Different effects of global osteopontin and macrophage osteopontin in glomerular injury. Am J Physiol Renal Physiol 315: F759–F768, 2018. First published May 2, 2018; doi:10.1152/ajprenal.00458.2017.—Osteo-pontin (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 OPN−/− mice in antiglomerular basement membrane reactive serum-induced immune (NTS) nephritis, an inflammatory and progressive model of kidney disease. Normal wild-type (WT) and OPN−/− mice did not show histological differences. However, nephritic kidneys from OPN−/− mice showed severe damage compared with WT mice. Glomerular proliferation, necrotizing lesions, crescent formation, and tubulointerstitial injury were significantly higher in OPN−/− mice. Macrophage infiltration was increased in the glomeruli and interstitium in OPN−/− mice, 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 OPN−/− mice. 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 OPN−/− mice. Notably, CD11b diphteria toxin receptor mice with NTS nephritis selectively depleted of macrophages and reconstituted with OPN−/− macrophages showed less kidney injury compared with mice receiving WT macrophages. These findings suggest that in global OPN−/− mice 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.
- Oxidative stress
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