Human renal fibroblast contraction of collagen I lattices is an integrin‐mediated process

Kelynack, Kristen J.; Hewitson, Tim D.; Nicholls, Kathy; Darby, Ian A.; Becker, Gavin J.

doi:10.1093/ndt/15.11.1766

Cited by 30 publications

(27 citation statements)

References 26 publications

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“…[102][103][104][105][106][107] BSA (Sigma-Aldrich, St. Louis, MO). Renal tubules were discarded after the first centrifugation (500 rpm for 10 minutes), and then, the remaining cells were collected after the second centrifugation (2000 rpm for 10 minutes).…”

Section: Fibroblast Isolation and Culturementioning

confidence: 99%

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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Section: Fibroblast Isolation and Culturementioning

confidence: 99%

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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“…Northern blot analysis with appropriate cDNA sequences to procollagen · 1 (I) (clone HF 677) [19] and ß1 integrin [20] was performed to examine the effect of PTH on collagen I transcription and expression of the ß1 integrin family of matrix receptors.…”

Section: Northern Hybridisationmentioning

confidence: 99%

Parathyroid Hormone Has a Prosclerotic Effect on Vascular Smooth Muscle Cells

Perkovic

Hewitson²,

Kelynack³

et al. 2003

Kidney Blood Press Res

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111

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Although accelerated atherosclerosis and arteriosclerosis are common in patients with renal failure, the pathogenesis of these changes is poorly understood. Parathyroid hormone (PTH) levels are elevated in renal failure, and have been linked to uraemic vascular changes in some studies. We examined the in vitro effects of increasing doses of the 1–34 fragment of PTH on human aortic vascular smooth muscle cells (VSMCs). Factors examined were: (1) collagen production using tritiated hydroxyproline incorporation and transcription of procollagen α₁(I) mRNA; (2) change in the surface area of collagen I lattices; (3) mRNA transcription of the collagen binding protein β1 integrin; (4) proliferation using tritiated thymidine incorporation, and (5) methyl tetrazolium salt conversion to estimate live cell number after 5 days’ exposure to PTH. PTH at a concentration of 200 pmol/l increased total collagen synthesis (188 ± 25% of control, p < 0.01) as well as transcription of procollagen α₁(I) mRNA (136 ± 11% of control, p < 0.005). PTH also increased reorganisation of collagen I lattices (surface area 47 ± 8% of well for control vs. 35.7 ± 2.5 and 34.3 ± 3.0% for PTH 100 and 200 pmol/l, respectively, p = 0.02) and upregulated β1 integrin mRNA expression (160 ± 20% of control at PTH concentration of 200 pmol/l, p < 0.05). PTH had no effect on VSMC proliferation or number at doses up to 200 pmol/l. In conclusion, PTH increases production and reorganisation of collagen by VSMCs in vitro. It is possible that more aggressive control of hyperparathyroidism in patients with renal failure may help to reduce the burden of cardiovascular disease in this patient population.

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“…This process appears to be integrin-mediated. [42][43][44][45] The severity of tubular atrophy and interstitial fibrosis is closely related with the extent of chronic glomerular lesions and the degree of TIN infiltration by activated mononuclear cells. Activation of tubular cells (e.g., HLA-DR (+) cells) may induce the influx of mononuclear cells in the tubulointerstitial space, as it can be suggested by the correlation between the numbers of tubular HLA-DR (+) and interstitial HLA-DR (+) cells.…”

Section: Discussionmentioning

confidence: 99%

Fibrotic Mechanisms in Idiopathic Rapidly Progressive Glomerulonephritis: The Role of TGF-β1 and C5b-9

et al. 2008

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Background. Idiopathic IRPGN is a form of renal vasculitis in which a high chronicity index is present despite minimal impairment of renal function. The present study investigated the mechanisms underlining the relatively early appearance of fibrosis. Methods. In all, 34 patients (17 males) with biopsy proven idiopathic RPGN were included. On light microscopy, the percentage and evolution stage of crescents, the presence of glomerular necrosis, the degree or severity of arteriosclerosis, as well as the extent of tubulointerstitial (TIN) infiltration, interstial fibrosis, and tubular atrophy were assessed. Monoclonal antibodies were used to identify infiltrating macrophages, HLA-DR (+), α-SMA (+), and PCNA (+) cells, the expression of the adhesion molecule ICAM-1, the growth factor TGF-β1, and the terminal complement component C5b-9. Results. The presence of glomerular necrosis correlated positively with the number of SMA (+) cells in TIN (p = 0.036). Glomerular TGF-β1 expression had positive correlation with tubular C5b-9 expression. The tubulointerstitial TGF-β1 expression correlated with tubular C5b-9 expression (p = 0.001) and TGF-β1 expression (p = 0.009). Independent factors predicting the severity of renal function impairment were the CRP levels (p = 0.002) and the degree of arteriosclerosis (p = 0.01). CRP levels correlated with the severity of interstitial infiltration and fibrosis (p = 0.02), the expression of TGF-β1 in the glomeruli (p = 0.009) and the interstitial space (p = 0.001), and the intensity of tubular ICAM-1 and C5b-9 expression (p = 0.023, p = 0.002, respectively). The severity of proteinuria showed a significant correlation with the expression of TGF-β1 in the glomeruli (p = 0.033) and the tubulointerstitium (p = 0.019). Conclusions. The activation of interstitial fibroblasts seems to be an early phenomenon that is related to the extent of glomerular necrosis. Glomerular TGF-β1 may induce tubular expression of C5b-9. Increased tubular C5b-9 expression may result in interstitial fibrosis through increased TGF-β1 production.

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Human renal fibroblast contraction of collagen I lattices is an integrin‐mediated process

Abstract: We postulate that collagen I fibril rearrangement by human renal fibroblasts in vitro appears to be an integrin-mediated process involving the alpha2beta1 integrin.

Cited by 30 publications

References 26 publications

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

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

Parathyroid Hormone Has a Prosclerotic Effect on Vascular Smooth Muscle Cells

Fibrotic Mechanisms in Idiopathic Rapidly Progressive Glomerulonephritis: The Role of TGF-β1 and C5b-9

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