RIPK3-deficient mice were not protected from nephrotoxic nephritis

N R Hill,R M Tarzi,C D Pusey,H T Cook

doi:10.1186/s12882-018-0850-4

N R Hill, R M Tarzi + Show 2 more

Open Access

https://doi.org/10.1186/s12882-018-0850-4

Copy DOI

Journal: BMC Nephrology	Publication Date: Mar 14, 2018
Citations: 3	License type: open-access

Affiliation: Hammersmith Hospital

Abstract

BackgroundNecrotizing glomerular lesions are a feature of severe glomerulonephritis. Unlike apoptosis, cellular necrosis has the potential to release damage-associated proteins into the microenvironment, thereby potentiating inflammation. Until recently necrosis was thought to be an unregulated cellular response to injury. However, recent evidence suggests that under certain circumstances receptor mediated necrosis occurs in response to death ligand signalling, one form of which is termed necroptosis. RIPK3, a receptor interacting protein, is a limiting step in the intracellular signalling pathway of necroptosis. A non-redundant role for RIPK3 has been implicated in mouse models of renal ischaemia reperfusion injury and toxic renal injury. The aim of this study was to investigate the role of RIPK3 in nephrotoxic nephritis (NTN), a model of immune complex glomerulonephritis in mice.MethodsWe induced NTN in RIPK3−/− and WT mice, comparing histology and renal function in both groups.ResultsThere was no improvement in urinary albumin creatinine ratio, serum urea, glomerular thrombosis or glomerular macrophage infiltration in the RIPK3−/− mice compared to WT. There was also no difference in number of apoptotic cells in glomeruli as measured by TUNEL staining between the RIPK3−/− and WT mice.ConclusionThe data suggests that RIPK3 is not on a critical pathway in the pathogenesis of nephrotoxic nephritis.

Highlights

Necrotizing glomerular lesions are a feature of severe glomerulonephritis
We found that receptorinteracting serine/threonine-protein kinase 3 (RIPK3)−/− mice were not protected from nephrotoxic nephritis (NTN) induced renal injury compared to Wild type (WT) mice
RIPK3−/− mice were not protected from NTN compared to WT mice NTN was induced in RIPK3−/− and WT controls

Summary

Introduction

Necrotizing glomerular lesions are a feature of severe glomerulonephritis. Unlike apoptosis, cellular necrosis has the potential to release damage-associated proteins into the microenvironment, thereby potentiating inflammation. Recent evidence suggests that under certain circumstances receptor mediated necrosis occurs in response to death ligand signalling, one form of which is termed necroptosis. RIPK3, a receptor interacting protein, is a limiting step in the intracellular signalling pathway of necroptosis. Necroptosis leads to plasma membrane rupture and cell death resulting in the potential release of danger associated molecular patterns (DAMPS), inducing the inflammatory process [1, 2]. RIP3K has been shown to be involved in cytokine production via the Linkermann et al 2012, demonstrated that murine ischaemia reperfusion injury (IRI) is mediated by. ZVAD, a caspase inhibitor was used to block apoptosis and necrostatin-1 (nec-1) to block necroptosis in C57BL/6 mice. The RIPK3 knockout mice had significantly improved renal function and reduction in kidney injury compared to WT mice, supporting the importance of RIPK3 and necroptosis in IRI [10]

Objectives

Methods

Results

Discussion

Conclusion