[Frontiers in Bioscience 14, 3496-3522, January 1, 2009]

NF-kappaB signalling in chronic kidney disease

Gopala Rangan1,2, Yiping Wang1,2, David Harris1,2

1Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital and Sydney-West Area Health Service, Sydney, Australia, 2Western Clinical School, Faculty of Medicine, University of Sydney, Sydney, Australia

TABLE OF CONTENTS

1. Abstract
2. Introduction to the NF-kappaB system
2.1. Components of the NF-kappaB system
2.1.1. NF-kappaB transcription factor family (complexes of Rel protein dimers)
2.1.1.1. Overview
2.1.1.2. Structure and function of Rel/NF-kappaB proteins
2.1.1.3. NF-kappaB isoforms and mechanisms of formation
2.1.2. Cytoplasmic inhibitors of NF-kappaB:IkappaB proteins/Rel protein precursors
2.2. Activation of the NF- kappaB system
2.2.1. Linking the extracellular environment to intracellular NF-kappaB activation
2.2.1.1. Angiotensin II
2.2.1.2. TLRs
2.2.2. Convergence of proximal signal transduction pathways onto IkappaB degradation
2.2.3. Canonical NF- kappaB activation (NEMO-IKKbeta-IkappaB-dependent)
2.2.3.1. Regulation of the canonical pathway
2.2.4. Non-canonical NF- kappaB activation (NIK-IKKalpha-p100-dependent)
2.2.5. Atypical NF- kappaB activation
2.2.5.1. IKK-independent pathways of activation
2.2.5.2. Alternative IKK-dependent pathways
2.2.6. Molecular phylogeny of NF- kappaB signalling
2.3. Cellular effects of NF- kappaB activation
2.4. Regulation of NF- kappaB transcriptional selectivity
3. Evidence of aberrant NF- kappaB expression in human CKD
3.1. Diabetic kidney disease
3.1.1. Immunohistology of NF-kappaB
3.1.2. Microarray mRNA analysis of NF-kappaB members and dependent genes
3.1.3. Peripheral blood mononuclear cell expression of NF-kappaB
3.1.3.1. Genetic polymorphisms of NF-kappaB predisposing to diabetic kidney disease
3.2. Chronic glomerulonephritis
3.2.1. IgA Nephropathy
3.2.2. Minimal change disease and membranous nephropathy
3.2.3. Immune-mediated inflammatory renal disease (crescentic glomerulonephritis and lupus nephritis)
3.3. Effects of renal impairment on NF- kappaB activation in circulating monocytes
4. Activators and pathways of NF- kappaB activation in renal cells
4.1. Glomerular cells
4.1.1. Podocytes
4.1.2. Mesangial cells
4.1.3. Glomerular endothelial and parietal epithelial cells
4.2. Cortical tubular epithelial cells
4.2.1. Pro-infammatory gene expression and stimulants
4.2.2. Role of NF-kappaB in TEC survival and proliferation
4.3. Renal Fibroblasts
5. Insights regarding NF- kappaB from animal models of CKD
5.1. Podocytopenia-associated proteinuria
5.2. Hypertension-induced renal injury
5.3. Hyperglycaemia-induced renal injury
5.4. Sterile renal Inflammation
5.5. Renal fibrosis
5.6. Renal cell apoptosis
6. Therapeutic approaches to modulate NF- kappaB in humans with CKD
7. Conclusions and perspectives
8. Acknowledgements
9. References

1. ABSTRACT

The mammalian NF-kappaB signalling pathway is an important intracellular transcription factor system that is induced in response to diverse extracellular stimuli. The hallmark of NF-kappaB activation is the nuclear translocation of dimeric Rel protein transcription factors, which regulate hundreds of kappaB-dependent genes that are involved in inflammation, immunity, apoptosis, cell proliferation and differentiation. In addition, cell-surface receptors (TNFR, Toll-like and angiotensin II, type 1 receptors), inhibitory kappaB kinases (IKK proteins), I kappaB proteins and factors regulating the post-translational modification of the Rel proteins (acetylation, phosphorylation), are other intracellular components that regulate NF-kappaB activation. Over the last decade, in vitro studies, animal models and human studies have provided evidence that upregulation of the canonical (RelA/p50) NF- kappaB isoform (in tubular epithelial cells, podocytes, mesangial cells, macrophages) has a pathogenic role in mediating chronic inflammation in chronic kidney disease (CKD). This review will examine current evidence regarding NF- kappaB isoforms and their potential role in the treatment of kidney failure due to CKD.