PDGF in organ fibrosis

Klinkhammer, Barbara M.; Floege, Jürgen; Boor, Peter

doi:10.1016/j.mam.2017.11.008

Cited by 170 publications

(131 citation statements)

References 228 publications

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“…TGFβ1 signaling in other renal injury models recruits Gli1+ MSC‐like progenitor cells from the perivascular space and promotes the conversion of these cells and Gli1− kidney‐resident MSC‐like cells into activated myofibroblasts capable of depositing extracellular matrix components, including collagens (Asada et al, 2011; Kramann, Schneider, et al, 2015; Wan et al, 2012; Wu et al, 2013). We used flow cytometry to interrogate the effect of androgen exposure on the populations of kidney‐resident MSC‐like cells (CD45−, E‐cadherin−, PDGFRβ+, Gli1−; consisting of fibroblasts, mesangial cells, and pericytes (Boor, Ostendorf, & Floege, 2014; Klinkhammer, Floege, & Boor, 2018; Wu et al, 2013)) and activated myofibroblasts (CD45−, E‐cadherin−, PDGFRβ+, Gli1+, αSMA+, and Nestin+ (Humphreys, 2018; Kramann, Schneider, et al, 2015)) in the kidney before and throughout UPEC pyelonephritis. Prior to the onset of UTI, the kidneys of TC‐treated mice harbored slightly more MSC‐like cells (Figure 4a) and significantly more activated myofibroblasts (Figure 4b) than in vehicle‐treated mice.…”

Section: Resultsmentioning

confidence: 99%

TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis

et al. 2020

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Renal scarring after pyelonephritis is linked to long‐term health risks for hypertension and chronic kidney disease. Androgen exposure increases susceptibility to, and severity of, uropathogenic Escherichia coli (UPEC) pyelonephritis and resultant scarring in both male and female mice, while anti‐androgen therapy is protective against severe urinary tract infection (UTI) in these models. This work employed androgenized female C57BL/6 mice to elucidate the molecular mechanisms of post‐infectious renal fibrosis and to determine how these pathways are altered by the presence of androgens. We found that elevated circulating testosterone levels primed the kidney for fibrosis by increasing local production of TGFβ1 before the initiation of UTI, altering the ratio of transcription factors Smad2 and Smad3 and increasing the presence of mesenchymal stem cell (MSC)‐like cells and Gli1 + activated myofibroblasts, the cells primarily responsible for deposition of scar components. Increased production of TGFβ1 and aberrations in Smad2:Smad3 were maintained throughout the course of infection in the presence of androgen, correlating with renal scarring that was not observed in non‐androgenized female mice. Pharmacologic inhibition of TGFβ1 signaling blunted myofibroblast activation. We conclude that renal fibrosis after pyelonephritis is exacerbated by the presence of androgens and involves activation of the TGFβ1 signaling cascade, leading to increases in cortical populations of MSC‐like cells and the Gli1 + activated myofibroblasts that are responsible for scarring.

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Section: Resultsmentioning

confidence: 99%

TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis

et al. 2020

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Section: Discussionmentioning

confidence: 99%

“…Masson trichrome staining showed that collagen deposition in bladder tissue was greater on days 15 and 21 postcystostomy than under noncystostomy conditions. It is well known that chronic inflammation over a long time may lead to tissue fibrosis and 25 The increased collagen deposition in bladder tissue was likely due to chronic inflammation caused by long-term catheterization. Although there was more fibrous tissue present in the bladders on days 15 and 21 than on days 5 to 11 postcystostomy, P ves.basal , P ves.max , and P ves.thre did not significantly differ between these time periods, indicating that mild fibrosis did not significantly impair bladder contraction.…”

