| First Author | Steinmetz OM | Year | 2011 |
| Journal | J Am Soc Nephrol | Volume | 22 |
| Issue | 3 | Pages | 472-83 |
| PubMed ID | 21183590 | Mgi Jnum | J:185881 |
| Mgi Id | MGI:5430456 | Doi | 10.1681/ASN.2010040435 |
| Citation | Steinmetz OM, et al. (2011) The Th17-defining transcription factor RORgammat promotes glomerulonephritis. J Am Soc Nephrol 22(3):472-83 |
| abstractText | Although Th17 responses may contribute to the pathogenesis of glomerulonephritis, whether the key transcription factor in Th17 cell development, RORgammat, also promotes glomerulonephritis is unknown. Here, we induced crescentic glomerulonephritis in wild-type and RORgammat-deficient (RORgammat(-/-)) mice. RORgammat(-/-) mice were protected from disease, with reduced histologic and functional injury and decreased leukocyte infiltration. Because RORgammat(-/-) mice lack lymph nodes, which may influence the development of nephritis, we performed cell-transfer studies. We reconstituted Rag1(-/-) mice, which lack adaptive immunity but otherwise have normal architecture of the lymphatic system, with splenocytes from naive wild-type or RORgammat(-/-) mice. Mice receiving wild-type splenocytes exhibited high mortality from renal failure after induction of nephritis whereas mice receiving RORgammat(-/-) cells were protected. To determine the effect of RORgammat deficiency specifically in T helper cells, we isolated naive CD4(+) T cells from wild-type and RORgammat(-/-) mice and transferred them into Rag1(-/-) animals. Recipients of wild-type CD4(+) T cells developed severe glomerulonephritis whereas recipients of RORgammat(-/-) cells developed less severe disease. To exclude effects of altered regulatory T cell (Treg) development caused by RORgammat deficiency, we transferred naive CD4(+) T cells depleted of Tregs into Rag1(-/-) mice. Recipients of wild-type, Treg-depleted, CD4(+) T cells developed severe glomerulonephritis whereas recipients of RORgammat(-/-), Treg-depleted CD4(+) T cells did not. Taken together, this study demonstrates that RORgammat promotes the development of crescentic glomerulonephritis by directing nephritogenic Th17 responses. |
