FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2034159586> ?p ?o ?g. }

• W2034159586 endingPage "1207" @default.
• W2034159586 startingPage "1199" @default.
• W2034159586 abstract "Regulation of mesangial cell proliferation. Regardless of the source of injury, an imbalance in the control of mesangial cell proliferation appears to play a direct role in the degree of progressive renal injury and glomerulosclerosis. Some of the regulatory mechanisms include specific soluble or non-soluble extracellular factors and a complex array of receptor-mediated signals that control the progression of the cell cycle or cell death. Understanding these regulatory processes could lead to novel therapeutic strategies to alleviate or arrest proliferative glomerular disease. Regulation of mesangial cell proliferation. Regardless of the source of injury, an imbalance in the control of mesangial cell proliferation appears to play a direct role in the degree of progressive renal injury and glomerulosclerosis. Some of the regulatory mechanisms include specific soluble or non-soluble extracellular factors and a complex array of receptor-mediated signals that control the progression of the cell cycle or cell death. Understanding these regulatory processes could lead to novel therapeutic strategies to alleviate or arrest proliferative glomerular disease. In the adult organism, normally quiescent cells exhibit increased replication rates during tumorigenesis or in the tissue repair processes following injury. In the renal glomerulus, very different types of injury are able to induce local inflammatory reactions involving resident glomerular cells. Lesions may be immune mediated, infectious, toxic, mechanical, or of other etiologies. A prominent histopathological feature of many human and experimental glomerular inflammatory diseases is cellular hyperplasia in the mesangium, which is caused by proliferation of mesangial cells (MCs) and an influx of leukocytes Figure 1. In this article we discuss the pathophysiological relevance of increased MC proliferation in the context of glomerular disease progression and review some of the extracellular factors and molecular mechanisms controlling MC growth. Because proliferation of MCs in the normal adult kidney is tightly regulated with a growth rate of less than 1%[1.Pabst R. Sterzel R.B. Cell renewal of glomerular cell types in normal rats: An autoradiographic analysis.Kidney Int. 1983; 24: 626-631Abstract Full Text PDF PubMed Scopus (202) Google Scholar], quiescent MCs can be assumed to interact with no or few mitogens and/or to be protected by either down-regulation of receptors or the presence of growth-inhibitory factors maintaining the low proliferative activity. Regardless of the injurious mechanism, an imbalance in the control of MC proliferation appears to play an early and crucial role in the pathogenesis of progressive glomerular injury and glomerulosclerosis. In experimental models of nephritis, MC proliferation frequently precedes and is linked to the increase of extracellular matrix (ECM) in the mesangium and glomerulosclerosis[2.Pesce C.M. Striker L.J. Peten E. Elliot S.J. Striker G.E. Glomerulosclerosis at both early and late stages is associated with increased cell turnover in mice transgenic for growth hormone.Lab Invest. 1991; 65: 601-605PubMed Google Scholar],[3.Floege J. Burns M.W. Alpers C.E. Yoshimura A. Pritzl P. Gordon K. Seifert R.A. Bowen-Pope D.F. Couser W.G. Johnson R.J. Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model.Kidney Int. 1992; 41: 297-309Abstract Full Text PDF PubMed Scopus (391) Google Scholar]. For example, mice transgenic for the SV40 T antigen, which has growth-promoting functions, develop MC proliferation followed by progressive sclerosis[4.MacKay K. Striker L.J. Pinkert C.A. Brinster R.L. Striker G.E. Glomerulosclerosis and renal cysts in mice transgenic for the early region of SV40.Kidney Int. 1987; 32: 827-837Abstract Full Text PDF PubMed Scopus (99) Google Scholar], and mice transgenic for growth hormone ultimately develop severe progressive mesangial sclerosis. They show a fivefold increase in the3H-thymidine–labeling index of glomerular cells. Interestingly, the labeling index remained high at late time points in densely sclerotic glomeruli[2.Pesce C.M. Striker L.J. Peten E. Elliot S.J. Striker G.E. Glomerulosclerosis at both early and late stages is associated with increased cell turnover in mice transgenic for growth hormone.Lab Invest. 