Section: Discussionmentioning

confidence: 99%

Changes in bladder function with time following cystostomy in rats

Chen

Wen

et al. 2019

Neurourology and Urodynamics

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Aims: To investigate bladder function patterns following cystostomy and determine the best time window for cystometric evaluation of bladder function in conscious rats.Materials and Methods: Cystostomy was performed in rats of the first seven groups; thereafter, cystometry was performed in the designed time interval.Noncystostomy rats of group 8 voided freely as control. Basal bladder pressure (P ves.basal ), maximum bladder pressure (P ves.max ), bladder threshold pressure (P ves.thre ), voiding interval (VI), bladder contraction duration (CD) , bladder compliance (ΔC), voided volume (VV), postvoiding residual urine (PVR), and bladder capacity (BC) were recorded and compared with cystostomy groups, with VV, PVR, BC compared with the control values. Bladders were collected after the urodynamic study for weighing, hematoxylin-eosin, and Masson staining to investigate pathological changes.Results: P ves.basal , P ves.max , and P ves.thre trended downward, while BC, VI, VV, and ΔC trended upward on days 1 to 5 postcystostomy. BC and VV significantly decreased on days 1 to 3 postcystostomy compared with control values; on days 5 to 15 postcystostomy, P ves.basal , P ves.max , P ves.thre , VI, VV, BC, and PVR were stable, and BC, VV, and PVR showed no significant differences from the control values. However, on day 21 postcystostomy, BC increased significantly compared with the controls. Bladder weight increased in the cystostomy groups compared with the controls. Pathological analysis showed severe acute bladder inflammation on days 1 to 3, mild inflammation on days 5 to 15, and increased collagen deposition in bladder tissue on day 21 postcystostomy. Conclusion: Cystometric evaluation of bladder function in conscious rats is best performed on days 5 to 15 postcystostomy. K E Y W O R D Sbladder, collagen, cystometry, cystostomy, HE staining, Masson staining, rat

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“…Unfortunately, literature information in this regard is very limited. In our experimental setting, the FMT inducer PDGF-AA activates PDGFR, a well-known "gateway" receptor on the cell surface that activates myriad of intracellular pathways 2,4 . However, whether PDGFR regulates PLK4 was not previously known.…”

Section: Blocking Pdgfr Kinase Activity Abrogates Aa-stimulated Plk4 mentioning

confidence: 99%

“…There are four PDGF ligands (PDGF-A, B, C, D) that activate two different receptor tyrosine kinases, PDGFR and PDGFR. The PDGF-AA homodimer selectively activates PDGFR, which is abundant in mesenchymal and fibroblastic cells yet inadequately explored for its role in FMT and vascular fibrosis 4 .…”

Section: Introductionmentioning

confidence: 99%

A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition

Urabe

Zhang

et al. 2019

Preprint

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Fibroblast-to-myofibroblast transition (FMT) is central to fibrosis. A divergent member of the polo-like kinase family, PLK4 is known for its canonical role in centriole duplication. Whether this mitotic factor regulates cell type transitions was underexplored. Here we investigated PLK4's activation and expression and regulations thereof in platelet-derived growth factor (PDGF)induced FMT of rat aortic adventitial fibroblasts.PLK4 inhibition (with centrinone-B or siRNA) diminished not only PDGF AA-induced proliferation/migration, but also smooth muscle -actin and its transcription factor serum response factor's activity. While PDGFR inhibition abrogated AA-stimulated PLK4 activation (phosphorylation) and mRNA/protein expression, inhibition of p38 downstream of PDGFR had a similar effect. Further, the transcription of PLK4 (and PDGFR) was blocked by pan-inhibition of the bromo/extraterminal-domains chromatin-bookmark readers (BRD2, BRD3, BRD4), an effect herein determined via siRNAs as mainly mediated by BRD4. In vivo, periadventitial administration of centrinone-B reduced collagen content and thickness of the adventitia in a rat model of carotid artery injury.Thus, we identified a non-canonical role for PLK4 in FMT and its regulation by a BRD4/PDGFR-dominated pathway. This study implicates a potential PLK4-targeted antifibrotic intervention.

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PDGF in organ fibrosis

Cited by 170 publications

References 228 publications

TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis

TGFβ1 orchestrates renal fibrosis following Escherichia coli pyelonephritis

Changes in bladder function with time following cystostomy in rats

A non-canonical role and regulations of polo-like kinase-4 in fibroblast cell-type transition

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