title: Astragaloside IV Attenuates Podocyte Apoptosis Mediated by Endoplasmic Reticulum Stress through Upregulating Sarco/Endoplasmic Reticulum Ca2+-ATPase 2 Expression in Diabetic Nephropathy.
abstract: Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) plays a central role in the pathogenesis of diabetes. This protein has been recognized as a potential target for diabetic therapy. In this study, we identified astragaloside IV (AS-IV) as a potent modulator of SERCA inhibiting renal injury in diabetic status. Increasing doses of AS-IV (2, 6, and 18 mg kg-1day-1) were administered intragastrically todb/dbmice for 8 weeks. Biochemical and histopathological approaches were conducted to evaluate the therapeutic effects of AS-IV. Cultured mouse podocytes were used to further explore the underlying mechanismin vitro. AS-IV dose-dependently increased SERCA activity and SERCA2 expression, and suppressed ER stress-mediated and mitochondria-mediated apoptosis indb/dbmouse kidney. AS-IV also normalized glucose tolerance and insulin sensitivity, improved renal function, and ameliorated glomerulosclerosis and renal inflammation indb/dbmice. In palmitate stimulated podocytes, AS-IV markedly improved inhibitions of SERCA activity and SERCA2 expression, restored intracellular Ca2+homeostasis, and attenuated podocyte apoptosis in a dose-dependent manner with a concomitant abrogation of ER stress as evidenced by the downregulation of GRP78, cleaved ATF6, phospho-IRE1α and phospho-PERK, and the inactivation of both ER stress-mediated and mitochondria-mediated apoptotic pathways. Furthermore, SERCA2b knockdown eliminated the effect of AS-IV on ER stress and ER stress-mediated apoptotic pathway, whereas its overexpression exhibited an anti-apoptotic effect. Our data obtained fromin vivoandin vitrostudies demonstrate that AS-IV attenuates renal injury in diabetes subsequent to inhibiting ER stress-induced podocyte apoptosis through restoring SERCA activity and SERCA2 expression.
authors.affiliation: Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Hengjiang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Aili
authors.initials: A
authors.lastname: Cao
authors.affiliation: Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Chu
authors.affiliation: Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Yunman
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Experimental Research Center, Putuo Hospital, Shanghai University of Traditional Chinese Medicine Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University Shanghai, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese MedicineShanghai, China; Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese MedicineShanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Peng
keywords: astragaloside IV; diabetic nephropathy; endoplasmic reticulum stress; podocyte apoptosis; sarco/endoplasmic reticulum Ca2+-ATPase 2