Mesangial cell integrin alphavbeta8 provides glomerular endothelial cell cytoprotection by sequestering TGF-beta and regulating PECAM-1.

摘要

Integrins are heterodimeric receptors that regulate cell adhesion, migration, and apoptosis. Integrin alphavbeta8 is most abundantly expressed in kidney and brain, and its major ligand is latent transforming growth factor-beta (TGF-beta). Kidney alphavbeta8 localizes to mesangial cells, which appose glomerular endothelial cells and maintain glomerular capillary structure by mechanical and poorly understood paracrine mechanisms. To establish kidney alphavbeta8 function, mice with homozygous Itgb8 deletion (Itgb8(-/-)) were generated on outbred and C57BL/6 congenic backgrounds. Most Itgb8(-/-) mice died in utero, and surviving Itgb8(-/-) mice failed to gain weight, and rarely survived beyond 6 weeks. A renal glomerular phenotype included azotemia and albuminuria, as well as increased platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, which was surprisingly not associated with conventional functions, such as endothelial cell hyperplasia, hypertrophy, or perivascular inflammation. Itgb8(-/-) mesangial cells demonstrated reduced latent TGF-beta binding, resulting in bioactive TGF-beta release, which stimulated glomerular endothelial cell apoptosis. Using PECAM-1 gain and loss of function strategies, we show that PECAM-1 provides endothelial cytoprotection against mesangial cell TGF-beta. These results clarify a singular mechanism of mesangial-to-endothelial cell cross-talk, whereby mesangial cell alphavbeta8 homeostatically arbitrates glomerular microvascular integrity by sequestering TGF-beta in its latent conformation. Under pathological conditions associated with decreased mesangial cell alphavbeta8 expression and TGF-beta secretion, compensatory PECAM-1 modulation facilitates glomerular endothelial cell survival.