title: Molecular mechanisms of FK506-induced hypertension in solid organ transplantation patients.
abstract: OBJECTIVE
  Tacrolimus (FK506) is an immunosuppressive drug, which is widely used to prevent rejection of transplanted organs. However, chronic administration of FK506 leads to hypertension in solid organ transplantation patients, and its molecular mechanisms are much more complicated. In this review, we will discuss the above-mentioned molecular mechanisms of FK506-induced hypertension in solid organ transplantation subjects.
  
  
  METHODS
  The data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed. The terms "FK506" or "tacrolimus" and "hypertension" were used for the literature search.
  
  
  METHODS
  Original articles with no limitation of research design and critical reviews containing data relevant to FK506-induced hypertension and its molecular mechanisms were retrieved, reviewed and analyzed.
  
  
  RESULTS
  There are several molecular mechanisms attributed to FK506-induced hypertension in solid organ transplantation subjects. First, FK506 binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and removes them from intracellular ryanodine receptors that induce a calcium ion leakage from the endoplasmic/sarcoplasmic reticulum. The conventional protein kinase C beta II (cPKCβII)-mediated phosphorylation of endothelial nitric oxide (NO) synthase at Thr495, which reduces the production of NO, was activated by calcium ion leakage. Second, transforming growth factor receptor/SMAD2/3 signaling activation plays an important role in Treg/Th17 cell imbalance in T cells which toget converge to cause inflammation, endothelial dysfunction, and hypertension following tacrolimus treatment. Third, the activation of with-no-K(Lys) kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus-induced hypertension. Finally, the enhanced activity of renal renin-angiotensin-aldosterone system seems to play a crucial role in the pathophysiology of FK506-induced hypertension.
  
  
  CONCLUSIONS
  FK506 plays a predominant role in the pathophysiology of hypertension in solid organ transplantation subjects.
authors.affiliation: Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
authors.forename: Jianglin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
authors.forename: Shikun
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
authors.forename: Shanru
authors.initials: S
authors.lastname: Zuo
authors.affiliation: Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China. Email: zuoxc08@126.com.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Zuo
mesh_terms: D006801:Humans; D006973:Hypertension / Q000139:chemically induced*; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016377:Organ Transplantation / Q000009:adverse effects*; D016559:Tacrolimus / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus