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• W2051867467 abstract "One complication of diabetes is a pronounced renal cellular hypertrophy, inevitably resulting in chronic fibrotic changes. Chuang and colleagues demonstrate that hypertrophy in vitro is dependent on an increased phosphoinositide 3-kinase (PI3K) activity and is correlated with increased levels of p21WAF1/Cip1, a cell-cycle regulator that was previously associated with renal fibrosis and sclerosis from nondiabetic causes. One complication of diabetes is a pronounced renal cellular hypertrophy, inevitably resulting in chronic fibrotic changes. Chuang and colleagues demonstrate that hypertrophy in vitro is dependent on an increased phosphoinositide 3-kinase (PI3K) activity and is correlated with increased levels of p21WAF1/Cip1, a cell-cycle regulator that was previously associated with renal fibrosis and sclerosis from nondiabetic causes. The response of hypertrophy occurs in organs, such as heart, lungs, and kidneys, usually in reaction to a demand for increased work load. This reaction, in which there is an increase in total cell volume without a similar increase in total cell number, has been suggested in older literature to be maladaptive.1.Goss R.J. Hypertrophy versus hyperplasia.Science. 1966; 153: 1615-1620Crossref PubMed Scopus (90) Google Scholar Renal hypertrophy is found in several different disorders and is associated with a progressive loss of kidney function and eventual glomerular and tubulointerstitial fibrosis. Although hypertrophy may be accompanied or preceded by a period of hyperplasia,2.Young B.A. Johnson R.J. Alpers C.A. et al.Cellular events in the evolution of experimental diabetic nephropathy.Kidney Int. 1995; 47: 935-944Abstract Full Text PDF PubMed Scopus (305) Google Scholar, 3.Huang H.-C. Preisig P.A. G1 kinases and transforming growth factor-β signaling are associated with a growth pattern switch in diabetes-induced renal growth.Kidney Int. 2000; 58: 162-172Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 4.Megyesi J. Price P.M. Tamayo E. Safirstein R.L. The lack of a functional p21WAF1/CIP1 gene ameliorates progression to chronic renal failure.Proc Natl Acad Sci USA. 1999; 96: 10830-10835Crossref PubMed Scopus (100) Google Scholar chronic fibrotic changes in the kidney are preceded by hypertrophic growth.5.O’Bryan G.T. Hostetter T.H. The renal hemodynamic basis of diabetic nephropathy.Semin Nephrol. 1997; 17: 93-100PubMed Google Scholar Several in vivo models, such as the rodent models of streptozotocin-induced diabetes and renal ablation, mimic clinically observed kidney and systemic changes. A similar hypertrophic response was also observed in vitro when kidney cells were cultured in high-glucose-containing medium.6.Ziyadeh F.N. Snipes E.R. Watanabe M. et al.High glucose induces cell hypertrophy and stimulates collagen gene transcription in proximal tubule.Am J Physiol. 1990; 259: F704-F714PubMed Google Scholar, 7.Wolf G. Sharma K. Chen Y. et al.High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-β.Kidney Int. 1992; 42: 647-656Abstract Full Text PDF PubMed Scopus (327) Google Scholar, 8.Fujita H. Omori S. Ishikura K. et al.ERK and p38 mediate high-glucose-induced hypertrophy and TGF-β expression in renal tubular cells.Am J Physiol Renal Physiol. 2004; 286: F120-F126Crossref PubMed Scopus (110) Google Scholar The commitment to hypertrophic growth by kidney cells in reaction to diabetes or ablation has recently been approached by the use of gene knockout studies. Early evidence had shown that proteins associated with cell-cycle regulation and inhibition were increased in the kidney after both acute and chronic stress,9.Megyesi J. Udvarhelyi N. Safirstein R.L. Price P.M. The p53-independent activation of transcription of p21WAF1/CIP1/SDI1 after acute renal failure.Am J Physiol. 1996; 271: F1211-F1216PubMed Google Scholar,10.Kuan C.-J. Al-Douahji M. Shankland S.J. The cyclin kinase inhibitor p21Waf1, Cip1 is increased in experimental diabetic nephropathy: potential role in glomerular hypertrophy.J Am Soc Nephrol. 