1991; 65: 601-605PubMed Google Scholar], indicating that increased MC turnover can be a significant feature associated with sclerosis, both at the onset and in later stages. Moreover, measures that reduce cell proliferation in glomerular disease models, such as treatment with heparin[5.Floege J. Eng E. Young B.A. Couser W.G. Johnson R.J. Heparin suppresses mesangial cell proliferation and matrix expansion in experimental mesangioproliferative glomerulonephritis.Kidney Int. 1993; 43: 369-380Abstract Full Text PDF PubMed Scopus (159) Google Scholar], low-protein diet[6.Fukui M. Nakamura T. Ebihara I. Nagaoka I. Tomino Y. Koide H. Low-protein diet attenuates increased gene expression of platelet-derived growth factor and transforming growth factor-β in experimental glomerular sclerosis.J Lab Clin Med. 1993; 121: 224-234PubMed Google Scholar], or neutralizing antibodies to platelet-derived growth factor (PDGF)[7.Johnson R.J. Raines E.W. Floege J. Yoshimura A. Pritzl P. Alpers C. Ross R. Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor.J Exp Med. 1992; 175: 1413-1416Crossref PubMed Scopus (349) Google Scholar], have been shown to reduce ECM expansion and sclerotic changes. Further evidence for the role of uncontrolled MC proliferation in the pathogenesis of glomerulosclerosis was provided by work of Pippin et al, who studied the effects of the pharmacological cdk2 inhibitor roscovitine on disease progression in mesangioproliferative anti-Thy1.1 nephritis of the rat[8.Pippin J.W. Qu Q. Meijer L. Shankland S.J. Direct in vivo inhibition of the nuclear cell cycle cascade in experimental mesangial proliferative glomerulonephritis with Roscovitine, a novel cyclin-dependent kinase antagonist.J Clin Invest. 1997; 100: 2512-2520Crossref PubMed Scopus (129) Google Scholar]. The application of the purine analogue roscovitine resulted in a significant reduction of MC proliferation and glomerular cellularity in nephritic animals. Notably, the decrease of MC replication was associated with a marked reduction of mesangial ECM accumulation and less deposition of collagen type IV, laminin, and fibronectin[8.Pippin J.W. Qu Q. Meijer L. Shankland S.J. Direct in vivo inhibition of the nuclear cell cycle cascade in experimental mesangial proliferative glomerulonephritis with Roscovitine, a novel cyclin-dependent kinase antagonist.J Clin Invest. 1997; 100: 2512-2520Crossref PubMed Scopus (129) Google Scholar]. Persistent MC hyperplasia caused by repetitive or continuous glomerular injury is thought to precede and lead to irreversible glomerular scarring and the loss of renal function. However, like in regular wound healing, the transient increase of MC proliferation presumably reflects a physiological response required for successful glomerular reconstitution and renal tissue repair. Evidence for this concept comes from observations in several types of human glomerular diseases, for example, poststreptococcal glomerulonephritis and some forms of lupus nephritis. These diseases show marked expansion of the mesangium because of MC hyperplasia, which may subsequently resolve completely once the inflammatory cause has subsided. In addition, experimental animal models of mesangiolytic injury characterized by a rapid loss of MCs, such as anti-Thy1.1 nephritis[9.Bagchus W.M. Hoedemaeker P.J. Rozing J. Bakker W.W. Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies: A sequential histological and ultrastructural study in the rat.Lab Invest. 1986; 55: 680-687PubMed Google Scholar] or Habu toxin glomerulopathy[10.Cattell V. Bradfield J.W. Focal mesangial proliferative glomerulonephritis in the rat caused by habu snake venom: A morphologic study.Am J Pathol. 