title: Mechanisms of cyclosporine-induced renal cell apoptosis: a systematic review.
abstract: OBJECTIVE
  Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is an important cause of chronic renal dysfunction with no effective clinical intervention. To further elucidate the mechanisms of renal cell apoptosis in CCN, all relevant in vivo studies on this subject were analyzed.
  
  
  METHODS
  We searched for in vivo studies on the mechanisms of CsA-induced renal cell apoptosis in Medline (1966-July 2010), Embase (1980-July 2010) and ISI (1986-July 2010). The studies were evaluated for their quality according to a set of in vivo standards, data extracted according to PICOS, and then synthesized.
  
  
  RESULTS
  Renal cell apoptosis was an important feature of CCN and an important factor of renal dysfunction. First, CsA could upregulate Fas/Fas ligand, downregulate Bcl-2/Bcl-XL, and increase caspase-1 and caspase-3. Second, it could induce oxidative stress and damage the antioxidant defense system. Third, it could increase endoplasmic reticulum stress protein in a dose- and time-dependent manner. Fourth, CsA could impair the urine concentration and decrease the expression of hypertonicity-induced genes. Fifth, CsA-induced renal cell apoptosis was significantly decreased by blocking the angiotensin II type 1 receptor using losartan.
  
  
  CONCLUSIONS
  The in vivo mechanisms for CCN are more complex than those found in vitro. CsA can induce renal cell apoptosis using five pathways in vivo and activated caspases might be the ultimate intersection of these pathways and the common intracellular pathway mediating apoptosis. These data provide new potential points for intervention and need to be confirmed by further studies.
authors.affiliation: Key Laboratory of Transplant Engineering and Immunology of the Ministry of Health of China, West China Hospital, Sichuan University, Chengdu, PR China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xiao
authors.forename: Juan
authors.initials: J
authors.lastname: Shan
authors.forename: Chengwen
authors.initials: C
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Luo
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Shengfu
authors.initials: S
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Long
authors.forename: Youping
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016572:Cyclosporine / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007674:Kidney Diseases / Q000139:chemically induced*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine