Journal
KIDNEY INTERNATIONAL
Volume 89, Issue 1, Pages 113-126Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2015.280
Keywords
chemokine; cytokine; glomerulonephritis; lupus
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Funding
- Swiss National Foundation [32003B_129710]
- CKM-Stiftung
- Fundacao Pesquisa e Desenvolvimento Humanitario
- Else Kroner-Fresenius Stiftung
- ERC starting grant (LiverCancerMechanisms)
- Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC)
- SFB [TR 36]
- Stiftung fur Biomedizinische Forschung (Hofschneider Foundation)
- Helmholtz-Zentrum Munchen
- Swiss National Science Foundation (SNF) [32003B_129710] Funding Source: Swiss National Science Foundation (SNF)
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Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin beta receptor (LT beta R) signaling is crucial for the formation of lymphoid tissue, and inhibition of LT beta R signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LT beta R signaling could also have a role in renal injury. Renal biopsies from patients with GN were found to express both LT alpha and LT beta ligands, as well as LT beta R. The LT beta R protein and mRNA were localized to tubular epithelial cells, parietal epithelial cells, crescents, and cells of the glomerular tuft, whereas LT beta was found on lymphocytes and tubular epithelial cells. Human tubular epithelial cells, mesangial cells, and mouse parietal epithelial cells expressed both LT alpha and LT beta mRNA upon stimulation with TNF in vitro. Several chemokine mRNAs and proteins were expressed in response to LT beta R signaling. Importantly, in a murine lupus model, LT beta R blockade improved renal function without the reduction of serum autoantibody titers or glomerular immune complex deposition. Thus, a preclinical mouse model and human studies strongly suggest that LT beta R signaling is involved in renal injury and may be a suitable therapeutic target in renal diseases.
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