1977; 87: 511-524PubMed Google Scholar], exhibit marked proliferation of MCs leading to transient MC hyperplasia and matrix accumulation. If no repetitive insult to the mesangium is added in these animals, both diseases show spontaneous repair of the glomerular tufts within a few weeks, indicating that early and pronounced MC replication may indeed be part of the physiological reconstitutive response of glomeruli to injury, such as mesangiolysis. Thus, therapeutical manipulations aiming to block MC mitogenesis could represent a double-edged sword. Although the available evidence suggests that control of overshooting MC replication is beneficial in reducing ECM accumulation, interference with reconstitutive proliferation of MCs could conceivably lead to incomplete cellular repopulation of the glomerular tuft and defective repair. Clearly, more precise markers than MC hyperplasia are needed to better characterize the dynamic nature of MC proliferation and its regulators in proliferative glomerulonephritis. This would also allow a more rational evaluation of the effects of growth-inhibitory manipulations in proliferative glomerular diseases following the loss of MCs and in chronic-progressive disease stages. Figure 2 schematically depicts two types of increased MC proliferation in response to glomerular injury. Conceptually, one can distinguish between “reconstitutive” proliferation of the remaining MCs after mesangiolysis from “nonreconstitutive” or “orthotopic” MC replication in response to activation of intact MCs, for example, by soluble growth factors. However, it should be noted that in vivo these histological features may occur simultaneously, even within the same glomerulus. Currently, the methodology is insufficient to discern the nature of the proliferative processes in glomerulonephritis. This problem is aggravated in the evaluation of human glomerular diseases because of the fact that a regular kidney biopsy specimen yields but a limited number of tissue sections with rather few glomeruli. Currently, these limitations prevent thorough and meaningful studies of glomerular cell turnover in patients. When recovery of mesangioproliferative disease occurs, how is the resolution of hypercellularity achieved? Theoretically, resolution would require the reduction of the baseline regeneration or proliferation rate and/or increased removal or death of MCs. Recent research has examined cell apoptosis, a process that uses a controlled program to achieve cell death. In glomeruli, apoptotic bodies can be found in renal biopsies from patients with proliferative glomerulonephritis[11.Harrison D.J. Cell death in the diseased glomerulus.Histopathology. 1988; 12: 679-683Crossref PubMed Scopus (88) Google Scholar]. Baker et al and Shimizu et al demonstrated that MC apoptosis is a cell clearance mechanism counterbalancing MC division in self-limited anti-Thy1.1 glomerulonephritis, thereby contributing to the resolution of glomerular hypercellularity caused by experimentally induced MC proliferation in rats[12.Baker A.J. Mooney A. Hughes J. Lombardi D. Johnson R.J. Savill J. Mesangial cell apoptosis: The major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis.J Clin Invest. 1994; 94: 2105-2116Crossref PubMed Scopus (395) Google Scholar],[13.Shimizu A. Kitamura H. Masuda Y. Ishizaki M. Sugisaki Y. Yamanaka N. Apoptosis in the repair process of experimental proliferative glomerulonephritis.Kidney Int. 1995; 47: 114-121Abstract Full Text PDF PubMed Scopus (176) Google Scholar]. In these experiments, mitotic and apoptotic cells were detected in the same glomerulus, suggesting that both processes can occur simultaneously. Although these studies imply a beneficial role of apoptosis as a mechanism leading to the reduction of MC hyperplasia and thereby contributing to the resolution of glomerular disease, other data indicate that excessive apoptosis can be harmful, leading to glomerular hypocellularity[14.Sugiyama H. Kashihara N. Makino H. Yamasaki Y. Ota A. Apoptosis in glomerular sclerosis.Kidney Int. 1996; 49: 103-111Abstract Full Text PDF PubMed Scopus (258) Google Scholar]. Again, these observations reflect the fact that glomerular MC numbers at any given stage during glomerular disease are determined by the rates of cell proliferation and loss. Clearly, homeostatic reconstitution of the glomerulus depends on a regulated balance between these two processes. The precise mechanisms controlling the glomerular cell turnover and net cell number in health and disease are currently incompletely understood. The division cycle of eukaryotic cells is controlled by a series of checkpoints and transitions in which temporal order is imposed by cyclin-dependent kinases (CDKs), acting in concert with their regulatory subunits, the cyclins Figure 3[15.Sherr