1998; 9: 986-993PubMed Google Scholar and that these inhibitors, transduced into kidney proximal tubular cells, caused hypertrophy.11.Terada Y. Inoshita S. Nakashima O. et al.Cell cycle inhibitors (p27Kip1 and p21CIP1) cause hypertrophy in LLC-PK1 cells.Kidney Int. 1999; 56: 494-501Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar In knockout models of one of these proteins, the p21 cyclin-dependent kinase inhibitor, hypertrophy, glomerulosclerosis, and interstitial fibrosis did not develop after partial renal ablation,4.Megyesi J. Price P.M. Tamayo E. Safirstein R.L. The lack of a functional p21WAF1/CIP1 gene ameliorates progression to chronic renal failure.Proc Natl Acad Sci USA. 1999; 96: 10830-10835Crossref PubMed Scopus (100) Google Scholar and glomerular hypertrophy did not occur in streptozotocin-treated mice.12.Al-Douahji M. Brugarolas J. Brown P.A.J. et al.The cyclin kinase inhibitor p21WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy.Kidney Int. 1999; 56: 1691-1699Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Thus it may be concluded that the hyperplastic increase in kidney cells observed in these models was not detrimental, but that hypertrophic growth was maladaptive. Preventive intervention in the p21-induced hypertrophic response may be possible if this pathway can be further elucidated and potential targets identified. Chuang et al.13.Chuang T.-D. Guh J.-Y. Chiou S.-J. et al.Phosphoinositide 3-kinase is required for high glucose-induced hypertrophy and p21WAF1 expression in LLC-PK1 cells.Kidney Int. 2007; 71: 867-874Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar (this issue), using LLC-PK1 cells, a porcine kidney proximal tubule-derived cell line, show that the hypertrophic response to culture in high-glucose medium is dependent on an increase in phosphoinositide 3-kinase (PI3K) activity, and as in other studies, hypertrophy was also associated with elevated p21. Inhibition of PI3K not only ameliorated hypertrophy but also lowered p21 levels. So can these two proteins, one an inhibitor of cell-cycle kinases, and the other a kinase activator of the oncoprotein Akt, have a common pathway that ultimately results in cellular hypertrophy? More than 500 protein kinases are encoded by the human genome. The functions of many are known, and these enzymes control protein expression and degradation and protein function, localization, and interactions. These kinases direct the function of the cell and, ultimately, its life and death. It is not surprising, therefore, that the fate of cells in the kidney, and the fate of the kidney as an organ, are also controlled by protein kinases. The p21 protein is a member of a family of proteins that inhibit the cyclin-dependent kinases responsible for progression through DNA synthesis and mitosis during the cell cycle. It is constitutively expressed at low levels and is usually localized to the nucleus. Its inhibitory activity and the finding that p21 is highly upregulated after DNA damage and other types of cellular stress led to the proposal that these inhibitors control the cell cycle, either allowing or inhibiting cell replication. The ‘regulation’ imposed on the cell cycle by p21 makes it possible for cells under various types of stress, many of which elevate p21, to interrupt replication and division until the stress is relieved and p21 returns to lower levels. On the other hand, the upregulation of p21 could work against this system unless the load is reduced. The inability to undergo cell division coupled with the stress imposed on an organ by increased work load may result in increased size by hypertrophy. This reaction is likely to be regulated by both the cell type and the extent of stress encountered. PI3K promotes cell-cycle activity by several different pathways, including inhibition of proteins that repress cell division and activation of proteins that stimulate replication. After activation, PI3K phosphorylates a phosphoinositide intermediate, allowing Akt, a downstream effector of PI3K, to be recruited and activated. Although many pathways are initiated by PI3K, the Akt pathway in particular is relevant to cell growth. As was first noted in Drosophila,14.Verdu J. Buratovich M.A. Wilder E.L. Birnbaum M.J. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB.Nat Cell Biol. 1999; 1: 500-506Crossref PubMed Scopus (302) Google Scholar overexpression of Dakt1 (the fly homologue of human Akt) caused cellular and organ hypertrophy, whereas disruption of the Dakt1 gene caused a significant decrease in size. This effect was also noted in knockout and overexpressing transgenic mice (cited by Shiojima et al.15.Shiojima I. Walsh K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway.Genes Dev. 2006; 20: 3347-3365Crossref PubMed Scopus (270) Google Scholar), even though the Akt gene in higher vertebrates is redundant (there are three Akt genes), and the effect of loss of one gene can be at least partially compensated for by the other genes. Chuang et al.13.Chuang T.-D. Guh J.-Y. Chiou S.