High mobility group box 1 (HMGB1) is a nuclear protein that can bind to DNA and act as a co-factor for gene transcription. When released into extracellular fluid, it plays a proinflammatory role by acting as a damage-associated molecular pattern molecule (DAMP) (also known as an alarmin) to initiate innate immune responses by activating multiple cell surface receptors such as the receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs), TLR2, TLR4 or TLR9. This proinflammatory role is now considered to be important in the pathogenesis of a wide range of kidney diseases whether they result from hemodynamic changes, renal tubular epithelial cell apoptosis, kidney tissue fibrosis or inflammation. This review summarizes our current understanding of the role of HMGB1 in kidney diseases and how the HMGB1-mediated signaling pathway may constitute a new strategy for the treatment of kidney diseases. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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. Data sources 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. Study selection 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 （cPKCI311）-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 receptodSMAD2/3 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/SPSl-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
Wang Jianglin Guo Ren Liu Shikun Chen Qingjie Zuo Shanru gang Meng Zuo Xiaocong
