The NF-\u03baB1 is a key regulator of acute but not chronic renal injury

Amy Fearn,Neil S Sheerin,Christopher Fox,Derek A Mann,Fiona Oakley,Anna Moles,Michael G Robson,Gerhard R Situmorang,Caroline L Wilson,Agklinta Kiosia,Rachel Howarth

doi:10.1038/cddis.2017.233

Abstract

The NF-κB family of transcription factors is important for many cellular functions, in particular initiation and propagation of inflammatory and immune responses. However, recent data has suggested that different subunits of the NF-κB family can suppress the inflammatory response. NF-κB1, from the locus nfκb1, can inhibit transcription, acting as a brake to the recognised pro-inflammatory activity of other NF-κB subunits. We tested the function of NF-κB1 in an acute (nephrotoxic serum (NTS) nephritis) and a chronic (unilateral ureteric obstruction (UUO)) model of renal injury using NF-κB1 (nfκb1−/−) knockout mice. Deficiency in NF-κB1 increased the severity of glomerular injury in NTS-induced nephritis and was associated with greater proteinuria and persistent pro-inflammatory gene expression. Induction of disease in bone marrow chimeric mice demonstrated that the absence of NF-κB1 in either bone marrow or glomerular cells increased the severity of injury. Early after UUO (day 3) there was more severe histological injury in the nfκb1−/− mice but by day 10, disease severity was equivalent in wild type and nfκb1−/− mice. In conclusion, NF-κB1 modifies acute inflammatory renal injury but does not influence chronic fibrotic injury.

Highlights

The NF-κB family of transcription factors is important for many cellular functions, in particular initiation and propagation of inflammatory and immune responses
These include, inflammatory cell influx to the kidney, proteinuria, and crescentic glomerulonephritis. In this model proteinuria and transient kidney injury is achieved by the administration of sheep anti-mouse glomerular basement membrane (GBM) heterologous antibodies which bind to target antigens in the recipient glomerulus
Research into the immune and inflammatory basis of glomerulonephritis tend to focus on the mechanisms that drive glomerular inflammation

Summary

Introduction

The NF-κB family of transcription factors is important for many cellular functions, in particular initiation and propagation of inflammatory and immune responses. Increasing evidence suggests important roles for NF-κB proteins in renal disease progression,[8] mediating renal inflammation by promoting gene expression in different cell types, including renal cells, innate immune cells and lymphocytes.[9] Many reports regarding NF-κB function in vivo focus on RelA/p50 heterodimers, overlooking the complexity of this transcription factor family. To characterise the contribution of NF-κB1 in the development of immune complex driven kidney disease we used the nephrotoxic serum (NTS) glomerulonephritis model In this manuscript we report that animals deficient in NF-κB1 (p50 and its precursor p105) had more severe glomerular injury and Received 09.1.17; revised 29.3.17; accepted 19.4.17; Edited by T Brunner a persistent inflammatory response following NTS injection. NF-κB1 has an important role driving the early inflammatory response in infiltrating and resident renal cells during the acute phase of glomerulonephritis

Methods

Results

Conclusion