Role of Ragulator in the Regulation of Mechanistic Target of Rapamycin Signaling in Podocytes and Glomerular Function

被引:17
作者
Yao, Yao [1 ]
Wang, Junying [1 ]
Yoshida, Sei [1 ,2 ]
Nada, Shigeyuki [5 ]
Okada, Masato [5 ]
Inoki, Ken [1 ,3 ,4 ]
机构
[1] Univ Michigan, Inst Life Sci, Room 6183A,210 Washtenow Ave, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA
[5] Osaka Univ, Microbial Dis Res Inst, Dept Oncogene Res, Osaka, Japan
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2016年 / 27卷 / 12期
基金
美国国家卫生研究院;
关键词
ENDOPLASMIC-RETICULUM STRESS; CHRONIC KIDNEY-DISEASE; DIABETIC-NEPHROPATHY; MAMMALIAN TARGET; RAG GTPASES; MTOR; PROTEINURIA; INSULIN; ACTIVATION; SIROLIMUS;
D O I
10.1681/ASN.2015010032
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Aberrant activation of mechanistic target of rapamycin complex 1 (mTORC1) in glomerular podocytes leads to glomerular insufficiency and may contribute to the development of glomerular diseases, including diabetic nephropathy. Thus, an approach for preventing mTORC1 activation may allow circumvention of the onset and progression of mTORC1-dependent podocyte injury and glomerular diseases. mTORC1 activation requires inputs from both growth factors and nutrients that inactivate the tuberous sclerosis complex (TSC), a key suppressor of mTORC1, on the lysosome. Previous studies in mice revealed that the growth factor-phosphatidylinositol 3-kinase pathway and mTORC1 are essential for maintaining normal podocyte function, suggesting that direct inhibition of the phosphatidylinositol 3-kinase pathway or mTORC1 may not be an ideal approach to sustaining physiologic podocyte functions under certain disease conditions. Here, we report the role of the Ragulator complex, which recruits mTORC1 to lysosomes in response to nutrient availability in podocytes. Notably, podocytes lacking Ragulator maintain basal mTORC1 activity. Unlike podocyte-specific mTORC1-knockout mice, mice lacking functional Ragulator in podocytes did not show abnormalities in podocyte or glomerular function. However, aberrant mTORC1 activation induced by active Rheb in podocyte-specific TSC1-knockout (podo-TSC1 KO) mice did require Ragulator. Moreover, ablation of Ragulator in the podocytes of podo-TSC1 KO mice or streptozotocin-induced diabetic mice significantly blocked the development of pathologic renal phenotypes. These observations suggest that the blockade of mTORC1 recruitment to lysosomes may be a useful clinical approach to attenuate aberrant mTORC1 activation under certain disease conditions.
引用
收藏
页码:3653 / 3665
页数:13
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