title: Loss of PTEN promotes podocyte cytoskeletal rearrangement, aggravating diabetic nephropathy.
abstract: In diabetic nephropathy (DN), podocyte cytoskeletal rearrangement occurs followed by podocyte effacement and the development of proteinuria. PTEN (phosphatase and tensin homologue) is a ubiquitously expressed phosphatase that plays a critical role in cell proliferation, cytoskeletal rearrangement, and motility. In mouse models of diabetes mellitus, PTEN expression is reportedly decreased in mesangial cells, contributing to expansion of the mesangial matrix, but how PTEN in the podocyte influences the development of DN is unknown. We observed that PTEN expression is down-regulated in the podocytes of diabetic db/db mice and patients with DN. In cultured podocytes, PTEN inhibition caused actin cytoskeletal rearrangement and this response was associated with unbalanced activation of the small GTPases Rac1/Cdc42 and RhoA. In mice treated with PTEN inhibitor, actin cytoskeletal rearrangement occurred in podocytes and was accompanied by increased albumin excretion. We also created mice with an inducible deletion of PTEN selectively in podocytes. These mice exhibited increased albumin excretion and moderate foot process effacement. When the mice were challenged with a high fat diet, podocyte-specific knockout of PTEN resulted in substantially increased proteinuria and glomeruloclerosis compared to control mice fed a high fat diet or mice with PTEN deletion fed a normal diet. These results indicate that PTEN is involved in the regulation of cytoskeletal rearrangement in podocytes and that loss of PTEN predisposes to the development of proteinuria and DN.
authors: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors: Jamie
authors: J
authors: Lin
authors: Nephrology Division, Second Hospital of Shanxi Medical University, Taiyuan, China.
authors: Yuanyuan
authors: Y
authors: Shi
authors: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors: Hui
authors: H
authors: Peng
authors: Renal Sections, Changhai Hospital, Shanghai, China.
authors: Xiaojie
authors: X
authors: Shen
authors: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors: Sandhya
authors: S
authors: Thomas
authors: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors: Yanlin
authors: Y
authors: Wang
authors: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
authors: Luan D
authors: LD
authors: Truong
authors: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.|Departments of Biology and Biochemistry, University of Houston, Houston, Texas, USA.
authors: Stuart E
authors: SE
authors: Dryer
authors: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.|Nephrology Division, Second Hospital of Shanxi Medical University, Taiyuan, China.
authors: Zhaoyong
authors: Z
authors: Hu
authors: Renal Sections, Changhai Hospital, Shanghai, China.
authors: Jing
authors: J
authors: Xu
mesh_terms: D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005920:Glomerular Mesangium / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse
keywords: PTEN; cytoskeletal rearrangement; diabetic nephropathy; podocyte
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