Fibrillin-1 and alpha8 integrin are co-expressed in the glomerulus and interact to convey adhesion of mesangial cells

Abstract

Fibrillin-1 is a microfibrillar extracellular matrix protein that was described to be a ligand for α8 integrin. α8 integrin is a matrix receptor specifically expressed in mesangial and smooth muscle cells of the kidney. In previous studies we detected glomerular expression of fibrillin-1. Moreover, fibrillin-1 promoted adhesion, migration, and proliferation of mesangial cells. We hypothesized that fibrillin-1 and α8 integrin might interact in the glomerulus, and thus, regulate mesangial cell properties. Our studies showed that fibrillin-1 and α8 integrin colocalize in the glomerular mesangium. Induction of experimental glomerulonephritis led to an increase of both fibrillin-1 and α8 integrin expression. In vitro studies revealed that mesangial cells deficient for α8 integrin adhere weaker to fibrillin-1 and migrate more easily on fibrillin-1 than wild-type mesangial cells. Baseline proliferation on fibrillin-1 is higher in α8 integrin-deficient mesangial cells, but the induction of proliferation is not different in α8 integrin-deficient and wild-type mesangial cells. We conclude that fibrillin-1 and α8 integrin interact, and thus, regulate mesangial cell adhesion and migration. The concomitant induction of both fibrillin-1 and α8 integrin in a self-limited model of glomerular injury points to a protective role of the interaction of fibrillin-1 with α8 integrin in the glomerulus resulting in reduced damage of the glomerular tuft as a consequence of firm adhesion of mesangial cells.

Fibrillin-1–enriched microenvironment drives endothelial injury and vascular rarefaction in chronic kidney disease

“…4). These data are supported by previous observations that FBN1 interacts with a variety of integrins ( 5  1 ,  5  6 ,  v  3 ,  v  6 , and  8  1 ) (30,31), of which  v  3 ,  v  6 , and  5  1 are expressed in endothelial cells (32,33). FBN1 does not affect integrin  1 and  3 expression in HUVECs, and blockade of  v  3 and  v  5 signaling fails to inhibit FBN1-mediated TGF- activation and endothelial cell apoptosis (fig.…”

“…, and  8  1 ) (30,31), of which  v  3 ,  v  6 , and  5  1 are expressed in endothelial cells (32,33). FBN1 does not affect integrin  1 and  3 expression in HUVECs, and blockade of  v  3 and  v  5 signaling fails to inhibit FBN1-mediated TGF- activation and fig.…”

Structural and functional failure of fibrillin‑1 in human diseases (Review)

“…In vitro studies on cells cultured on FBN-1 RGD-containing peptides have established the impact of this interaction on cell adhesion and gene expression(99). Cellular interactions have been reported to be mediated via integrins (α 5 β 1 , α 5 β 6 , α v β 3 , α v β 6 and α 8 β 1 )(19,(99)(100)(101)(102)(103) and, potentially, by other cellular sensors, including angiotensin II type 1 receptor (AT1) and proteoglycans, such as syndecans(35,(104)(105)(106). Mutations in regions close to the RGD binding site in FBN-1 lead to a condition that is termed stiff skin syndrome (SSS), a pathological condition that is characterized by excessive skin fibrosis and microfibril…”

Mesangial cell: A hub in lupus nephritis

“…Evidence demonstrates that a single hematopoietic stem cell can differentiate into glomerular MCs (5). Notably, alpha8 integrin (Itga8) is strongly and exclusively expressed in MCs (6), promoting cellular adhesion while inhibiting their migration and proliferation (7,8). MCs are damaged in renal diseases, directly or indirectly affecting the functions of the kidney when the lesions occur and eventually causing renal failure.…”

“…Evidence demonstrates that a single hematopoietic stem cell can differentiate into glomerular MCs ( 5 ). Notably, alpha8 integrin (Itgα8) is strongly and exclusively expressed in MCs ( 6 ), promoting cellular adhesion while inhibiting their migration and proliferation ( 7 , 8 ).…”