Myofibroblasts and the progression of crescentic glomerulonephritis

Γούμενος, Δ.; Tsomi, K; Iatrou, Christos; Oldroyd, S.; Sungur, Arzu; Papaioannides, Dimitrios; Moustakas, G.; Ziroyannis, P.; Mountokalakis, T.; Nahas, A. Meguid El

doi:10.1093/ndt/13.7.1652

Cited by 60 publications

(54 citation statements)

References 3 publications

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“…However, although we show increased mRNA expression in the interstitial cells that was noticeably greater than in remnant kidneys, the contribution of this toward the total tTg pool is still minimal when compared with that of tubular cells (8,9). Therefore, although myofibroblasts may contribute significantly to the level of ECM components available for deposition during renal scarring (33)(34)(35), it is the perturbation of tTg production and its release by tubular cells that is likely to lead to the enhanced levels of ⑀(␥-glutamyl) lysine found in the ECM both in human as well as in experimental scarring (8,9). Of particular relevance is the observed close association and correlation between tTg and interstitial fibrosis, with an extremely high predictive value for the presence of tTg extracellular crosslink products and that of histologic abnormality.…”

Section: Discussionmentioning

confidence: 66%

Tissue Transglutaminase and the Progression of Human Renal Scarring

Johnson

El‐Koraie

Skill³

et al. 2003

Journal of the American Society of Nephrology

103

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Abstract. Experimental renal scarring indicates that tissue transglutaminase (tTg) may be associated with the accumulation of extracellular matrix (ECM), both indirectly via TGF-␤1 activation and directly by the formation of ⑀(␥-glutamyl) lysine dipeptide bonds within the ECM. The latter potentially accelerates deposition and confers the ECM with resistance to proteolytic digestion. Studied were 136 human renal biopsy samples from a range of chronic renal diseases (CRD) to determine changes in tTg and ⑀(␥-glutamyl) lysine crosslinking. Immunofluorescence for insoluble tTg showed a 14-fold increase in the kidneys of CRD patients (5.3 Ϯ 0.5 versus 76 Ϯ 54 mV/cm 2 ), which was shown to be active by a similar 11-fold increase in the ⑀(␥-glutamyl) lysine crosslink (1.8 Ϯ 0.2 versus 19.3 Ϯ 14.2 mV/cm 2 ). Correlations were obtained with renal function for tTg and crosslink. In situ hybridization for tTg mRNA showed that tubular epithelial cells were the major source of tTg; however, both mesangial and interstitial cells also contributed to elevated levels in CRD. This mRNA pattern was consistent with immunohistochemistry for soluble tTg. Changes in renal tTg and its product, the ⑀(␥-glutamyl) lysine crosslink, occur in progressive renal scarring in humans independently of the original etiology and in a similar manner to experimental models. tTg may therefore play a role in the pathogenesis of renal scarring and fibrosis in patients with CRD and can therefore be considered a potential therapeutic target.

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Section: Discussionmentioning

confidence: 66%

Tissue Transglutaminase and the Progression of Human Renal Scarring

Johnson

El‐Koraie

Skill³

et al. 2003

Journal of the American Society of Nephrology

103

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“…Previous studies have reported that not only collagens type I and III but also collagen type IV, a basal membrane protein, is increased in patients with renal fibrosis such as crescentic glomerulonephritis. 19,20 Goumenos et al demonstrated that the site of synthesis of collagen III and IV appeared to be confined to fibroblasts in crescentic glomerulonephritis. 20 These findings suggest that renal fibroblasts play an important role in renal fibrosis through the synthesis of collagen types I, III, and IV.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin in Rat Renal Fibroblasts

et al. 2008

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Abstract-Osteopontin (OPN), a proinflammatory cytokine, plays an important role in renal fibrosis. We reported that plasma OPN levels were higher in patients with primary aldosteronism than with essential hypertension. However, the regulatory mechanism of OPN by aldosterone remains unclear. Here, we report the transcriptional regulation of OPN expression by aldosterone and the functional effects of aldosterone-mediated OPN transcription in renal fibroblasts. Aldosterone induced OPN expression in a dose-dependent manner with significant responses at 10 nmol/L (1.6Ϯ0. OPN expression is induced by many growth factors and cytokines such as angiotensin II, basic fibroblast growth factor, 3 and aldosterone. Aldosterone binds to the mineralocorticoid receptor (MR) and plays an important role in the pathophysiology of renal disease. An animal model of hypertension caused by aldosterone and salt overload exhibits renal injury with increasing proinflammatory cytokines including OPN. 4 Aldosterone directly acts on the MR of endothelial cells to induce OPN gene expression 5 and it is therefore of interest that we have recently reported the independent association of plasma OPN levels with serum aldosterone levels in patients with essential hypertension. 6 In addition, plasma OPN levels were higher in patients with primary aldosteronism than with essential hypertension. 7 One of the direct actions of aldosterone may be the induction of systemic fibrosis by increasing proinflammatory cytokines including OPN.Previous studies have shown that various inducers regulate OPN expression at the transcriptional level with transcription factors such as Sp-1, 8 activator protein 1 (AP-1), 9,10 and nuclear factor kappa B (NFB). 10 However, the transcriptional regulatory mechanism of OPN by aldosterone remains unclear. In the present study, we demonstrated that aldosterone induces the transcription of the OPN gene through AP-1 and NFB via MR and plays an important role in renal fibrosis via OPN induction.

