[Frontiers in Bioscience 14, 2448-2465, January 1, 2009]

TGF-beta signal transduction in chronic kidney disease

H. William Schnaper1, Sara Jandeska2, Constance E. Runyan1, Susan C. Hubchak1, Rajit K. Basu1, Jessica F. Curley1, Ronald D. Smith1, Tomoko Hayashida1

1Division of Kidney Diseases, Department of Pediatrics, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave.; Chicago, IL 60611-3008, and Children's Memorial Research Center, Chicago, IL, 2Department of Pediatrics, Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. TGF-beta and the pathogenesis of kidney disease
4. The canonical TGF-beta signaling pathway
5. Regulation of TGF-beta expression and activity
6. Regulation of TGF-beta signaling
6.1. Regulation of at the level of the receptor
6.2. Smad expression
6.3. Post-translational modification of Smads
6.4. Adaptor molecules
6.5. Regulation of transcriptional activity
6.5.1. Enhancers
6.5.2. Inhibitors
6.6. Cross-talk with other signaling pathways
7. Interaction of TGF- beta signaling with other growth factors/hormonal mediators
7.1. Bone morphogenetic protein
7.2. Hepatocyte growth factor
7.3. Glucose and angiotensin II
7.4. Connective tissue growth factor
7.5. Nuclear receptor-associated hormones
8. Regulation of tissue functions in the kidney
8.1. The podocyte and the glomerular filtration barrier
8.2. Hyperplasia and hypertrophy
8.3. Epithelial-to-mesenchymal transition
9. Perspective
10. Acknowledgments
11. References

1. ABSTRACT

Transforming growth factor (TGF)-beta is a central stimulus of the events leading to chronic progressive kidney disease, having been implicated in the regulation of cell proliferation, hypertrophy, apoptosis and fibrogenesis. The fact that it mediates these varied events suggests that multiple mechanisms play a role in determining the outcome of TGF-beta signaling. Regulation begins with the availability and activation of TGF-beta and continues through receptor expression and localization, control of the TGF-beta family-specific Smad signaling proteins, and interaction of the Smads with multiple signaling pathways extending into the nucleus. Studies of these mechanisms in kidney cells and in whole-animal experimental models, reviewed here, are beginning to provide insight into the role of TGF-beta in the pathogenesis of renal dysfunction and its potential treatment.