| First Author | Bruggeman LA | Year | 2011 |
| Journal | Lab Invest | Volume | 91 |
| Issue | 3 | Pages | 413-25 |
| PubMed ID | 21221075 | Mgi Jnum | J:169237 |
| Mgi Id | MGI:4940141 | Doi | 10.1038/labinvest.2010.199 |
| Citation | Bruggeman LA, et al. (2011) TNFR2 interposes the proliferative and NF-kappaB-mediated inflammatory response by podocytes to TNF-alpha. Lab Invest 91(3):413-25 |
| abstractText | The development of proliferative podocytopathies has been linked to ligation of tumor necrosis factor receptor 2 (TNFR2) expressed on the renal parenchyma; however, the TNFR2-positive cells within the kidney responsible for podocyte injury are unknown. We detected de novo expression of TNFR2 on podocytes before hyperplastic injury in crescentic glomerulonephritis of mice with nephrotoxic nephritis, and in collapsing glomerulopathy of Tg26(HIV/nl) mice, kd/kd mice, and human beings. We further found that serum levels of soluble TNF-alpha and TNFR2 correlated significantly with renal injury in Tg26(HIV/nl) mice. Thus, we asked whether ligand binding of TNFR2 on podocytes ex vivo precipitates the characteristic proliferative and pro-inflammatory diseased podocyte phenotypes. Soluble TNF-alpha activated NF-kappaB and dose-dependently induced podocyte proliferation, marked by the expression of the podocyte G(1) cyclin and NF-kappaB target gene, cyclin D1. Microarray gene and chemokine protein expression profiling showed a marked pro-inflammatory NF-kappaB signature, and activated podocytes secreting CCL2- and CCL5-induced macrophage migration in transwell assays. Neutralization of TNFR2 on podocytes with blocking antibodies abrogated NF-kappaB activation and the induction of cyclin D1 by TNF-alpha, and identified TNFR2 as the primary receptor that induced IkappaBalpha degradation, the initiating event in NF-kappaB activation. These results suggest that TNFR2 expressed on podocytes and its canonical NF-kappaB signaling may directly interpose the compound pathogenic responses by podocytes to TNF-alpha, in the absence of other TNFR2-positive renal cell types in proliferative podocytopathies. |