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“…Several clinical studies have reported that interstitial mRNA expression of fiber-forming collagens (collagen types I and III) and collagen type IV, which is usually situated in cell basement membranes, is significantly increased in patients with renal fibrosis. 27,28 Interestingly, it was also demonstrated that the increased amounts of renal interstitial collagens were co-localized with fibroblasts. 28 These findings suggest that fibroblasts play a role in renal fibrosis through the synthesis of types I, III, and IV collagen.…”

Section: Discussionmentioning

confidence: 99%

“…27,28 Interestingly, it was also demonstrated that the increased amounts of renal interstitial collagens were co-localized with fibroblasts. 28 These findings suggest that fibroblasts play a role in renal fibrosis through the synthesis of types I, III, and IV collagen. In the present study, aldosterone Figure 3.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Stimulates Collagen Gene Expression and Synthesis Via Activation of ERK1/2 in Rat Renal Fibroblasts

et al. 2005

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Abstract-Recently, we demonstrated that in rats treated chronically with aldosterone and salt, severe tubulointerstitial fibrosis is associated with the activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERK1/2). Here, we investigated whether aldosterone stimulates collagen synthesis via ERK1/2-dependent pathways in cultured rat renal fibroblasts. Gene expression of mineralocorticoid receptor (MR) and types I, II, III, and IV collagen was measured by real-time polymerase chain reaction (PCR). MR protein expression and ERK1/2 activity were evaluated by Western blotting analysis with anti-MR and anti-phospho-ERK1/2 antibodies, respectively. Collagen synthesis was determined by [ 3 H]-proline incorporation. Significant levels of MR mRNA and protein expression were observed in rat renal fibroblasts. Treatment with aldosterone (0.1 to 10 nmol/L) increased ERK1/2 phosphorylation in a concentration-dependent manner with a peak at 5 minutes. Aldosterone (10 nmol/L) also increased the mRNA levels of types I, III, and IV collagen at 36 hours but had no effect on the type II collagen mRNA level.[3 H]-proline incorporation was significantly increased by aldosterone in both the medium and cell layer at 48 hours. Aldosterone-induced ERK1/2 phosphorylation was markedly attenuated by pretreatment with eplerenone (10 mol/L), a selective MR antagonist, or PD98059 (10 mol/L), a specific inhibitor of MAPK kinase/ERK kinase, which is the upstream activator of ERK1/2. In addition, both eplerenone and PD98059 prevented the aldosterone-induced increases in types I, III, and IV collagen mRNA and [ Key Words: aldosterone Ⅲ collagen Ⅲ fibroblasts Ⅲ mineralocorticoids R ecent studies have indicated the usefulness of mineralocorticoid receptor (MR) antagonists in ameliorating renal injury. [1][2][3][4][5][6][7][8][9][10][11][12][13] In stroke-prone spontaneously hypertensive rats 4 and rats treated with angiotensin II and a nitric oxide synthase inhibitor, 5 cyclosporine A, 6 or radiation, 7 MR antagonists had no effect on systemic blood pressure but markedly ameliorated glomerular and tubulointerstitial fibrosis. In clinical studies, the addition of a nonselective MR antagonist, spironolactone, to angiotensin-converting enzyme inhibitors had no hemodynamic effects but markedly reduced proteinuria in patients with chronic renal failure 8 and early diabetic nephropathy. 9 It has also been shown that monotherapy with spironolactone 10 or eplerenone, 11 a selective MR antagonist, is more effective than angiotensin-converting enzyme inhibitors in reducing proteinuria in hypertensive patients. Furthermore, White et al 12 showed that in hypertensive patients, eplerenone had a similar blood pressurelowering effect to that of a calcium antagonist, amlodipine, but reduced the urinary albumin-to-creatinine ratio to a greater extent. These observations suggest that MR blockade has renoprotective effects through mechanisms that cannot be simply explained by blood pressure and hemodynamic changes.R...

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Myofibroblasts and the progression of crescentic glomerulonephritis

Cited by 60 publications

References 3 publications

Tissue Transglutaminase and the Progression of Human Renal Scarring

Tissue Transglutaminase and the Progression of Human Renal Scarring

Osteopontin in Rat Renal Fibroblasts

Aldosterone Stimulates Collagen Gene Expression and Synthesis Via Activation of ERK1/2 in Rat Renal Fibroblasts

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