title: The lack of cyclin kinase inhibitor p27(Kip1) ameliorates progression of diabetic nephropathy.
abstract: Cyclin kinase inhibitor p27(Kip(1)) (p27) has been shown to be upregulated in glomeruli of diabetic animals and mesangial cells cultured under high glucose. This study was an investigation of the role of p27 in the progression of diabetic nephropathy. Mice deficient in p27 (p27 -/-) and wild-type mice (p27 +/+) were studied 12 wk after diabetes induction by streptozotocin. Blood glucose and BP were comparable between diabetic p27 +/+ and p27 -/- mice. The kidney weight to body weight ratio and glomerular volume increased in diabetic p27 +/+ mice. In contrast, these parameters did not change in diabetic p27 -/- mice. Similarly, albuminuria developed in diabetic p27 +/+ mice but not in diabetic p27 -/- mice. The mesangial expansion was significantly milder in diabetic p27 -/- mice than that in diabetic p27 +/+ mice. These changes were associated with a similar increase in glomerular TGF-beta expression in diabetic p27 +/+ and p27 -/- mice. However, glomerular protein expression of fibronectin, a target of TGF-beta, increased only in diabetic p27 +/+ mice. In mesangial cells cultured from p27 +/+ mice, exposure to high glucose caused significant increases in total protein content and [(3)H]-leucine incorporation. On the other hand, high glucose caused a significant reduction in these parameters in cells from p27 -/- mice. Phosphorylation of 4E-BP1, the translation inhibitor, increased after exposure to high glucose in p27 +/+ cells. In p27 -/- cells, the level of phosphorylated 4E-BP1 was higher than that in control p27 +/+ cells and decreased under high glucose conditions. In conclusion, renal hypertrophy, glomerular hypertrophy, and albuminuria did not develop, and mesangial expansion was milder in diabetic p27 -/- mice despite glomerular TGF-beta upregulation. These results suggest that controlling p27 function may ameliorate diabetic nephropathy.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan. awazu@sc.itc.keio.ac.jp
authors.forename: Midori
authors.initials: M
authors.lastname: Awazu
authors.forename: Sayu
authors.initials: S
authors.lastname: Omori
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishikura
authors.forename: Mariko
authors.initials: M
authors.lastname: Hida
authors.forename: Hisayo
authors.initials: H
authors.lastname: Fujita
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001789:Blood Group Antigens; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D039642:Eukaryotic Initiation Factors; D005353:Fibronectins / Q000032:analysis; D005920:Glomerular Mesangium / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D007930:Leucine / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D013936:Thymidine / Q000493:pharmacokinetics; D016212:Transforming Growth Factor beta / Q000032:analysis; D014316:Tritium; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001789:Blood Group Antigens; D002352:Carrier Proteins; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D005353:Fibronectins; D010750:Phosphoproteins; D018809:Proliferating Cell Nuclear Antigen; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D014316:Tritium; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007930:Leucine; D013936:Thymidine