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      Role of mTOR in podocyte function and diabetic nephropathy in humans and mice.

      The Journal of clinical investigation

      Adaptor Proteins, Signal Transducing, Transcription Factors, physiology, genetics, deficiency, Trans-Activators, antagonists & inhibitors, TOR Serine-Threonine Kinases, therapeutic use, Sirolimus, prevention & control, physiopathology, etiology, Proteinuria, Proteins, pathology, drug effects, Podocytes, Adult, Nephrosis, Lipoid, Multiprotein Complexes, Mice, Transgenic, Mice, Knockout, Mice, Inbred ICR, Mice, Inbred C57BL, Mice, Kidney Glomerulus, Humans, Genetic Predisposition to Disease, Gene Dosage, Disease Progression, Diabetic Nephropathies, complications, Diabetes Mellitus, Experimental, Carrier Proteins, Animals

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          Abstract

          Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while dysregulation of mTOR facilitated glomerular diseases. Genetic deletion of mTOR complex 1 (mTORC1) in mouse podocytes induced proteinuria and progressive glomerulosclerosis. Furthermore, simultaneous deletion of both mTORC1 and mTORC2 from mouse podocytes aggravated the glomerular lesions, revealing the importance of both mTOR complexes for podocyte homeostasis. In contrast, increased mTOR activity accompanied human diabetic nephropathy, characterized by early glomerular hypertrophy and hyperfiltration. Curtailing mTORC1 signaling in mice by genetically reducing mTORC1 copy number in podocytes prevented glomerulosclerosis and significantly ameliorated the progression of glomerular disease in diabetic nephropathy. These results demonstrate the requirement for tightly balanced mTOR activity in podocyte homeostasis and suggest that mTOR inhibition can protect podocytes and prevent progressive diabetic nephropathy.

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          Author and article information

          Journal
          10.1172/JCI44774
          3104746
          21606591

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