-J. et al.Phosphoinositide 3-kinase is required for high glucose-induced hypertrophy and p21WAF1 expression in LLC-PK1 cells.Kidney Int. 2007; 71: 867-874Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar correlated the activation of PI3K, Akt, and elevated p21 with hypertrophic growth of cells in high-glucose medium. Hypertrophy in their study was measured by an increased protein–DNA ratio. Inhibition of PI3K, either by the drug LY294002 or by transfection of a dominant-negative plasmid that inhibits the regulatory subunit (p85) of PI3K, lessened both hypertrophy and the level of p21. The increase in p21 protein was probably because of transcriptional upregulation, since the measured half-life of both p21 protein and mRNA actually decreased in cells grown in high-glucose medium, while the activity of the p21 promoter increased severalfold in high-glucose medium. Whether the hypertrophic growth was because of the effect of PI3K on p21 levels or was independent of p21 was not investigated. It is possible to speculate, because of Chuang and colleagues' finding of transcriptional regulation of the p21 promoter,13.Chuang T.-D. Guh J.-Y. Chiou S.-J. et al.Phosphoinositide 3-kinase is required for high glucose-induced hypertrophy and p21WAF1 expression in LLC-PK1 cells.Kidney Int. 2007; 71: 867-874Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar that PI3K either directly or indirectly activated p21 promoter-interacting transcription factors, which were responsible for the increased level of p21 protein, resulting in hypertrophy. PI3K and Akt were previously shown to activate several transcription factors,16.García Z. Kumar A. Marqués M. et al.Phosphoinositide 3-kinase controls early and late events in mammalian cell division.EMBO J. 2006; 25: 655-661Crossref PubMed Scopus (106) Google Scholar but whether these or other undetermined PI3K-dependent proteins can modulate p21 promoter activity remains to be determined. On the other hand, Akt was shown in other studies to phosphorylate p21 at a region that dissociated it from its normally inhibitory binding of PCNA, a DNA polymerase subunit necessary for DNA synthesis, while at the same time promoting p21 translocation from the nucleus into the cytoplasm.17.Zhou B.P. Liao Y. Xia W. et al.Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells.Nat Cell Biol. 2001; 3: 245-252Crossref PubMed Scopus (876) Google Scholar These results demonstrate that the p21 and PI3K pathways intersect in at least two ways: first, by PI3K-dependent induction of p21 transcription, and second, by direct interaction between Akt and p21. Although these intersections may be sufficient to explain the dependence of hypertrophy on PI3K, p21 has roles beyond that of cell-cycle inhibition depending on the cellular stress and environment. One of the original descriptions of p21 was as an inducer of cellular senescence,18.Noda A.F. Ning Y. Venable S. et al.Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen.Exp Cell Res. 1994; 211: 90-98Crossref PubMed Scopus (1294) Google Scholar and p21 deletion was shown to prolong the lifespan of telomerase-deficient cells and mice,19.Choudhury A.R. Ju Z. Djojosubroto M.W. et al.Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation.Nat Genet. 2007; 39: 99-105Crossref PubMed Scopus (331) Google Scholar a condition associated with shortened lifespan in humans and in mice. Coincidently, p21 but not p16 (another cyclin-dependent inhibitor) was found to be involved in telomere shortening-induced senescence of human cells,20.Herbig U. Jobling W.A. Chen B.P.C. et al.Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53 and p21CIP1, but not p16INK4a.Mol Cell. 2004; 14: 501-513Abstract Full Text Full Text PDF PubMed Scopus (886) Google Scholar and transduction of p21 but not of p16 caused hypertrophy in renal proximal tubule cells.11.Terada Y. Inoshita S. Nakashima O. et al.Cell cycle inhibitors (p27Kip1 and p21CIP1) cause hypertrophy in LLC-PK1 cells.Kidney Int. 1999; 56: 494-501Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Perhaps the consequences of renal hypertrophy and the fibrotic changes associated with aging are both controlled by the same PI3K/Akt/p21 pathways. These possibilities should be fruitful areas for future investigations. In summary (Figure 1), both p21 and the PI3K/Akt pathways have been shown to be associated with cellular and organ hypertrophy. The work of Chuang et al.13.Chuang T.-D. Guh J.-Y. Chiou S.-J. et al.Phosphoinositide 3-kinase is required for high glucose-induced hypertrophy and p21WAF1 expression in LLC-PK1 cells.Kidney Int. 2007; 71: 867-874Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar reiterates this concept and at the same time shows that these pathways may be mutually interdependent. More work is needed to support these interactions and to elucidate fully the pathway of hypertrophy. At the same time, however, this work has pointed out possible intervention strategies, by PI3K/Akt inhibition, to ameliorate hypertrophy." @default.
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• W2051867467 title "Diabetes: Caught in the Akt?" @default.
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