Interstitial Myof ibroblasts in Experimental Renal Infection and Scarring

Hewitson, Tim D.; Wu, Huiling; Becker, Gavin J.

doi:10.1159/000168875

Cited by 97 publications

(76 citation statements)

References 18 publications

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“…The presence of interstitial myofibroblasts correlates with the extent of tubulointerstitial scarring and functional outcome in clinical glomerulonephritis (51,52). Therefore, specific inhibition of fibroblast activation may lead to new approaches in the treatment of progressive renal disease.…”

Section: Discussionmentioning

confidence: 99%

Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

Yamashita¹,

Maeshima

Kojima

et al. 2004

Journal of the American Society of Nephrology

130

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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Section: Discussionmentioning

confidence: 99%

Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

Yamashita¹,

Maeshima

Kojima

et al. 2004

Journal of the American Society of Nephrology

130

110

View full text Add to dashboard Cite

show abstract

“…Point counting was done in the renal cortex and in the corticomedullary junction for each rat following routinely established methods [24]. In each field, 100 points were counted on a 1 cm 2 eyepiece graticule with 10 equidistant grid lines.…”

Section: Methodsmentioning

confidence: 99%

Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat

et al. 2004

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Aims/hypothesis. Diabetic renal disease has been postulated to progress as a result of an interaction between metabolic and haemodynamic pathways. Our aim was to assess the functional, structural, molecular and cellular aspects of renal disease in an experimental model of diabetes with associated hypertension. Method. Streptozotocin-induced diabetic spontaneously hypertensive rats were randomised to no treatment, the ACE inhibitor, perindopril (2 mg/l), the AGE formation inhibitor, aminoguanidine (1 g/l) and a combination of both agents and were followed for 32 weeks. Results. Diabetes was associated with a considerable increase in albumin excretion rate. Both aminoguanidine and perindopril retarded the increase in albuminuria, which was completely abrogated by combination therapy. Glomerulosclerosis and tubulointerstitial damage was reduced by both monotherapies with further renoprotection afforded by combination therapy in both cases. Combination therapy was also associated with a superior restoration in diabetes-induced nephrin protein depletion compared to either monotherapy. TGFβ1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine. Conclusion/interpretation. These findings indicate that in the context of diabetes-related renal injury, blocking both the renin-angiotensin and advanced glycation pathways offers superior renoprotection and could be considered as a therapeutic strategy in the prevention and retardation of progressive-diabetic renal injury. [Diabetologia (2004) Based on clinical and experimental studies, the two main risk factors linked to the pathogenesis of diabetic vascular complications are hyperglycaemia and systemic hypertension [1,2,3,4]. However, the interaction between these two pathways and their involvement in the pathogenesis of diabetic renal microvascular complications is not clear. Studies by our own group and others, in both the experimental and clinical setting have shown the renoprotective effects of antihypertensive agents that block the renin-angiotensin system (RAS) [1,5,6,7]. The renal effects of these agents include reduced development of albuminuria and less glomerular and tubulointerstitial injury [8]. The effects of ACE inhibitors on renal structural injury have been mediated via the prosclerotic cytokine,

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“…The evaluation of tubulointerstitial area (TIA) was assessed using a point-counting technique and carried out in the renal cortex and corticomedullary junction for each animal following routine established methods [39]. In each field, 100 points were counted on a 1 cm 2 eyepiece graticule with 10 equidistant grid lines.…”

Section: Localisation Of Acementioning

confidence: 99%

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

et al. 2003

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Aims. Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. Methods. Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg·kg −1 · day −1 ) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg·kg −1 ·day −1 for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor β, β-inducible geneh3 and nephrin were also quantitated.Results. Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFβ and βig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. Conclusion/Interpretation. These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease. [Diabetologia (2003) 46:961-971]

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Interstitial Myof ibroblasts in Experimental Renal Infection and Scarring

Cited by 97 publications

References 18 publications

Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

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