Cytokines and Fas regulate apoptosis in murine renal interstitial fibroblasts

Laboratorio de Nefrología, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 01/1998; 8(12):1845-54.
Source: PubMed


Renal fibrosis is characterized by an increased number of fibroblasts and excessive deposition of extracellular matrix. Apoptotic cell death is a physiological mechanism to limit cell numbers, and an insufficient rate of death may contribute to fibroblast accumulation. However, little is known about the regulation of renal fibroblast survival. The authors have studied the interaction of cytokines and the Fas receptor in the regulation of apoptosis of renal fibroblasts and have observed that murine renal fibroblasts express Fas and the Fas ligand. Tumor necrosis factor alpha (TNFalpha) and agonistic anti-Fas antibodies induce apoptosis of renal fibroblasts in a time- and dose-dependent manner. Serum contains survival factors for renal fibroblasts. Both serum deprivation and TNFalpha increase the sensitivity to Fas-induced death and the expression of fas mRNA and Fas receptor. By contrast, insulin-like growth factor-1 decreases apoptosis induced by both serum deprivation and Fas activation and partially prevents the increase in Fas receptor expression induced by serum deprivation. Murine renal fibroblasts express constitutively both fas ligand mRNA and cell-surface Fas ligand, but the authors could not demonstrate a role for Fas ligand in the autocrine regulation of fibroblast survival. These data suggest that Fas and other cytokines cooperate to regulate renal fibroblast apoptosis. Modulation of the Fas death-signaling pathway in renal fibroblasts could represent a new therapeutic target for renal fibrosis.

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Available from: Francisco O'Valle
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    • "TFB is a murine renal interstitial fibroblast cell line originally isolated from SJL mouse kidney and was a generous gift from Eric G. Neilson. These cells have been extensively characterized, and they express the fibroblast specific protein (FSP-1) [14] [30]. Murine embryonic fibroblasts (MEFs) were isolated from mice embryos at 10 days post-coitum. "
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    ABSTRACT: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) regulates apoptosis, proliferation and inflammation in renal epithelial cells and plays a role in acute kidney injury. However, there is little information on the chronic effects of TWEAK. We hypothesized that TWEAK may influence renal fibrosis and regulate kidney fibroblast biology, in part, through Ras pathway. We studied a chronic model of experimental unilateral ureteral obstruction in wild type and TWEAK deficient mice, and a murine model of systemic TWEAK overexpression. TWEAK actions were also explored in cultured renal and embryonic fibroblasts. TWEAK and TWEAK receptor expression was increased in the obstructed kidneys. The absence of TWEAK decreased early kidney tubular damage, inflammatory infiltrates and myofibroblast number. TWEAK deficient mice had decreased renal fibrosis 21days after obstruction, as assessed by extracellular matrix staining. In mice without prior underlying kidney disease, systemic overexpression of TWEAK induced kidney inflammation and fibrosis. In cultured fibroblasts, TWEAK induced proliferation through activation of the Ras/ERK pathway. TWEAK also activated nuclear factor κB (NFκB)-dependent inflammatory chemokine production in murine renal fibroblasts. In conclusion, lack of TWEAK reduces renal fibrosis in a model of persistent kidney insult and overexpression of TWEAK led to renal fibrosis. TWEAK actions on renal fibroblasts may contribute to the in vivo observations, as TWEAK promotes inflammatory activity and proliferation in fibroblast cultures.
    Full-text · Article · Jun 2013 · Biochimica et Biophysica Acta
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    • "Murine renal cortical fibroblasts (TFB cell line) originally obtained from Dr. Eric Neilson (Vanderbilt University) were grown in RPMI 1640 with 10% FBS, 2 mM glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin in 5% CO2 at 37°C [55]. At 60–70% of confluence, cells were growth-arrested in serum-free medium for 24 hours before the experiments. "
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    ABSTRACT: Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1) has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.
    Full-text · Article · Jul 2012 · PLoS ONE
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    • "Fas activation promotes apoptosis of cultured mesangial cells [66] and fibroblasts [18]. However, tubular cells are resistant to Fas-dependent apoptosis under basal conditions, despite the constitutive, low-level Fas expression [18, 59, 67]. Activation of these low amounts of Fas receptors results in JNK activation, not apoptosis, in renal tubular cells [68]. "
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    ABSTRACT: Members of the TNF superfamily participate in kidney disease. Tumor necrosis factor (TNF) and Fas ligand regulate renal cell survival and inflammation, and therapeutic targeting improves the outcome of experimental renal injury. TNF-related apoptosis-inducing ligand (TRAIL and its potential decoy receptor osteoprotegerin are the two most upregulated death-related genes in human diabetic nephropathy. TRAIL activates NF-kappaB in tubular cells and promotes apoptosis in tubular cells and podocytes, especially in a high-glucose environment. By contrast, osteoprotegerin plays a protective role against TRAIL-induced apoptosis. Another family member, TNF-like weak inducer of apoptosis (TWEAK induces inflammation and tubular cell death or proliferation, depending on the microenvironment. While TNF only activates canonical NF-kappaB signaling, TWEAK promotes both canonical and noncanonical NF-kappaB activation in tubular cells, regulating different inflammatory responses. TWEAK promotes the secretion of MCP-1 and RANTES through NF-kappaB RelA-containing complexes and upregulates CCl21 and CCL19 expression through NF-kappaB inducing kinase (NIK-) dependent RelB/NF-kappaB2 complexes. In vivo TWEAK promotes postnephrectomy compensatory renal cell proliferation in a noninflammatory milieu. However, in the inflammatory milieu of acute kidney injury, TWEAK promotes tubular cell death and inflammation. Therapeutic targeting of TNF superfamily cytokines, including multipronged approaches targeting several cytokines should be further explored.
    Full-text · Article · Oct 2010 · Mediators of Inflammation
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