The Lack of Cyclin Kinase Inhibitor p27Kip1 Ameliorates Progression of Diabetic Nephropathy

Awazu, Midori; Omori, Sayu; Ishikura, Kenji; Hida, Mariko; Fujita, Haruhisa

doi:10.1097/01.asn.0000051726.41601.c0

Cited by 80 publications

(91 citation statements)

References 36 publications

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“…Zheng et al (5) found that mesangial cells isolated from kidneys of postmenopausal mice were enlarged and had elevated amounts of p27 kip1 protein expression as assessed by immunochemistry. Other studies (35)(36)(37) also showed that p21 cip1 and p27 kip1 were required for retinoblastoma protein-mediated senescence, demonstrating not only that p21 cip1 and p27 kip1 gene transfer could promote cell senescence but also that antisense p21 cip1 and p27 kip1 had some effects on retarding the progress of cell hypertrophy or senescence. Our results showed that Cx43 knockdown significantly increased p21 cip1 and p27 kip1 expression in GMC, whereas Cx43 gene overexpression decreased p21 cip1 and p27 kip1 protein levels in GMC cultured in high glucose, indicating that Cx43 could control cell proliferation and senescence progression through cell-cycle regulation.…”

Section: Discussionmentioning

confidence: 90%

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Zhang

Chen

et al. 2006

Journal of the American Society of Nephrology

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Connexin 43 (Cx43) plays an important role in cell differentiation and growth control, but whether it can be regulated by high glucose and whether it can mediate in glomerular mesangial cells (GMC) the phenotype alterations that are induced by high glucose still remain to be explored. In this study, RNA interference and gene transfer techniques were used to knock down and overexpress Cx43 gene in rat GMC to determine the contribution of Cx43 to GMC senescence that was induced by high glucose. The results show that high glucose (30 mM) not only downregulated Cx43 mRNA and protein expression (P < 0.05) but also increased the percentage of senescence-associated ␤-galactosidase (SA-␤-gal) stained cells and expression of p21 cip1 and p27 kip1 (P < 0.05), indicating that high glucose promoted rat GMC senescence. Knocking down Cx43 gene expression significantly increased the percentage of SA-␤-gal stained cells and p27 kip1 and p21 cip1 expression in GMC (P < 0.05), whereas overexpression of Cx43 significantly decreased the percentage of SA-␤-gal stained cells (P < 0.05). These results demonstrate for the first time that downregulation of Cx43 expression by high glucose promotes the senescence of GMC, which may be involved in the pathogenesis of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 90%

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Zhang

Chen

et al. 2006

Journal of the American Society of Nephrology

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“…Furthermore, treatment of BBdp rats, a model of autoimmune diabetes mellitus Type 1, with angiotensin-converting enzyme inhibitors reduced the glomerular expression of p27 Kip1 and this was accompanied by a decrease in renal hypertrophy [20]. In addition, p21 Cip1 -/- [21] and p27 Kip1 -/- [22] mice are protected to some extent of the development of morphological and functional changes of diabetic nephropathy. These studies clearly show a pivotal role for these specific CDK-inhibitors in the development of glomerular hypertrophy of diabetes mellitus.…”

Section: Discussionmentioning

confidence: 96%

Erk 1,2 phosphorylates p27 Kip1 : Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells

et al. 2003

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Aims/hypothesis. Mesangial cell hypertrophy is one of the earliest morphological abnormalities of diabetic nephropathy. We have previously shown that high glucose induces p27 Kip1 by a post-transcriptional mechanism and that mesangial cell hypertrophy depends on G 1 -phase arrest mediated by this CDK-inhibitor. However, it remains poorly understood how high glucose stimulates p27 Kip1 expression in mesangial cells. Methods. Mesangial cells were isolated from p27 Kip1 +/+ and -/-mice and characterized by light microscopy and immunohistochemistry. It was tested by Western blotting and autoradiography whether high glucose medium activates Erk 1,2 and whether this activation phosphorylates p27 Kip1 . The three consensus phosphorylation sites of p27 Kip1 were mutated and these constructs were expressed in p27 Kip1 -/-mesangial cells. Hypertrophy was assessed by different methods.Results. High glucose stimulates phosphorylation of MAP kinases Erk 1,2 in p27 Kip1 +/+ and -/-mesangial cells. Activation of Erk 1,2 leads to phosphorylation of p27 Kip1 in vitro and in vivo . Mutations of serine 10 or threonine 187 still supported high glucose-induced hypertrophy. In contrast, a mutation of serine 178 converted the hypertrophic response into a proliferative phenotype. Mutation of serine 178 leads to the attenuated expression of p27 Kip1 protein in the presence of high glucose. Conclusions/interpretation. Our study shows that high glucose stimulates Erk 1,2 that phosphorylate p27 Kip1 at serine 178 increasing its expression. This is an important molecular mechanism of high glucose-induced hypertrophy of mesangial cells. [Diabetologia (2003[Diabetologia ( ) 46:1090[Diabetologia ( -1099

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“…It has also been reported that MC isolated from p27 Ϫ/Ϫ mice did not undergo cellular hypertrophy under high glucose conditions (25,26). More recently, the significance of p27 in the progression of diabetic nephropathy in vivo has also been established (44). However, the underlying upstream mediators of Ang II-induced MC hypertrophy are not fully identified.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27

Zeng¹,

Xu²,

Chew

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Recent experimental observations have suggested that statins may exert modulatory effects on a number of pathobiological processes beyond their cholesterol-lowering properties. Some of the pleiotropic effects of statins seem to be mediated by their ability to block the synthesis of isoprenoid intermediates, which serve as important lipid attachments required for the proper function and activation of the small GTP-binding proteins. The current study explored the modulatory effects of simvastatin (SMV) on the angiotensin II (Ang II)-induced Rac1-mediated, upregulation of cyclin-dependent kinase inhibitor p27. Ang II (100 nM) stimulation of rat mesangial cells induced a significant increase in p27 protein expression. Co-treatment of cells with SMV (1 M) inhibited Ang II-induced upregulation of p27 protein. Addition of mevalonate (200 M) or geranylgeranyl pyrophosphate (5 M) reversed the inhibitory effect of SMV on p27 protein expression, suggesting that the effect of SMV is geranylgeranyl dependent. This study also provides evidence for a sequential link between Ang II stimulation and downstream activation of Rac1, intracellular H 2 O 2 production, and Akt kinase leading to upregulation of p27 protein in mesangial cells. It was also shown that SMV, by inhibiting Rac1 activity, reversed Ang II-induced increase in intracellular H 2 O 2 production, Akt activation, and p27 protein expression. The data presented in this study not only elucidate Ang II-mediated signaling cascade in mesangial cells but also demonstrate for the first time the modulatory effects of SMV on Ang II-induced signaling pathway at the cell cycle level.

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The Lack of Cyclin Kinase Inhibitor p27Kip1 Ameliorates Progression of Diabetic Nephropathy

Abstract: Abstract. Cyclin kinase inhibitor p27 Kip 1

Cited by 80 publications

References 36 publications

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Erk 1,2 phosphorylates p27 Kip1 : Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells

Simvastatin Modulates Angiotensin II Signaling Pathway by Preventing Rac1-Mediated Upregulation of p27

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