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

Abstract

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.

Role of integrin alpha8 in murine model of lung fibrosis

“…A similar finding was reported for cells in the glomerulus of ITGA8 global KO kidneys [ 23 , 24 ]. Thus, ITGA8 signaling may attenuate activation of PDGFRβ+ cells in vitro , as seen previously in renal fibroblasts [ 15 ]. Based on these in vitro observations, we speculated that lack of ITGA8 expression in lung PDGFRβ+ stromal cells would exacerbate the pro-fibrotic response following injury.…”

“…Targeted spatial deletions of ITGA8, however, do not result in developmental abnormalities seen in ITGA8 knockout mice. Studies of fibrosis in kidneys suggest ITGA8 signaling might attenuate renal fibrosis, but the functional role of ITGA8 in lung fibrosis has never been studied [ 15 – 17 ]. Since ITGA8 expression is restricted to stromal cells in the lung, we investigated the functional role of ITGA8 expression in myofibroblasts in lung fibrosis.…”

Comparative proteomic analysis of silica-induced pulmonary fibrosis in rats based on tandem mass tag (TMT) quantitation technology

“…ITGA8 may participate in the degradation of extracellular matrix, including collagen type XI alpha 1, aggrecan, collagen type VI alpha 1 [ 48 ]. Additionally, ITGA8 attenuated tubulointerstitial fibrosis by regulation of TGF-β /Smad2/3 signaling, fibroblast activation and immune cell infiltration [ 49 ]. Deficiency of ITGA8 worsened tubulointersititial fibrosis [ 50 ] and delayed healing in a model of glomerulonephritis [ 51 ].…”

Lysyl oxidase-like 2 is expressed in kidney tissue and is associated with the progression of tubulointerstitial fibrosis

“…Contributing signal transduction pathways and mechanisms include the Wnt/β-catenin pathway, platelet-derived growth factors, epithelial-mesenchymal transition and autophagy ( 19 ). Recently, knowledge regarding the mechanisms underlying the pathogenesis of tubulointerstitial fibrosis has increased, and an animal study regarding its prevention has produced promising results ( 20 ). However, few therapeutic agents for clinical use have been developed.…”