C.J. d-type cyclins.Trends Biochem Sci. 1995; 20: 187-190Abstract Full Text PDF PubMed Scopus (854) Google Scholar]. Cyclin kinase inhibitors (CKIs), such as p21Waf-1, p27Kip1, and members of the INK4 family of CDK inhibitors, negatively regulate the cell cycle by inhibiting the formation or activation of cyclin-CDK complexes[16.Funk J.O. Galloway D.A. Inhibiting CDK inhibitors: New lessons from DNA tumor viruses.Trends Biochem Sci. 1998; 23: 337-341Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. In the past few years, considerable advances have been made in this field of research, and nephrologists are applying this knowledge to elucidate the molecular control of cell cycle progression of renal cells, including MCs. New findings on molecular mechanisms of cell cycle control were presented at this symposium and are the subject of recent reviews[16.Funk J.O. Galloway D.A. Inhibiting CDK inhibitors: New lessons from DNA tumor viruses.Trends Biochem Sci. 1998; 23: 337-341Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 17.Shankland S.J. Cell-cycle control and renal disease.Kidney Int. 1997; 52: 294-308Abstract Full Text PDF PubMed Scopus (96) Google Scholar, 18.Terada Y. Inoshita S. Nakashima O. Kuwahara M. Sasaki S. Marumo F. Cyclins and the cyclin-kinase system—their potential roles in nephrology.Nephrol Dial Transplant. 1998; 13: 1913-1916Crossref PubMed Scopus (12) Google Scholar, 19.Dyson N. The regulation of E2F by pRB-family proteins.Genes Dev. 1998; 12: 2245-2262Crossref PubMed Scopus (1936) Google Scholar]. The rat anti-Thy1.1 model of mesangioproliferative glomerulonephritis has been used to study the in vivo expression of cell cycle regulators in glomerular cells. Shankland et al showed that the onset of MC replication in this model is associated with significant and transient increases of cyclin A and cdk2 protein[20.Shankland S.J. Hugo C. Coats S.R. Nangaku M. Pichler R.H. Gordon K.L. Pippin J. Roberts J.M. Couser W.G. Johnson R.J. Changes in cell-cycle protein expression during experimental mesangial proliferative glomerulonephritis.Kidney Int. 1996; 50: 1230-1239Abstract Full Text PDF PubMed Scopus (102) Google Scholar]. Moreover, the increase of cdk2 protein expression in the course of nephritis correlated with an increase of cdk2 activity, as measured by histone H1 kinase assay in isolated glomeruli. In normal rat glomeruli, the expression of the CKI p27Kip1 was high, whereas the levels of p21Waf-1 were low. The onset of MC proliferation in the anti-Thy1.1 model was associated with a reduction of p27Kip1 levels. The resolution of MC proliferation was associated with a return to baseline levels for p27Kip1, whereas the expression for p21Waf-1 further increased and remained elevated following the resolution of proliferation[20.Shankland S.J. Hugo C. Coats S.R. Nangaku M. Pichler R.H. Gordon K.L. Pippin J. Roberts J.M. Couser W.G. Johnson R.J. Changes in cell-cycle protein expression during experimental mesangial proliferative glomerulonephritis.Kidney Int. 1996; 50: 1230-1239Abstract Full Text PDF PubMed Scopus (102) Google Scholar]. The relevance of the sustained p21Waf-1 was not fully explained, but one could speculate that p21Waf-1 has a functional role in the long-term resolution of mesangioproliferative disease. Currently, however, this interpretation is unproven. Indeed, recent data have shown that p21Waf-1 has divergent functions. The CKI p21Waf-1 can act as an assembly factor of cdk4/cyclin D complexes or as an inhibitor of CDK/cyclin complexes[16.Funk J.O. Galloway D.A. Inhibiting CDK inhibitors: New lessons from DNA tumor viruses.Trends Biochem Sci. 1998; 23: 337-341Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar],[21.Labaer J. Garrett M.D. Stevenson L.F. Slingerland J.M. Sandhu C. Chou H.S. Fattaey A. Harlow E. New functional activities for the p21 family of CDK inhibitors.Genes Dev. 1997; 11: 847-862Crossref PubMed Scopus (1183) Google Scholar]. We have recently examined how soluble regulators of MC growth affect p21Waf-1 expression in cultured MCs. We found that PDGF causes a marked increase of p21Waf-1 protein in MCs[22Lang S, Hartner A, Sterzel RB, Schoecklmann HO. Requirement of cyclin D1 in mesangial cell mitogenesis. submitted for publicationGoogle Scholar]. The induction of p21Waf-1 protein by PDGF was also reported in p53-deficient as well as in normal mouse fibroblasts, supporting the interpretation of p53-independent up-regulation of p21Waf-1 by PDGF[23.Michieli P. Chedid M. Lin D. Pierce J.H. Mercer W.E. Givol D. Induction of WAF1/CIP1 by a p53-independent pathway.Cancer Res. 1994; 54: 3391-3395PubMed Google Scholar]. In other cell types, the growth-inhibitory cytokine transforming growth factor-β1 (TGF-β1) was found to enhance p21Waf-1 expression by p53-independent mechanisms[24.Datto M.B. Li Y. Panus J.F. Howe D.J. Xiong Y. Wang X.F. Transforming growth factor β induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism.Proc Natl Acad Sci USA. 1995; 92: 5545-5549Crossref PubMed Scopus (841) Google Scholar]. However, our experiments showed that in cultured rat MCs, TGF-β1 led to a slight reduction of the p21Waf-1 expression, which was induced by PDGF[22Lang S, Hartner A, Sterzel RB, Schoecklmann HO. Requirement of cyclin D1 in mesangial cell mitogenesis. submitted for publicationGoogle Scholar], whereas it strongly stimulated p27Kip1. These divergent findings indicate that the nature of TGF-β1–mediated effects on cell cycle regulatory proteins differs considerably between cell types. In our studies, we observed that increased nuclear abundance of cyclin D1 protein in MCs precedes the peak of MC hypercellularity in anti-Thy1.1 glomerulonephritis Figure 1, suggesting its involvement in the development of mesangioproliferative disease[22Lang S, Hartner A, Sterzel RB, Schoecklmann HO. Requirement of cyclin D1 in mesangial cell mitogenesis. submitted for publicationGoogle Scholar]. To further examine the relevance of the in vivo finding of enhanced cyclin D1 expression for MC hyperplasia, we studied the effects of soluble regulators of MC growth on cyclin D1 expression in vitro. In growth-arrested rat MCs in culture, mitogenic stimulation with serum or PDGF led to a rapid increase of cyclin D1 protein expression. TGF-β1 inhibited PDGF-related induction of cyclin D1 protein. Because cyclin D1 is a key regulator of early G1-phase progression and adenovirus-mediated overexpression of cyclin D1 in MCs increased MC mitogenesis[25.Terada Y. Yamada T. Nakashima O. Tamamori M. Ito H. Sasaki S. Marumo F. Overexpression of cell cycle inhibitors (p16INK4 and p21Cip1) and cyclin D1 using adenovirus vectors regulates proliferation of rat mesangial cells.J Am Soc Nephrol. 1997; 8: 51-60PubMed Google Scholar], we examined whether the reduction of cyclin D1 protein abundance by transfection of antisense oligonucleotides (ODNs) is sufficient to inhibit cdk4 kinase activity and MC proliferation. Several studies successfully employed transfection of antisense ODNs to examine the roles of MC growth regulators and to block MC replication. In cultured MCs, proliferation could be inhibited by using antisense ODNs against the early growth response gene Egr-1[26.Hofer G. Grimmer C. Sukhatme V.P. Sterzel R.B. Rupprecht H.D. Transcription factor Egr-1 regulates glomerular mesangial cell proliferation.J Biol Chem. 1996; 271: 28306-28310Crossref PubMed Scopus (59) Google Scholar] or other cell cycle-associated proteins such as PCNA or Ki-67[27.Maeshima Y. Kashihara N. Sugiyama H. Makino H. Ota Z. Antisense oligonucleotides to proliferating cell nuclear antigen and Ki-67 inhibit human mesangial cell proliferation.J Am Soc Nephrol. 1996; 7: 2219-2229Crossref PubMed Google Scholar]. We observed that antisense ODNs against cyclin D1 reduced the serum- or PDGF-induced protein expression of cyclin D1 to 48% or 10% of control levels, respectively[22Lang S, Hartner A, Sterzel RB, Schoecklmann HO. Requirement of cyclin D1 in mesangial cell mitogenesis. submitted for publicationGoogle Scholar]. These inhibitory effects correlated with diminished cdk4 activity. Subsequently, the MC proliferation caused by serum or PDGF was markedly inhibited by antisense ODNs against cyclin D1, as measured by [3H]-thymidine uptake and MC counts. Antisense ODNs against cyclin D1 have also been shown to diminish the increase of DNA synthesis of rat MCs induced by endothelin-1[28.Terada Y. Inoshita S. Nakashima O. Yamada T. Tamamori M. Ito H. Sasaki S. Marumo F. Cyclin D1, p16, and retinoblastoma gene regulate mitogenic signaling of endothelin in rat mesangial cells.Kidney Int. 1998; 53: 76-83Abstract Full Text PDF PubMed Scopus (26) Google Scholar]. Thus, strategies aiming to reduce cyclin D1 expression, for example, by transfer of antisense ODNs or by specific cyclin antagonists, might represent an effective means to inhibit MC proliferation in vivo. Other studies investigated whether or not MC replication is reduced by suppressing the activity of transcription factor E2F. E2F controls the expression of several genes involved in cell cycle progression, including c-myc, c-myb, proliferating cell nuclear antigen (PCNA), and cdk2 kinase[19.Dyson N. The regulation of E2F by pRB-family proteins.Genes Dev. 1998; 12: 2245-2262Crossref PubMed Scopus (1936) Google Scholar]. In order to inhibit E2F, decoy ODNs that contained the consensus E2F binding site sequence as a competitive inhibitor were transfected. Transfection of E2F decoy ODNs effectively reduced the proliferation of serum-stimulated MCs in vitro[29.Tomita N. Horiuchi M. Tomita S. Gibbons G.H. Kim J.Y. Baran D. Dzau V.J. An oligonucleotide decoy for transcription factor E2F inhibits mesangial cell proliferation in vitro.Am J Physiol. 1998; 275: F278-F284PubMed Google Scholar]. Moreover, an in vivo tranfection of E2F decoy ODNs into rat kidneys 36 hours after the induction of anti-Thy1.1 suppressed MC proliferation by 71%[30.Maeshima Y. Kashihara N. Yasuda T. Sugiyama H. Sekikawa T. Okamoto K. Kanao K. Watanabe Y. Kanwar Y.S. Makino H. Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo.J Clin Invest. 1998; 101: 2589-2597Crossref PubMed Scopus (86) Google Scholar]. These results correlated with reduced glomerular expression of PCNA[30.Maeshima Y. Kashihara N. Yasuda T. Sugiyama H. Sekikawa T. Okamoto K. Kanao K. Watanabe Y. Kanwar Y.S. Makino H. Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo.J Clin Invest. 1998; 101: 2589-2597Crossref PubMed Scopus (86) Google Scholar], indicating that decoy ODNs can inhibit the activity of E2F and may have the potential to treat proliferative forms of glomerulonephritis. In vitro and in vivo studies have identified a multitude of extracellular factors that stimulate or inhibit MC proliferation, including various soluble cytokines, autacoids, hormones, as well as insoluble ECM molecules. Many of these ligands are produced by MCs and possess autocrine growth-modulating activities[31.Schoecklmann H.O. Rupprecht H.D. Sterzel R.B. Mesangial cell growth control in glomerular inflammation.Proc R Coll Phys Edinb. 1996; 26: 352-373Google Scholar]. Although numerous reports exist on promitogenic factors and signaling pathways in MCs, less is known about antimitogenic mechanisms that are able to block MC proliferation and might be involved in the maintenance of MC quiescence in the normal kidney and/or in the resolution of mesangioproliferative disease. TGF-β is a potent endogenous growth-inhibitory factor with the capacity to counterbalance MC mitogenesis; it is secreted by MCs and can act in an autocrine fashion[32.Shankland S.J. Johnson R.J. TGF-β in glomerular disease.Miner Electrolyte Metab. 1998; 24: 168-173Crossref PubMed Scopus (23) Google Scholar]. Multiple studies of MCs in culture have confirmed the antimitogenic and ECM-promoting action of TGF-β[32.Shankland S.J. Johnson R.J. TGF-β in glomerular disease.Miner Electrolyte Metab. 1998; 24: 168-173Crossref PubMed Scopus (23) Google Scholar, 33.MacKay K. Striker L.J. Stauffer J.W. Doi T. Agodoa L.Y. Striker G.E. Transforming growth factor-β: Murine glomerular receptors and responses of isolated glomerular cells.J Clin Invest. 1989; 83: 1160-1167Crossref PubMed Scopus (217) Google Scholar, 34.Border W.A. Okuda S. Languino L.R. Ruoslahti E. Transforming growth factor-β regulates production of proteoglycans by mesangial cells.Kidney Int. 1990; 37: 689-695Abstract Full Text PDF PubMed Scopus (329) Google Scholar, 35.Schoecklmann H.O. Rupprecht H.D. Zauner I. Sterzel R.B. TGF-β1-induced cell cycle arrest in renal mesangial cells involves inhibition of cyclin E-cdk 2 activation and retinoblastoma protein phosphorylation.Kidney Int. 1997; 51: 1228-1236Abstract Full Text PDF PubMed Scopus (55) Google Scholar]. Furthermore, in studies of experimental glomerular disease, TGF-β has been found to induce both beneficial, antimitogenic, anti-inflammatory effects[36.Kitamura M. Burton S. English J. Kawachi H. Fine L.G. Transfer of a mutated gene encoding active transforming growth factor-β1 suppresses mitogenesis and IL-1 response in the glomerulus.Kidney Int. 1995; 48: 1747-1757Abstract Full Text PDF PubMed Scopus (75) Google Scholar] and harmful fibrogenesis leading to glomerular scarring[37.Border W.A. Okuda S. Languino L.R. Sporn M.B. Ruoslahti E. