title: Role of Ragulator in the Regulation of Mechanistic Target of Rapamycin Signaling in Podocytes and Glomerular Function.
abstract: 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.
authors.affiliation: Life Sciences Institute.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Life Sciences Institute.
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.affiliation: Life Sciences Institute.|Department of Microbiology and Immunology.
authors.forename: Sei
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nada
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
authors.affiliation: Life Sciences Institute, inokik@umich.edu yaoyao@umich.edu.|Department of Molecular and Integrative Physiology, and.|Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Ken
authors.initials: K
authors.lastname: Inoki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D007678:Kidney Glomerulus / Q000502:physiology*; D008247:Lysosomes / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C577278:LAMTOR2 protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: diabetic glomerulopathy; glomerulopathy; nutrition; podocyte; renal cell biology; signaling