title: Rapamycin slows IgA nephropathy progression in the rat.
abstract: BACKGROUND
  IgA nephropathy (IgAN) is the most frequent glomerulonephritis worldwide. Different therapeutic approaches have been tested against IgAN. The present study was designed to explore the renoprotective potential of low-dose mammalian target of rapamycin (mTOR) inhibitor rapamycin in an IgAN rat model and the possible mechanism of action.
  
  
  METHODS
  After establishing an IgAN model, the rats were randomly divided into four groups: control, control with rapamycin treatment, IgAN model, and IgAN model with rapamycin treatment. Coomassie Brilliant Blue was utilized to measure 24-hour urinary protein levels. Hepatic and renal function was determined with an autoanalyzer. Proliferation was assayed via 5-bromo-2'-deoxyuridine incorporation. Real-time PCR and immunohistochemistry were utilized to detect the expression of α-SMA, collagen I, collagen III, TGF-β1 and platelet-derived growth factor. Western blotting and immunohistochemistry were performed to determine p-S6 protein levels.
  
  
  RESULTS
  Low-dose mTOR inhibitor rapamycin prevented an additional increase in proteinuria and protected kidney function in a model of IgAN. Rapamycin directly or indirectly interfered with multiple key pathways in the progression of IgAN to end-stage renal disease: (1) reduced the deposition of IgA and inhibited cell proliferation; (2) decreased the expression of fibrosis markers α-SMA and type III collagen, and (3) downregulated the expression of the profibrotic growth factors platelet-derived growth factor and TGF-β1. The expression of p-S6 was significantly elevated in IgAN rats.
  
  
  CONCLUSIONS
  The mTOR pathway was activated in IgAN rats and the early application of low-dose mTOR inhibitor rapamycin may slow the renal injury of IgAN in rats.
authors.affiliation: Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Shanxi Provincial People's Hospital, Shanxi Kidney Disease Institute, Taiyuan, PR China.
authors.forename: Jihua
authors.initials: J
authors.lastname: Tian
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoshuang
authors.initials: X
authors.lastname: Zhou
authors.forename: Yanjiao
authors.initials: Y
authors.lastname: Li
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Jiaming
authors.initials: J
authors.lastname: Li
authors.forename: Rongshan
authors.initials: R
authors.lastname: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000188:drug therapy* / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus