Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation

Strutz, Frank; Zeisberg, Michael; Hemmerlein, Bernhard; Sattler, B; Hummel, Klaus M.; Becker, Volker; Müller, Gerhard A.

doi:10.1046/j.1523-1755.2000.00997.x

Cited by 170 publications

(156 citation statements)

References 54 publications

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“…Also, VEGF has been reported to enhance collagen synthesis via the activation of ERK (3). bFGF was acknowledged to elicit the proliferation of both fibroblasts and mesangial cells (44,46) and thereby is involved in renal fibrogenesis. Because these four growth factors are involved in the development of DN, it is conceivable that the negative modulation of their signaling by BK may be of therapeutical relevance in DN.…”

Section: Discussionmentioning

confidence: 99%

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Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Cellier

Mage

Duchêne

et al. 2003

American Journal of Physiology-Renal Physiology

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Several experimental data report both mitogenic and antimitogenic effects of bradykinin (BK). To conciliate these apparent opposite effects, we hypothesized that, depending on cell context activation, BK could reduce the mitogenic effect of growth factors. Therefore, in the present study we assessed the existence of possible negative cross talk between BK and potential pathogenic growth factors in freshly isolated rat glomeruli (IG). Next, we determined whether this cross talk could be pharmacologically recruited during angiotensin-converting enzyme (ACE) inhibition in the diabetic rat. In IG from normal rats, BK, via activation of the B2 kinin receptor (B2R), causes a transient stimulation of ERK1/2 phosphorylation, whereas it inhibits ERK1/2 phosphorylation induced by IGF-1, PDGF-BB, VEGF, or basic FGF. The reduction of growth factor-induced ERK1/2 phosphorylation is abolished by an inhibitor of tyrosine phosphatase. In glomeruli from diabetic rats, hyperglycemia increased the phosphorylation level of ERK-1/2 as well as oxidative stress. The reversal of these events by ACE inhibition is mediated via B2R activation. These observations are consistent with a potential therapeutic role of BK and B2R during glomerulosclerosis.

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Section: Discussionmentioning

confidence: 99%

“…These growth factors are suggested to be involved in the hyperplasia and extracellular matrix accumulation associated with acute or chronic glomerulosclerosis (1,8,23,36,46). The effects of these growth factors are likely occurring via the phosphorylation of the MAPK ERK1/2 (3,13,14).…”

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confidence: 99%

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Cellier

Mage

Duchêne

et al. 2003

American Journal of Physiology-Renal Physiology

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“…For instance, there have been reports that transformed tubular epithelial and endothelial cells as well as bone marrow-derived cells may potentially constitute a part of this cell population in the diseased kidney (3,4). However, ample evidence suggests that resident interstitial fibroblasts represent a significant, if not major, source of (myo)fibroblast recruitment (5)(6)(7)(8). Hence, suppression of fibroblast proliferation in the injured kidney may diminish the number of scar tissue generating cells and could thus yield an option to halt progression of renal fibrosis.…”

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confidence: 99%

“…According to current understanding, resident fibroblast activation and proliferation in the kidney is triggered by locally secreted fibrogenic chemokines including TGF␤ 1 , PDGF, CTGF, and bFGF. TGF␤ 1 potently promotes proliferation of renal fibroblasts via a downstream mechanism that is largely mediated by bFGF (7,12).…”

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confidence: 99%

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Grgic

Kiss

Kaistha

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca 2+ -activated K + channel (K Ca 3.1) has been proposed to promote mitogenesis in several cell types and contribute to disease states characterized by excessive proliferation. Here, we hypothesized that K Ca 3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of K Ca 3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated K Ca 3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of K Ca 3.1 functions potently inhibited fibroblast proliferation by G 0 /G 1 arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of K Ca 3.1 in affected kidneys. Mice lacking K Ca 3.1 (K Ca 3.1 −/− ) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and αSMA + cells in kidneys after UUO, whereas functional renal parenchyma was better preserved. Pharmacological treatment with the selective K Ca 3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild-type mice and rats. In conclusion, our data demonstrate that K Ca 3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that K Ca 3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease.

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“…Connective tissue growth factor, a novel profibrogenic factor, may be an important downstream mediator of TGF-␤ profibrotic activities (14,15). Basic fibroblast growth factor (FGF), a mitogenic factor for various types of renal cells, is upregulated in fibrotic kidneys (16) and mediates TGF-␤-induced cell proliferation in renal interstitial fibroblasts (17). Basic FGF is also implicated in tubular epithelial-mesenchymal transdifferentiation (TEMT) (18).…”

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Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

Yamashita¹,

Maeshima

Kojima

et al. 2004

Journal of the American Society of Nephrology

131

110

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Abstract. The present study was conducted to examine the involvement of the activin-follistatin system in the fibrotic process of the kidney. Immunoreactive activin A was upregulated in tubular cells in the kidneys with unilateral ureteral obstruction but not in normal and contralateral kidneys. Activin A promoted cell proliferation, enhanced the expression of type I collagen mRNA, and induced the production of ␣-smooth muscle actin in a rat kidney fibroblast cell line (NRK-49F cells) as well as in primary cultured renal interstitial fibroblasts. In contrast, activin A did not affect the expressions of ␣-smooth muscle actin and type I collagen in renal epithelial tubular cell lines LLC-PK1, and MDCK. Follistatin, an antagonist of activin A, significantly inhibited cell proliferation in NRK-49F cells. Blockade of activin signaling by overexpression of truncated type II activin receptor, which lacked the intracellular kinase domain, decreased cell proliferation and reduced the expression level of type I collagen mRNA in NRK-49F cells. The expression of activin A was induced by TGF-␤1 or activin A itself. Induction of type I collagen expression by TGF-␤1 was reduced by follistatin or by overexpression of truncated type II activin receptor. These results suggest that activin A produced by tubular cells acts as a paracrine factor that activates renal interstitial fibroblasts during the fibrotic processes of the kidney.

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Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation

Abstract: Interstitial FGF-2 protein and mRNA expression correlate with interstitial scarring. FGF-2 is a strong mitogen for cortical kidney fibroblasts and may promote autocrine fibroblast growth. Expression of FGF-2 correlates with interstitial and tubular proliferation in vivo.

Cited by 170 publications

References 54 publications

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

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Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation

Abstract: Interstitial FGF-2 protein and mRNA expression correlate with interstitial scarring. FGF-2 is a strong mitogen for cortical kidney fibroblasts and may promote autocrine fibroblast growth. Expression of FGF-2 correlates with interstitial and tubular proliferation in vivo.

Cited by 170 publications

References 54 publications

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Bradykinin reduces growth factor-induced glomerular ERK1/2 phosphorylation

Renal fibrosis is attenuated by targeted disruption of K Ca 3.1 potassium channels

Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

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Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels