Different effects of global osteopontin and macrophage osteopontin in glomerular injury.

Abstract

Osteopontin (OPN) is a pro-and anti-inflammatory molecule that simultaneously attenuates oxidative stress. Both inflammation and oxidative stress play a role in the pathogenesis of glomerulonephritis and in the progression of kidney injury. Importantly, OPN is highly induced in nephritic kidneys. To characterize further the role of OPN in kidney injury we used OPNmice in antiglomerular basement membrane reactive serum-induced immune (NTS) nephritis, an inflammatory and progressive model of kidney disease. Normal wild-type (WT) and OPNmice did not show histological differences. However, nephritic kidneys from OPNmice showed severe damage compared with WT mice. Glomerular proliferation, necrotizing lesions, crescent formation, and tubulointerstitial injury were significantly higher in OPNmice. Macrophage infiltration was increased in the glomeruli and interstitium in OPNmice, with higher expression of IL-6, CCL2, and chemokine CXCL1. In addition, collagen (Col) I, Col III, and Col IV deposition were increased in kidneys from OPNmice. Elevated expression of the reactive oxygen species-generating enzyme Nox4 and blunted expression of Nrf2, a molecule that inhibits reactive oxygen species and inflammatory pathways, was observed in nephritic kidneys from OPNmice. Notably, CD11b diphteria toxin receptor mice with NTS nephritis selectively depleted of macrophages and reconstituted with OPNmacrophages showed less kidney injury compared with mice receiving WT macrophages. These findings suggest that in global OPNmice there is increased inflammation and redox imbalance that mediate kidney damage. However, absence of macrophage OPN is protective, indicating that macrophage OPN plays a role in the induction and progression of kidney injury in NTS nephritis.