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1.Nature. 1990; 346: 371-374Crossref PubMed Scopus (927) Google Scholar, 38.Border W.A. Noble N.A. Yamamoto T. Harper J.R. Yamaguchi Y. Pierschbacher M.D. Ruoslahti E. Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease.Nature. 1992; 360: 361-364Crossref PubMed Scopus (914) Google Scholar, 39.Isaka Y. Fujiwara Y. Ueda N. Kaneda Y. Kamada T. Imai E. Glomerulosclerosis induced by in vivo transfection of transforming growth factor-β or platelet-derived growth factor gene into the rat kidney.J Clin Invest. 1993; 92: 2597-2601Crossref PubMed Scopus (498) Google Scholar]. Data from Kitamura et al demonstrated that mesangial overexpression of active TGF-β1 by the use of MCs as a vector for gene delivery to the renal glomerulus reduced increased glomerular mitogenesis in anti-Thy1.1 nephritis, implying that TGF-β1 acts as a suppressor of glomerular inflammation[36.Kitamura M. Burton S. English J. Kawachi H. Fine L.G. Transfer of a mutated gene encoding active transforming growth factor-β1 suppresses mitogenesis and IL-1 response in the glomerulus.Kidney Int. 1995; 48: 1747-1757Abstract Full Text PDF PubMed Scopus (75) Google Scholar]. We have investigated nuclear regulatory events induced by TGF-β1 in MCs[35.Schoecklmann H.O. Rupprecht H.D. Zauner I. Sterzel R.B. TGF-β1-induced cell cycle arrest in renal mesangial cells involves inhibition of cyclin E-cdk 2 activation and retinoblastoma protein phosphorylation.Kidney Int. 1997; 51: 1228-1236Abstract Full Text PDF PubMed Scopus (55) Google Scholar]. TGF-β1 abrogated mitogenesis of cultured MCs stimulated by PDGF, epidermal growth factor (EGF), serotonin, endothelin-1, or basic fibroblast growth factor (bFGF). By FACS analysis, we observed that the incubation of cultured MCs with TGF-β1 blocks the progression of the MC cycle in the G1 phase of the cell cycle. One of the molecular mechanisms used by TGF-β1 to arrest MCs in G1 phase was the significantly diminished activation of cyclin E/cdk2-complexes induced by PDGF. Subsequently, the decrease of cyclin E/cdk2 activity was reflected by less phosphorylation of the retinoblastoma tumor suppressor (pRb), a negative cell cycle regulator[35.Schoecklmann H.O. Rupprecht H.D. Zauner I. Sterzel R.B. TGF-β1-induced cell cycle arrest in renal mesangial cells involves inhibition of cyclin E-cdk 2 activation and retinoblastoma protein phosphorylation.Kidney Int. 1997; 51: 1228-1236Abstract Full Text PDF PubMed Scopus (55) Google Scholar]. Deactivation of pRb via phosphorylation by G1 phase CDKs is a required step for successful G1-phase progression and S-phase entry[40.Grana X. Garriga J. Mayol X. Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth.Oncogene. 1998; 17: 3365-3383Crossref PubMed Scopus (280) Google Scholar]. Furthermore, in immunoprecipitation experiments we found that the presence of TGF-β1 prevented the release of the CKI p27Kip1 from cyclin E/cdk2 complexes in the presence of soluble mitogens (unpublished results). This appears to be one molecular mechanism by which cdk2 activity is negatively regulated by TGF-β1 in MCs. Transforming growth factor-β1 has also been reported to cause hypertrophy of renal cells, including renal epithelial cells[41.Franch H.A. Shay J.W. Alpern R.J. Preisig P.A. Involvement of pRB family in TGFβ-dependent epit" @default.
• W2034159586 created "2016-06-24" @default.
• W2034159586 creator A5009063862 @default.
• W2034159586 creator A5028285417 @default.
• W2034159586 creator A5062157203 @default.
• W2034159586 date "1999-10-01" @default.
• W2034159586 modified "2023-09-27" @default.
• W2034159586 title "Regulation of mesangial cell proliferation" @default.
• W2034159586 cites W1753444805 @default.
• W2034159586 cites W1970517174 @default.
• W2034159586 cites W1970709922 @default.
• W2034159586 cites W1971878230 @default.
• W2034159586 cites W1972172786 @default.
• W2034159586 cites W1972820874 @default.
• W2034159586 cites W1973047647 @default.
• W2034159586 cites W1977093600 @default.
