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.

Tanshinone IIA ameliorates diabetic cardiomyopathy by inhibiting Grp78 and CHOP expression in STZ‑induced diabetes rats

“…As a key component of S. miltiorrhiza, TSIIA has been used to treat multiple diseases, including Alzheimer's disease, chronic kidney disease, cerebral ischemic injury and DCM (23)(24)(25)(26). Furthermore, previous studies have demonstrated that TSIIA could attenuate myocardial ischemia reperfusion injury due to its antioxidant capacity (27).…”

Chinese Herbal Medicine Improves the Long-Term Survival Rate of Patients With Chronic Kidney Disease in Taiwan: A Nationwide Retrospective Population-Based Cohort Study

“…In addition, the magnesium lithospermate B isolated from SM had inhibitory effects on urine protein excretion, blood urine nitrogen, mesangial proliferation, tubule-interstitial lesion, and glomerular sclerotic change in nephrectomized rats ( Yokozawa et al, 1995 ). Another major compound, tanshinone IIA, inhibited over-activity of glycogen synthase kinase 3β to protect transition of kidney injury from acute to chronic changes ( Jiang et al, 2016 ). AM is one of the most important herbs to tonify Qi.…”

Tanshinone II Aattenuates renal damage in STZ-induced diabetic rats via inhibiting oxidative stress and inflammation

“…A large number of reports demonstrated Tan has been used for the treatment of multiple diseases, including cardiovascular disease [ 11 ], cerebral ischemia [ 12 ] and bone diseases such as osteoporosis [ 13 ]. In kidney disease, Tan not only protects against acute kidney injury [ 14 , 15 ], but also has protective effects on chronic kidney disease, including uric acid nephropathy [ 16 ], doxorubicin induced nephropathy [ 17 ], 5/6 nephrectomy induced chronic kidney disease [ 18 ] and hypothermic kidney preservation [ 19 ]. Although Kim et al [ 20 ] demonstrated that Tan exerted protective effect on the early stage of diabetic nephropathy in animal model, the mechanisms remain largely unknown.…”