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The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression.

ABSTRACT: The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. A key question is how parietal epithelial cells (PECs) invade glomerular capillaries, thereby promoting injury and kidney failure. Here we show that expression of the tetraspanin CD9 increases markedly in PECs in mouse models of CGN and FSGS, and in kidneys from individuals diagnosed with these diseases. Cd9 gene targeting in PECs prevents glomerular damage in CGN and FSGS mouse models. Mechanistically, CD9 deficiency prevents the oriented migration of PECs into the glomerular tuft and their acquisition of CD44 and ?1 integrin expression. These findings highlight a critical role for de novo expression of CD9 as a common pathogenic switch driving the PEC phenotype in CGN and FSGS, while offering a potential therapeutic avenue to treat these conditions.

SUBMITTER: Lazareth H

PROVIDER: S-EPMC6656772 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression.

Lazareth Hélène H Henique Carole C Lenoir Olivia O Puelles Victor G VG Flamant Martin M Bollée Guillaume G Fligny Cécile C Camus Marine M Guyonnet Lea L Millien Corinne C Gaillard François F Chipont Anna A Robin Blaise B Fabrega Sylvie S Dhaun Neeraj N Camerer Eric E Kretz Oliver O Grahammer Florian F Braun Fabian F Huber Tobias B TB Nochy Dominique D Mandet Chantal C Bruneval Patrick P Mesnard Laurent L Thervet Eric E Karras Alexandre A Le Naour François F Rubinstein Eric E Boucheix Claude C Alexandrou Antigoni A Moeller Marcus J MJ Bouzigues Cédric C Tharaux Pierre-Louis PL

Nature communications 20190724 1

The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. A key question is how parietal epithelial cells (PECs) invade glomerular capillaries, thereby promoting injury and kidney failure. Here we show that expression of the tetraspanin CD9 increases markedly in PECs in mouse models of CGN and FSGS, and in kidneys from individuals diagnosed with these diseases. Cd9 gene targeting ...[more]

PMID: 31341160

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Project description:Tetraspanins are a family of proteins with four transmembrane domains that associate between themselves and cluster with other partner proteins, conforming a distinct class of membrane domains, the tetraspanin-enriched microdomains (TEMs). These TEMs constitute macromolecular signaling platforms that regulate key processes in several cellular settings controlling signaling thresholds and avidity of receptors. In this study, we investigated the role of CD9, a tetraspanin that regulates major biological processes such as cell migration and immunological responses, in two mouse models of colitis that have been used to study the pathogenesis of inflammatory bowel disease (IBD). Previous in vitro studies revealed an important role in the interaction of leukocytes with inflamed endothelium, but in vivo evidence of the involvement of CD9 in inflammatory diseases is scarce. Here, we studied the role of CD9 in the pathogenesis of colitis in vivo. Colitis was induced by administration of dextran sodium sulfate (DSS), a chemical colitogen that causes epithelial disruption and intestinal inflammation. CD9-/- mice showed less severe colitis than wild-type counterparts upon exposure to DSS (2% solution) and enhanced survival in response to a lethal DSS dose (4%). Decreased neutrophil and macrophage cell infiltration was observed in colonic tissue from CD9-/- animals, in accordance with their lower serum levels of TNF-?, IL-6, and other proinflammatory cytokines in the colon. The specific role of CD9 in IBD was further dissected by transfer of CD4+ CD45RBhi naive T cells into the Rag1-/- mouse colitis model. However, no significant differences were observed in these settings between both groups, ruling out a role for CD9 in IBD in the lymphoid compartment. Experiments with bone marrow chimeras revealed that CD9 in the non-hematopoietic compartment is involved in colon injury and limits the proliferation of epithelial cells. Our data indicate that CD9 in non-hematopoietic cells plays an important role in colitis by limiting epithelial cell proliferation. Future strategies to repress CD9 expression may be of therapeutic benefit in the treatment of IBD.

Dataset Information

The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression.

Publications

The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression.

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