Interstitial Fibroblast-Like Cells Express Renin-Angiotensin System Components in a Fibrosing Murine Kidney

Okada, Hirokazu; Inoue, Tsutomu; Kanno, Yoshihiko; Kobayashi, Tatsuya; Watanabe, Yusuke; Kopp, Jeffrey B.; Carey, Robert M.; Suzuki, Hiromichi

doi:10.1016/s0002-9440(10)64898-5

Cited by 30 publications

(26 citation statements)

References 31 publications

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“…TGF-␤1 transgenic mice that had been anesthestized and received wound suture but were not nephrectomized were used as negative controls. We confirmed that the control, transgenic mice did not show any significant renal fibrosis up to 17 wk of age, although we have reported that some older animals do develop renal fibrosis (7,13). Our laboratory and others reported that when a given antisense ODN was injected intravenously into rodents, it was absorbed into the proximal tubular epithelium, where it was retained for nearly 48 h and during which time it could block transcription of a target gene (14 -16).…”

Section: Animal Experimentssupporting

confidence: 78%

“…Five-week-old TGF-␤1 transgenic mice that had undergone SNx were used in this study and served as a model of renal fibrosis (7,13). These mice reproducibly develop significant interstitial fibrosis at approximately 8 to 10 wk after surgery.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…A portion of this work was presented at the 35th Annual Meeting of the American Society of Nephrology; November [13][14][15][16] 2003; San Diego, CA.…”

Section: Acknowledgmentsmentioning

confidence: 99%

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Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis

Okada

Kikuta

Kobayashi

et al. 2005

Journal of the American Society of Nephrology

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166

145

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Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-␤. However, its precise role in renal interstitial fibrogenesis has not yet been clarified. It was demonstrated previously that CTGF was expressed in tubular epithelial cells that had been engulfed by interstitial fibrosis in the remnant kidney of the subtotal nephrectomy (SNx) model. In the present study, co-cultures of tubular epithelial cells (mProx24) and tubulointerstitial fibroblasts (TFB) that mimic the subepithelial mesenchyme in the kidney were used to study the profibrotic effects of TGF-␤1-induced CTGF. In these co-cultures, TGF-␤1 treatment resulted in significantly increased mRNA levels of type I collagen and fibronectin in the TFB. These effects were both direct and indirect, with the latter being mediated by CTGF derived from the co-cultured mProx24. C onnective tissue growth factor (CTGF) is a 38-kD cysteine-rich peptide that belongs to the emerging CCN (CTGF, cyr 61/cef 10, nov) family of multifunctional growth factors (1-4). Murine CTGF, which is also called fisp-12, promotes chemotaxis, migration, adhesion, proliferation, and differentiation or formation of the extracellular matrix (ECM), depending on whether the target cell is a fibroblast, chondrocyte, or vascular endothelial cell (2). CTGF is induced exclusively by TGF-␤ and is thought to mediate the latter's profibrotic effects by modulating fibroblast cell growth and ECM protein synthesis (1,4). CTGF expression has been shown to increase in a variety of human diseases and experimental disease models that are characterized by fibrosis, including those that affect the kidney, skin, blood vessels, lung, and liver (1,2). In the case of the kidney, CTGF mRNA was shown to be expressed primarily in glomerular mesangial, epithelial, and endothelial cells in IgA nephropathy, focal and segmental glomerulosclerosis, and diabetic nephropathy (5,6). Moreover, CTGF mRNA overexpression was found in tubular epithelial cells and interstitial cells at sites of chronic interstitial damage (5,6). In the remnant kidney of the subtotal nephrectomy (SNx) model and in the kidneys with ureteral obstruction, tubular CTGF was shown to be expressed in response to renal interstitial fibrosis (7,8). These findings strongly suggest that renal interstitial fibrogenesis is mediated by CTGF that is expressed in the tubular epithelial cells. However, whether CTGF plays a direct role in vivo in renal interstitial fibrogenesis remains to be elucidated. In the present study, we demonstrated, using neutralization protocols, that tubular CTGF directly and significantly contributed to TGF-␤1-dependent renal interstitial fibrogenesis. Materials and Methods CTGF Antisense OligodeoxynucleotidesPhosphorothioate-capped oligodeoxynucleotides (ODN) were synthesized by an automated synthesizer. After deprotection, ODN were dissolved in water, extracted with phenol/chloroform/isoamyl alco-

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Section: Animal Experimentssupporting

confidence: 78%

Section: Animal Experimentsmentioning

confidence: 99%

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Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis

