter 1; D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D002364:Caseins; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D003404:Creatinine; D006861:Hydrogen Peroxide; D006903:Hydroxymethylglutaryl CoA Reductases; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases