title: Inflammatory stress exacerbates lipid accumulation and podocyte injuries in diabetic nephropathy.
abstract: OBJECTIVE
  Diabetic nephropathy (DN) is a chronic inflammatory disease that is accompanied by different degrees of lipid disorders. The present study was conducted to determine whether inflammatory stress exacerbates lipid accumulation in podocytes and to investigate its underlying mechanisms in DN using in vitro and in vivo studies.
  
  
  METHODS
  We used IL-1β stimulation in podocytes in vitro and casein injections in db/db mice in vivo to induce inflammatory stress. The plasma levels of serum inflammatory cytokines were determined using an enzyme-linked immunosorbent assay. The renal pathology was evaluated using pathological staining and electron microscopy. Intracellular lipid accumulation was evaluated by Oil Red O staining and a cholesterol quantitative assay. The gene and protein expression levels of extracellular matrix proteins, biomarkers of podocyte injury, and molecules involved in the LDLr pathway were evaluated using immunofluorescence staining, real-time PCR, and western blot analysis.
  
  
  RESULTS
  Increased plasma levels of inflammatory cytokines in the casein-injected db/db mice indicated a successful induction of the inflamed DN model. The kidney morphological changes, podocyte injury, and epithelial mesenchymal transition (EMT) were more significant in casein-injected db/db mice. Moreover, inflammation increased the lipid droplet accumulation in the kidneys of db/db mice, which resulted from the increased protein expression levels of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), and SREBP-2 in the kidneys of db/db mice. The in vitro studies further demonstrated that inflammation increased the lipid accumulation in the podocytes and induced podocyte EMT, which were correlated with inflammation-mediated increases in the expression levels of LDLr, SCAP, and SREBP-2, and increased translocation of the SCAP/SREBP-2 complex from the endoplasmic reticulum to the Golgi in the podocytes.
  
  
  CONCLUSIONS
  Inflammation induced lipid accumulation and the EMT of podocytes through the dysregulation of the LDLr pathway, which contributed to podocyte injury and accelerated the progression of DN.
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, No. 87, Ding Jia Qiao Road, Nanjing City, 210009, Jiangsu Province, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, No. 87, Ding Jia Qiao Road, Nanjing City, 210009, Jiangsu Province, China. klma05@163.com.
authors.forename: Kun Ling
authors.initials: KL
authors.lastname: Ma
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, No. 87, Ding Jia Qiao Road, Nanjing City, 210009, Jiangsu Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, No. 87, Ding Jia Qiao Road, Nanjing City, 210009, Jiangsu Province, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, No. 87, Ding Jia Qiao Road, Nanjing City, 210009, Jiangsu Province, China.
authors.forename: Ze Bo
authors.initials: ZB
authors.lastname: Hu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, No. 87, Ding Jia Qiao Road, Nanjing City, 210009, Jiangsu Province, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, No. 87, Ding Jia Qiao Road, Nanjing City, 210009, Jiangsu Province, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Lu
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, No. 87, Ding Jia Qiao Road, Nanjing City, 210009, Jiangsu Province, China.
authors.forename: Xiao Liang
authors.initials: XL
authors.lastname: Zhang
authors.affiliation: Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, No. 87, Ding Jia Qiao Road, Nanjing City, 210009, Jiangsu Province, China.
authors.forename: Bi Cheng
authors.initials: BC
authors.lastname: Liu
mesh_terms: D000818:Animals; D002364:Caseins; D016207:Cytokines / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D007668:Kidney / Q000473:pathology; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D011973:Receptors, LDL / Q000378:metabolism; D013268:Stimulation, Chemical
chemical_list: D002364:Caseins; D016207:Cytokines; D053583:Interleukin-1beta; D011973:Receptors, LDL
keywords: Diabetic nephropathy; Inflammation; Low-density lipoprotein receptor; Podocytes