Mesangial Cell lntegrin αvβ8 Provides Glomerular Endothelial Cell Cytoprotection by Sequestering TGF-β and Regulating PECAM-1

Integrins are heterodimeric receptors that regulate cell adhesion, migration, and apoptosis. Integrin alpha v beta 8 is most abundantly expressed in kidney and brain, and its major ligand is latent transforming growth factor-beta (TGF-beta). Kidney alpha v beta 8 localizes to mesangial cells, which appose glomerular endothelial cells and maintain glomerular capillary structure by mechanical and poorly understood paracrine mechanisms. To establish kidney alpha v beta 8 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 alpha v beta 8 homeostatically arbitrates glomerular microvascular integrity by sequestering TGF-beta in its latent conformation. Under pathological conditions associated with decreased mesangial cell alpha v beta 8 expression and TGF-beta secretion, compensatory PECAM-1 modulation facilitates glomerular endothelial cell survival. (Am f Pathol 2011, 178:609-620; DOI. 10.1016/j.ajpalh.2010.10.031)