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 β1 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.

Cellular regeneration of podocytes from parietal cells: the debate is still open

“…Regarding the role of PECs in driving progression, Kaverina et al confirm that upon induction of FSGS, PECs become activated and migrate to the capillary tuft into sclerotic lesions or proliferate to form cellular crescents. This is in line with an increasing number of independent groups that have confirmed an essential and deleterious role of PECs for lesion formation and progression in FSGS (see Lazareth et al 6 ), and this aspect of PEC biology has become generally accepted in the field (Figure 1a and b).…”

mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans

“…Interestingly, a recent publication shows that blocking tetraspanin CD9 signaling in PECs is sufficient to prevent glomerulosclerosis (44), which may be directly related to the capacity of PECs to sense signals from neighboring cells (e.g., endothelial cells or podocytes). Thus, there is growing interest in the field of PEC biology as they emerge as potential therapeutic targets.…”

Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?

“…Several recent studies highlighted a critical role for the de novo expression of CD9 and, subsequently, of CD44 as a pathogenic switch of PECs from a quiescent to an activated phenotype in CGN and in FSGS [ 16 , 51 , 52 ], confirming the pathogenic role of PECs in these diseases and offering new molecular targets for glomerular disease therapy. In support of this idea, Kaverina et al showed that PECs lose CD44 expression when differentiating into podocytes in injured glomeruli of old mice, suggesting that a CD44 increase in PECs represents not a regenerative but a pathological transition [ 53 ].…”