Tubulointerstitial De Novo Expression of the α8 Integrin Chain in a Rodent Model of Renal Fibrosis – A Potential Target for Anti-Fibrotic Therapy?

Hartner, Andrea; Menendez-Castro, Carlos; Cordasic, Nada; Marek, Ines; Volkert, Gudrun; Klanke, Bernd; Rascher, Wolfgang; Hilgers, Karl F.

doi:10.1371/journal.pone.0048362

Cited by 17 publications

(23 citation statements)

References 30 publications

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“…Overexpression of ITGA8 can lead to glomerulosclerosis. It can also induce tissue fibrosis of the liver, lung, and heart in animal models [29]. ITGA8 is also known to participate in organ development.…”

Section: Discussionmentioning

confidence: 99%

ITGA2B and ITGA8 are predictive of prognosis in clear cell renal cell carcinoma patients

et al. 2015

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Integrins play an important role in cancer growth and metastasis. This study aimed at determining the predictive ability of integrins and associated genes identified through molecular network in clear cell renal cell carcinoma. A total of 525 patients with ccRCC from The Cancer Genome Atlas (TCGA) cohorts were collected in this study. The expression profile of integrins and related genes were obtained from the TCGA RNAseq database. Clinicopathological characteristics, including age, gender, tumor size, tumor node metastasis (TNM), tumor grade, stage, laterality, and overall survival were collected. Cox proportional hazards regression model as well as Kaplan-Meier curve were used to assess the relative factors. Genes of integrin family that showed certain correlations with overall survival (OS) were further validated in the Fudan University Shanghai Cancer Center (FUSCC) cohort. In the TCGA cohort, after Cox proportional hazards analysis, ITGA2B (hazards ratio (HR) = 1.232, 95 % CI 1.097 to 1.383) and ITGA8 (HR = 0.804, 95 % CI 0.696 to 0.930) were shown predictive of ccRCC prognosis. Low ITGA8 expression was associated with poor prognosis for OS (log-rank test, p < 0.0001), while high level of ITGA2B expression was correlated with poor prognosis for OS (log-rank test, p < 0.0001). This finding was validated in FUSCC cohort (log-rank test, all p < 0.05). As a result, low ITGA8 expression was associated with poor prognosis for OS (log-rank test, p = 0.0053), while high level of ITGA2B expression was correlated with poor prognosis for OS (log-rank test, p < 0.0001). Plus, low ITGA8 expression was associated with poor prognosis for disease-free survival (DFS) in the TCGA cohort (log-rank test, p < 0.0001). In the gene cluster network analysis, GIT1 and SHC1 associated with ITGA2B and ITGA8 were identified as independent predictive factors of overall survival of ccRCC. ITGA2B, ITGA8, GIT1, and SHC1 were identified as independent prognostic factors of overall survival of ccRCC. This method may act as a tool to reveal more prognostic-associated genes in ccRCC.

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Section: Discussionmentioning

confidence: 99%

ITGA2B and ITGA8 are predictive of prognosis in clear cell renal cell carcinoma patients

et al. 2015

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“…As described previously [ 12 ], Itga8 -deficient mice were from Dr. Ulrich Muller (Scripps Institute, LaJolla, USA) [ 15 ]. They were maintained on a mixed genetic background (C57BL/6x129Sv).…”

Section: Methodsmentioning

confidence: 99%

“…Findings in cultivated vascular smooth muscle cells and cell lines suggest that Itga8 might regulate cell growth and survival [ 10 , 11 ]. In murine UUO, Itga8 is de novo expressed by tubulointerstitial fibroblasts and tubular epithelial cells [ 12 ]. We have previously shown that renal fibrosis after UUO is more severe in mice with a deficiency for the Itga8 chain [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…In murine UUO, Itga8 is de novo expressed by tubulointerstitial fibroblasts and tubular epithelial cells [ 12 ]. We have previously shown that renal fibrosis after UUO is more severe in mice with a deficiency for the Itga8 chain [ 12 ]. The mechanism by which Itga8 expression attenuates the development of tubulointerstitial fibrosis is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover

et al. 2016

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The α8 integrin (Itga8) chain contributes to the regulation of cell proliferation and apoptosis in renal glomerular cells. In unilateral ureteral obstruction Itga8 is de novo expressed in the tubulointerstitium and a deficiency of Itga8 results in more severe renal fibrosis after unilateral ureteral obstruction. We hypothesized that the increased tubulointerstitial damage after unilateral ureteral obstruction observed in mice deficient for Itga8 is associated with altered tubulointerstitial cell turnover and apoptotic mechanisms resulting from the lack of Itga8 in cells of the tubulointerstitium. Induction of unilateral ureteral obstruction was achieved by ligation of the right ureter in mice lacking Itga8. Unilateral ureteral obstruction increased proliferation and apoptosis rates of tubuloepithelial and interstitial cells, however, no differences were observed in the tubulointerstitium of mice lacking Itga8 and wild type controls regarding fibroblast or proliferating cell numbers as well as markers of endoplasmic reticulum stress and apoptosis after unilateral ureteral obstruction. In contrast, unilateral ureteral obstruction in mice lacking Itga8 led to more pronounced tubulointerstitial cell activation i.e. to the appearance of more phospho-SMAD2/3-positive cells and more α-smooth muscle actin-positive cells in the tubulointerstitium. Furthermore, a more severe macrophage and T-cell infiltration was observed in these animals compared to controls. Thus, Itga8 seems to attenuate tubulointerstitial fibrosis in unilateral ureteral obstruction not via regulation of cell turnover, but via regulation of TGF-β signalling, fibroblast activation and/or immune cell infiltration.

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“…Hartner et al described de novo a8b1 expression on renal fibroblasts after UUO. 10 They found that mice lacking a8b1 suffered worse UUO-induced renal fibrosis compared with wild-type controls, suggesting a possible protective effect of a8b1. a8b1 has been reported to bind LAP but does not activate TGFb1.…”

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confidence: 99%

Pharmacologic Blockade of αvβ1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo

Chang

Lau

Jo³

et al. 2017

JASN

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Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells is poorly understood. PDGF receptor (PDGFR) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR promoter-driven Cre system to delete v integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFR-Cre line to isolate and study renal fibroblasts We found that renal fibroblasts express threev integrins, namely v1, v3, and v5. Blockade of v1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-1 and prevented activation of the latent TGF- complex. Continuous administration of a recently described potent small molecule inhibitor of v1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of v1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.

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Tubulointerstitial De Novo Expression of the α8 Integrin Chain in a Rodent Model of Renal Fibrosis – A Potential Target for Anti-Fibrotic Therapy?

Cited by 17 publications

References 30 publications

ITGA2B and ITGA8 are predictive of prognosis in clear cell renal cell carcinoma patients

ITGA2B and ITGA8 are predictive of prognosis in clear cell renal cell carcinoma patients

Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover

Pharmacologic Blockade of αvβ1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo

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