[Frontiers in Bioscience S1, 171-187, June 1, 2009]

Mitogen activated protein kinases in renal fibrosis

Frank Y Ma, Mythily Sachchithananthan, Robert S Flanc, David J Nikolic-Paterson

Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, 3168, Australia

TABLE OF CONTENTS

1. Abstract
2. Introduction
2.1. Overview of MAP kinase pathways
2.2. MAP kinase pathways in renal physiology
3. In vitro studies of the pro-fibrotic actions of MAP kinase signalling
3.1. MAP kinase regulation of TGF-beta1 production and activity
3.2. Cross-talk between MAP kinases and TGF-beta1 signalling
3.2.1. TGF-beta1 activates MAP kinases
3.2.2. MAP kinase modulation of Smad signalling
3.3. MAP kinase regulation of fibroblast recruitment and differentiation
3.4. MAP kinase signalling in epithelial-mesenchymal transition
3.5. MAP kinase regulation of extracellular matrix production and deposition
4. In vivo studies of MAP kinase signalling in animal models of renal fibrosis
4.1. p38 MAP kinase in experimental renal fibrosis
4.2. JNK in experimental renal fibrosis
4.3. ERK in experimental renal fibrosis
5. MAP kinase signalling in human renal fibrosis
6. Therapeutic potential for targeting MAP kinases in renal fibrosis
7. Acknowledgements
8. Conflict of interest statement
9. References

1. ABSTRACT

The mitogen-activated protein (MAP) kinases are involved in both normal renal physiology and in the pathology of various forms of kidney injury, including renal fibrosis. In vitro studies have shown a role for all three MAP kinase (ERK, p38 and JNK) in the production of the major pro-fibrotic factor, transforming growth factor-beta1 (TGF-beta1) by intrinsic renal cell types. There is also considerable cross-talk between TGF-beta1 and MAP kinase signalling pathways in the synthesis and turnover of extracellular matrix by fibroblast-like cells in the kidney. In addition, MAP kinase signalling contributes to TGF-beta1 induced transition of tubular epithelial cells into myofibroblasts. Administration of specific inhibitors of individual MAP kinases has identified a pathogenic role for both p38 and JNK pathways in animal models of renal fibrosis. There is also evidence to suggest that MAP kinases are activated in human renal fibrosis. Thus, blockade of p38 and JNK pathways may have therapeutic potential for the treatment of chronic renal fibrosis.