title: Rescue therapy with Tanshinone IIA hinders transition of acute kidney injury to chronic kidney disease via targeting GSK3β.
abstract: Acute kidney injury (AKI) remains challenging for clinical practice and poses a risk of developing progressive chronic kidney disease (CKD) with no definitive treatment available yet. Tanshinone IIA, an active ingredient of Chinese herbal Salvia miltiorrhiza, has been widely used in Asia for the remarkable organoprotective activities. Its effect on established AKI, however, remains unknown. In mice with folic acid-induced AKI, delayed treatment with Tanshinone IIA, commenced early or late after injury, diminished renal expression of kidney injury markers, reduced apoptosis and improved kidney dysfunction, concomitant with mitigated histologic signs of AKI to CKD transition, including interstitial fibrosis and tubular atrophy, and with an ameliorated inflammatory infiltration in tubulointerstitium and a favored M2-skewed macrophage polarization. Mechanistically, Tanshinone IIA blunted glycogen synthase kinase (GSK)3β overactivity and hyperactivation of its downstream mitogen-activated protein kinases that are centrally implicated in renal fibrogenesis and inflammation. Inhibition of GSK3β is likely a key mechanism mediating the therapeutic activity of Tanshinone IIA, because sodium nitroprusside, a GSK3β activator, largely offset its renoprotective effect. In confirmatory studies, rescue treatment with Tanshinone IIA likewise ameliorated ischemia/reperfusion-induced kidney destruction in mice. Our data suggest that Tanshinone IIA represents a valuable treatment that improves post-AKI kidney salvage via targeting GSK3β.
authors.affiliation: Department of Nephrology, Affiliated Nanjing Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, China.|Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
authors.forename: Chunming
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Nephrology, Affiliated Nanjing Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Urology, Affiliated Nanjing Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Nephrology, Affiliated Nanjing Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Qiuyuan
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Department of Cardiology, Affiliated Nanjing Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Nephrology, Affiliated Nanjing Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
mesh_terms: D045784:Abietanes / Q000627:therapeutic use*; D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D005492:Folic Acid / Q000633:toxicity; D000071679:Glycogen Synthase Kinase 3 beta / Q000187:drug effects* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000473:pathology; D051379:Mice
chemical_list: D045784:Abietanes; C021751:tanshinone; D005492:Folic Acid; D000071679:Glycogen Synthase Kinase 3 beta