Okada

Kikuta

Kobayashi

et al. 2005

Journal of the American Society of Nephrology

Self Cite

166

145

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“…In addition, angiotensin II prolongs tubular expression of chemokines and promotes mononucleolar cell infiltration, worsening interstitial pathology. 33,34 Renal interstitial cells express AT1 receptors, possibly facilitating collagen synthesis and accelerating renal fibrosis. 33 Previous studies have demonstrated that either ARB or ACEI exerts renoprotective actions in diabetic and nondiabetic CKDs.…”

Section: Arterial Stiffnessmentioning

confidence: 99%

Vascular compliance is secured under angiotensin inhibition in non-diabetic chronic kidney diseases

et al. 2007

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“…27 The following primary antibodies were used in this study: rabbit polyclonal anti-ERK2 (sc-154; Santa Cruz Biotechnology, Santa Cruz, CA), anti-phosphorylated ERK1/2 (p-ERK1/2) (no. 442705; Calbiochem, San Diego, CA), anti-SHP-1 (sc-287; Santa Cruz Biotechnology), anti-AT 2 R antibody 28 (generously provided by Prof. Robert M. Carey, University of Virginia Health System, Charlottesville, VA), mouse monoclonal anti-p38 (no. 05-454; Upstate, Lake Placid, NY), anti-phosphorylated p38 (p-p38) (M8177; Sigma), and anti-actin (sc-8432; Santa Cruz Biotechnology).…”

Section: Western Blotmentioning

confidence: 99%

A Possible Anti-Inflammatory Role of Angiotensin II Type 2 Receptor in Immune-Mediated Glomerulonephritis during Type 1 Receptor Blockade

Okada

Inoue

Kikuta

et al. 2006

The American Journal of Pathology

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We previously reported that angiotensin II type 1 receptor (AT 1 R) blockade attenuates renal inflammation/fibrogenesis in immune-mediated glomerulonephritis via angiotensin II type 2 receptor (AT 2 R). In the present study, further in vivo experiments revealed that AT 2 R was expressed in tubular epithelial cells of nephritic kidneys in mice, and feedback activation of the renin-angiotensin system during AT 1 R blockade significantly reduced p-ERK, but not intranuclear nuclear factor-B, levels via AT 2 R. This led to reduction in mRNA levels of the proinflammatory mediator monocyte chemoattractant protein-1 and overall interstitial inflammation and subsequent fibrogenesis. Specific blockade of ERK expression in tubular epithelium by anti-sense oligodeoxynucleotides also attenuated interstitial inflammation, mimicking the anti-inflammatory action of AT 2 R in nephritic kidneys. Alternatively, we succeeded in confirming such an AT 2 R function by demonstrating that AT 1 R blockade did not confer renoprotection in nephritic, The potent vasoactive peptide angiotensin II (Ang II) binds two main subtypes of receptors, ie, type 1 and 2 receptors (AT 1 R and AT 2 R) that belong to the superfamily of G protein-coupled receptors but that display primarily opposite biological and physiological effects.1 Animals with anti-glomerular basement membrane (anti-GBM) nephritis, protein-overload nephropathy, subtotal nephrectomy, unilateral ureteral obstruction, or diabetic nephropathy that were treated with AT 1 R blockers, as well as AT 1A R gene-deficient mice with such kidney diseases, exhibited renoprotection.2-7 Although the anti-inflammatory and anti-fibrotic effects of AT 1 R blockade have been reported in the cardiovascular system, 8,9 similar effects have also been found in the liver.10 These findings suggest that AT 1 R mediates not only hemodynamic but also proinflammatory/fibrogenic functions. The effects of AT 1 R blockers, however, cannot be attributed solely to the action of AT 1 R. In most instances, feedback activation of the renin-angiotensin system may result in increased stimulation of AT 2 Rs that are freed from AT 1 R blockers. 2In contrast to AT 1 R, the pathophysiological role of AT 2 R remains controversial and has not yet been fully elucidated.11 AT 2 R activates unconventional signaling pathways that generally do not involve coupling to classical regulatory G proteins. In many cell types, AT 2 R is capable of activating protein tyrosine phosphatases

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Interstitial Fibroblast-Like Cells Express Renin-Angiotensin System Components in a Fibrosing Murine Kidney

Cited by 30 publications

References 31 publications

Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis

Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis

Vascular compliance is secured under angiotensin inhibition in non-diabetic chronic kidney diseases

A Possible Anti-Inflammatory Role of Angiotensin II Type 2 Receptor in Immune-Mediated Glomerulonephritis during Type 1 Receptor Blockade

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