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-α and TNFR2 correlated significantly with renal injury in Tg26HIV/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-α activated NF-κB and dose-dependently induced podocyte proliferation, marked by the expression of the podocyte G 1 cyclin and NF-κB target gene, cyclin D1. Microarray gene and chemokine protein expression profiling showed a marked pro-inflammatory NF-κB signature, and activated podocytes secreting CCL2- and CCL5-induced macrophage migration in transwell assays. Neutralization of TNFR2 on podocytes with blocking antibodies abrogated NF-κB activation and the induction of cyclin D1 by TNF-α, and identified TNFR2 as the primary receptor that induced IBα degradation, the initiating event in NF-κB activation. These results suggest that TNFR2 expressed on podocytes and its canonical NF-κB signaling may directly interpose the compound pathogenic responses by podocytes to TNF-α, in the absence of other TNFR2-positive renal cell types in proliferative podocytopathies.
Bibliographical noteFunding Information:
We thank Volker Vielhauer and Tanya Mayadas for helpful comments and suggestions. This work was supported by the National Institutes of Health Grants DK065498 (PJN), DK079498 (PJN), DK083375 (PJN), and DK061395 (LAB). PJN and LB are members of the Nephrotic Syndrome Study Network (NEPTUNE) funded by Grant DK083912. PED was supported by training Grant DK007470, and LAB is a member of the Case Center for AIDS Research supported by Grant AI36219.
- collapsing glomerulopathy
- gene expression
- tumor necrosis factor