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

Hélène Lazareth ,Sylvie Fabrega ,Chantal Mandet ,Eric Rubinstein ,Alexandre Karras ,Patrick Bruneval ,Victor G Puelles ,Florian Grahammer ,Guillaume Bollée ,Eric Camerer ,Fabian Braun ,Léa Guyonnet ,Laurent Mesnard ,Antigoni Alexandrou ,Neeraj Dhaun ,François Le Naour ,Marcus J Moeller ,Cédric Bouzigues ,Corinne Millien ,F Gaillard ,Carole Hénique ,Anna Chipont ,Dominique Nochy ,Olivia Lenoir ,Marine Camus ,Éric Thervet ,B Robin ,Cécile Fligny ,Oliver Kretz ,Tobias B Huber ,Martin Flamant ,Claude Boucheix ,Pierre‐Louis Tharaux

doi:10.1038/s41467-019-11013-2

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.

Highlights

The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood
CD9 has been described to associate with CD44 and the pre-β1 integrin subunit[6,7], the growth factor heparin-binding EGF-like growth factor (HB-EGF)[8], as well as with epidermal growth factor receptor (EGFR)[9] and plateletderived growth factor receptor (PDGFR)[10]
HB-EGF-dependent EGFR activation and PDGF triggering have been previously implicated in CGN and membranoproliferative glomerulonephritis[11,12,13,14,15], it is unknown if they modulate the parietal epithelial cells (PECs) phenotype

Summary

Introduction

The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. 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. Over the past years, increasing evidence supports the notion that glomerular parietal epithelial cells (PEC) are implicated in the formation of crescents in CGN and in glomerular scarring during FSGS1–3. In these two diseases, the common feature is the invasion of the glomerulus, the blood-filtering unit of the kidney, by PECs leading to its destruction. HB-EGF-dependent EGFR activation and PDGF triggering have been previously implicated in CGN and membranoproliferative glomerulonephritis[11,12,13,14,15], it is unknown if they modulate the PEC phenotype

Methods

Results

Conclusion