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Content Provider | World Health Organization (WHO)-Global Index Medicus |
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Author | Jiang, Lei Xu, Lingling Mao, Junhua Li, Jianzhong Fang, Li Zhou, Yang Liu, Wei He, Weichun Zhao, Allan Zijian Yang, Junwei Dai, Chunsun |
Description | Country affiliation: China Author Affiliation: Jiang L ( Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.) |
Abstract | Ras homolog enriched in brain (Rheb) is a small GTPase that regulates cell growth, differentiation, and survival by upregulating mammalian target of rapamycin complex 1 (mTORC1) signaling. The role of Rheb/mTORC1 signaling in the activation of kidney fibroblasts and the development of kidney fibrosis remains largely unknown. In this study, we found that Rheb/mTORC1 signaling was activated in interstitial myofibroblasts from fibrotic kidneys. Treatment of rat kidney interstitial fibroblasts (NRK-49F cell line) with TGFß1 also activated Rheb/mTORC1 signaling. Blocking Rheb/mTORC1 signaling with rapamycin or Rheb small interfering RNA abolished TGFß1-induced fibroblast activation. In a transgenic mouse, ectopic expression of Rheb activated kidney fibroblasts. These Rheb transgenic mice exhibited increased activation of mTORC1 signaling in both kidney tubular and interstitial cells as well as progressive interstitial renal fibrosis; rapamycin inhibited these effects. Similarly, mice with fibroblast-specific deletion of Tsc1, a negative regulator of Rheb, exhibited activated mTORC1 signaling in kidney interstitial fibroblasts and increased renal fibrosis, both of which rapamycin abolished. Taken together, these results suggest that Rheb/mTORC1 signaling promotes the activation of kidney fibroblasts and contributes to the development of interstitial fibrosis, possibly providing a therapeutic target for progressive renal disease. |
File Format | HTM / HTML |
ISSN | 10466673 |
e-ISSN | 15333450 |
DOI | 10.1681/ASN.2012050476 |
Journal | Journal of the American Society of Nephrology |
Issue Number | 7 |
Volume Number | 24 |
Language | English |
Publisher | American Society of Nephrology |
Publisher Date | 2013-06-01 |
Publisher Place | United States |
Access Restriction | Open |
Subject Keyword | Discipline Nephrology Fibroblasts Metabolism Pathology Kidney Monomeric Gtp-binding Proteins Neuropeptides Proteins Animals Cell Line Disease Models, Animal Fibrosis Immunohistochemistry Mice Drug Effects Multiprotein Complexes Signal Transduction Sirolimus Pharmacology Tor Serine-threonine Kinases Transforming Growth Factor Beta1 Research Support, Non-u.s. Gov't |
Content Type | Text |
Resource Type | Article |
Subject | Nephrology |
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