Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by antioxidants

Pat, Betty; Yang, Tao; Kong, Chuize; Watters, Dianne Josephine; Johnson, David W.; Gobé, Glenda C.

doi:10.1111/j.1523-1755.2005.00157.x

Cited by 124 publications

(114 citation statements)

References 46 publications

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“…48,49 Thus, HO-1 activity, through its antioxidant properties, may impair oxidant formation and, hence, reduce EMT. HO-1 protein is upregulated in the obstructed kidney as early as 6 h after UUO and persists up to at least 7 d. 20,21 In this study, HO-1 was expressed in the renal tubules in the sham and CL kidneys of HO-1 ϩ/ϩ mice and was markedly increased in the obstructed kidneys. HO-1 induction has been previously shown to have antifibrotic effects.…”

Section: Discussionmentioning

confidence: 81%

“…The time point was chosen on the basis of previous studies demonstrating that at 7 d, cellular recruitment and growth factor-dependent matrix accumulation have begun and HO-1 is induced. 20,21,60 At the time of killing, both kidneys were removed and cut transversely, and sections were fixed (10% buffered formaldehyde solution) for histopathologic studies or snap-frozen in liquid nitrogen for Western analysis. …”

Section: Animals Surgery and Tissue Preparationmentioning

confidence: 99%

“…At the age of 6 to 8 wk, HO-1 Ϫ/Ϫ and HO-1 ϩ/ϩ mice have similar phenotypes, 59 and renal Fn levels, as measured by Western blot analysis, are the same (unpublished observations). UUO surgery was performed as described by Pat et al 21 Mice were anesthetized with inhalation of isoflurane (2.5%). In the UUO group, the left ureter was exposed through a mid-abdominal incision and ligated twice, approximately 1 cm below the renal hilum, using a 4-0 silk suture.…”

Section: Animals Surgery and Tissue Preparationmentioning

confidence: 99%

See 2 more Smart Citations

Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis

Kie

Kapturczak

Traylor

et al. 2008

Journal of the American Society of Nephrology

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Induction of heme oxygenase-1 (HO-1) is associated with potential antifibrogenic effects. The effects of HO-1 expression on epithelial-mesenchymal transition (EMT), which plays a critical role in the development of renal fibrosis, are unknown. In this study, HO-1 Ϫ/Ϫ mice demonstrated significantly more fibrosis after 7 d of unilateral ureteral obstruction compared with wild-type mice, despite similar degrees of hydronephrosis. The obstructed kidneys of HO-1 Ϫ/Ϫ mice also had greater macrophage infiltration and renal tubular TGF-␤1 expression than wild-type mice. In addition, the degree of EMT was more extensive in obstructed HO-1 Ϫ/Ϫ kidneys, as assessed by ␣-smooth muscle actin and expression of S100A4 in proximal tubular epithelial cells. In vitro studies using proximal tubular cells isolated from HO-1 Ϫ/Ϫ and wild-type kidneys confirmed these observations. In conclusion, HO-1 deficiency is associated with increased fibrosis, tubular TGF-␤1 expression, inflammation, and enhanced EMT in obstructive kidney disease. Modulation of the HO-1 pathway may provide a new therapeutic approach to progressive renal diseases.

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Section: Discussionmentioning

confidence: 81%

Section: Animals Surgery and Tissue Preparationmentioning

confidence: 99%

Section: Animals Surgery and Tissue Preparationmentioning

confidence: 99%

See 1 more Smart Citation

Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis

Kie

Kapturczak

Traylor

et al. 2008

Journal of the American Society of Nephrology

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“…71,86 Furthermore, the ERK signaling pathway is activated in UUO and may provide approaches in preventing progression of renal fibrosis. 100,101 As expected, a-SMA expression as well as ERK1/2 phosphorylation, renal fibroblasts proliferation, and activation increased in obstructed kidneys. In vivo, TRPC3 inhibition abrogated these changes, pointing toward an important role of TRPC3 in the pathogenesis of kidney disease simulated by the UUO model.…”

Section: +mentioning

confidence: 78%

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

Saliba¹,

Karam²,

Smayra

et al. 2015

Journal of the American Society of Nephrology

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Transient receptor potential canonical (TRPC) Ca 2+ -permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II-and 1-oleoyl-2-acetyl-sn-glycerol-induced Ca 2+ entry in these cells, which was detected by fura-2 Ca 2+ imaging. TRPC3 blockade or Ca 2+ removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signalregulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca 2+ entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca 2+ -mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease.

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“…ERK1/2 is an important mediator of the intracellular signal transduction pathway responsible for collagen synthesis in cardiovascular tissues, including the kidney. 14 Pat et al 29 revealed that tubulointerstitial fibrosis induced by unilateral ureteral obstruction was associated with ERK1/2 phosphorylation in rats. Interestingly, unilateral ureteral obstruction-induced tubulointerstitial fibrosis was reported to be markedly attenuated by treatment with spironolactone, suggesting that aldosterone/MR may contribute to its pathogenesis.…”

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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Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by antioxidants

Cited by 124 publications

References 46 publications

Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis

Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis

Evidence of a Role for Fibroblast Transient Receptor Potential Canonical 3 Ca2+ Channel in Renal Fibrosis

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

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