• W2034159586 cites W1978747049 @default.
• W2034159586 cites W1981271183 @default.
• W2034159586 cites W1985401585 @default.
• W2034159586 cites W1988171238 @default.
• W2034159586 cites W1992608929 @default.
• W2034159586 cites W1993851092 @default.
• W2034159586 cites W1995700570 @default.
• W2034159586 cites W1997080687 @default.
• W2034159586 cites W2011612528 @default.
• W2034159586 cites W2017096535 @default.
• W2034159586 cites W2019469243 @default.
• W2034159586 cites W2023342066 @default.
• W2034159586 cites W2032846458 @default.
• W2034159586 cites W2033596435 @default.
• W2034159586 cites W2034277114 @default.
• W2034159586 cites W2035641694 @default.
• W2034159586 cites W2042046137 @default.
• W2034159586 cites W2056906256 @default.
• W2034159586 cites W2057655548 @default.
• W2034159586 cites W2058488557 @default.
• W2034159586 cites W2058689244 @default.
• W2034159586 cites W2072670533 @default.
• W2034159586 cites W2078322208 @default.
• W2034159586 cites W2078663145 @default.
• W2034159586 cites W2083358105 @default.
• W2034159586 cites W2091501883 @default.
• W2034159586 cites W2091552383 @default.
• W2034159586 cites W2092433658 @default.
• W2034159586 cites W2094103805 @default.
• W2034159586 cites W2098573045 @default.
• W2034159586 cites W2123264165 @default.
• W2034159586 cites W2127791872 @default.
• W2034159586 cites W2140437192 @default.
• W2034159586 cites W2153549628 @default.
• W2034159586 cites W2154169742 @default.
• W2034159586 cites W2155103945 @default.
• W2034159586 cites W2166529745 @default.
• W2034159586 cites W2170431739 @default.
• W2034159586 cites W2296839105 @default.
• W2034159586 cites W2299893108 @default.
• W2034159586 cites W2324266222 @default.
• W2034159586 cites W4251554787 @default.
• W2034159586 doi "https://doi.org/10.1046/j.1523-1755.1999.00710.x" @default.
• W2034159586 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/10610410" @default.
• W2034159586 hasPublicationYear "1999" @default.
• W2034159586 type Work @default.
• W2034159586 sameAs 2034159586 @default.
• W2034159586 citedByCount "89" @default.
• W2034159586 countsByYear W20341595862013 @default.
• W2034159586 countsByYear W20341595862014 @default.
• W2034159586 countsByYear W20341595862015 @default.
• W2034159586 countsByYear W20341595862016 @default.
• W2034159586 countsByYear W20341595862017 @default.
• W2034159586 countsByYear W20341595862018 @default.
• W2034159586 countsByYear W20341595862019 @default.
• W2034159586 countsByYear W20341595862020 @default.
• W2034159586 countsByYear W20341595862021 @default.
• W2034159586 countsByYear W20341595862022 @default.
• W2034159586 countsByYear W20341595862023 @default.
• W2034159586 crossrefType "journal-article" @default.
• W2034159586 hasAuthorship W2034159586A5009063862 @default.
• W2034159586 hasAuthorship W2034159586A5028285417 @default.
• W2034159586 hasAuthorship W2034159586A5062157203 @default.
• W2034159586 hasBestOaLocation W20341595861 @default.
• W2034159586 hasConcept C126322002 @default.
• W2034159586 hasConcept C2779131090 @default.
• W2034159586 hasConcept C2780091579 @default.
• W2034159586 hasConcept C502942594 @default.
• W2034159586 hasConcept C54355233 @default.
• W2034159586 hasConcept C62112901 @default.
• W2034159586 hasConcept C71924100 @default.
• W2034159586 hasConcept C86803240 @default.
• W2034159586 hasConcept C95444343 @default.
• W2034159586 hasConceptScore W2034159586C126322002 @default.
• W2034159586 hasConceptScore W2034159586C2779131090 @default.
• W2034159586 hasConceptScore W2034159586C2780091579 @default.
• W2034159586 hasConceptScore W2034159586C502942594 @default.
• W2034159586 hasConceptScore W2034159586C54355233 @default.
• W2034159586 hasConceptScore W2034159586C62112901 @default.
• W2034159586 hasConceptScore W2034159586C71924100 @default.
• W2034159586 hasConceptScore W2034159586C86803240 @default.
• W2034159586 hasConceptScore W2034159586C95444343 @default.

• next