mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease

被引：37
作者：
Belibi, Franck
Ravichandran, Kameswaran
Zafar, Iram
He, Zhibin
Edelstein, Charles L. [1 ]
机构：
[1] Univ Colorado Denver, Div Renal Dis & Hypertens, Aurora, CO 80262 USA
来源：
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY | 2011年 / 300卷 / 01期
基金：
美国国家卫生研究院;
关键词：
cyst volume; kidney size; autosomal dominant polycystic kidney disease; AUTOSOMAL-DOMINANT; CELL-PROLIFERATION; TRANSGENIC MICE; CYST FORMATION; C-MYC; PROGRESSION; ACTIVATION; APOPTOSIS; PATHWAY; KINASE;
D O I：
10.1152/ajprenal.00129.2010
中图分类号：
Q4 [生理学];
学科分类号：
071003 ;
摘要：
Belibi F, Ravichandran K, Zafar I, He Z, Edelstein CL. mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease. Am J Physiol Renal Physiol 300: F236-F244, 2011. First published October 13, 2010; doi: 10.1152/ajprenal.00129.2010.-Rapamycin slows disease progression in the male Han: SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in female Cy/+ rats. Female Cy/+ rats were treated with rapamycin from 4 to 12 wk of age. In vehicle-treated Cy/+ rats, kidney volume increased by 40% and cyst volume density (CVD) was 19%. Phosphorylated S6 (p-S6) ribosomal protein, a marker of mTORC1 activity, was increased in Cy/+ rats compared with normal littermate controls (+/+) and decreased by rapamycin. Despite activation of mTORC1 in female Cy/+ rats, rapamycin had no effect on kidney size, CVD, number of PCNA-positive cystic tubular cells, caspase-3 activity, or the number of terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive apoptotic cells. To determine a reason for the lack of effect of rapamycin, we studied the mTORC2 signaling pathway. On immunoblot of kidney, phosphorylated (Ser(473)) Akt (p-Akt), a marker of mTORC2 activity, was increased in female Cy/+ rats treated with rapamycin. Phosphorylated (Ser(657)) PKC alpha, a substrate of mTORC2, was unaffected by rapamycin in females. In contrast, in male rats, where rapamycin significantly decreases PKD, p-Akt (Ser(473)) was decreased by rapamcyin. PKC alpha (Ser(657)) was increased in male Cy/+ rats but was unaffected by rapamycin. In summary, in female Cy/+ rats, rapamycin had no effect on PKD and proproliferative p-Akt (Ser(473)) activity was increased by rapamycin. There were differential effects of rapamycin on mTORC2 signaling in female vs. male Cy/+ rats.
引用
收藏
页码：F236 / F244
页数：9
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