title: Insulin deficiency induces rat renal mesangial cell dysfunction via activation of IGF-1/IGF-1R pathway.
abstract: OBJECTIVE
  Diabetic nephropathy is one of the major complications of diabetes and the major cause of end-stage renal disease. In this study we investigated the insulin deficiency (ID) induced changes in renal mesangial cells (MCs) and in the kidney of STZ-induced diabetic rats.
  
  
  METHODS
  Cultured rat renal MCs were incubated in ID media. Cell proliferation was analyzed using BrdU incorporation assay. The expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), phosphorylated IGF-1R, fibronectin, and collagen IV was determined with Western blot analysis. STZ-induced diabetic rats were treated with an IGF-1R antagonist picropodophyllin (PPP, 20 mg·kg(-1)·d(-1), po) for 8 weeks. After the rats were euthanized, plasma and kidneys were collected. IGF-1 levels in renal cortex were measured with RT-PCR or ELISA. The morphological changes in the kidneys were also examined.
  
  
  RESULTS
  Incubation in ID media significantly increased cell proliferation, the synthesis of fibronectin and collagen IV, and the expression of IGF-1 and IGF-1R and phosphorylated IGF-1R in renal MCs. Pretreatment of the cells with PPP (50 nmol/L) blocked ID-induced increases in cell proliferation and the synthesis of fibronectin and collagen IV; knockdown of IGF-1R showed a similar effect as PPP did. In contrast, treatment of the cells with IGF-1 (50 ng/mL) exacerbated ID-induced increases in cell proliferation. In the kidneys of diabetic rats, the expression of IGF-1, IGF-1R and phosphorylated IGF-1R were significantly elevated. Treatment of diabetic rats with PPP did not lower the blood glucose levels, but significantly suppressed the expression of TGF-β, fibronectin and collagen IV in the kidneys, the plasma levels of urinary nitrogen and creatinine, and the urinary protein excretion.
  
  
  CONCLUSIONS
  Insulin deficiency increases the expression of IGF-1 and IGF-1R in renal MCs and the kidney of diabetic rats, which contributes to the development of diabetic nephropathy.
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Ya-li
authors.initials: YL
authors.lastname: Kong
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ni
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: De-cui
authors.initials: DC
authors.lastname: Shao
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Nai-jun
authors.initials: NJ
authors.lastname: Miao
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Jin-lan
authors.initials: JL
authors.lastname: Xu
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
authors.forename: Xiao-xia
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Li-min
authors.initials: LM
authors.lastname: Lu
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1