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Mechanisms of tubulointerstitial fibrosis
Masayuki Iwano1, Eric G Neilson
1First Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Purpose Of Review:
Tubulointerstitial fibrosis is the final common pathway to end-stage renal disease. Understanding the mechanisms of tubulointerstitial fibrosis is essential in establishing novel therapeutic strategies for the prevention or arrest of progressive kidney diseases. The present review focuses on a newly proposed mechanism of tubulointerstitial fibrosis, one that emphasizes the roles of epithelial-mesenchymal transition and cellular activation.
Recent Findings:
Among the cells that accumulate in the renal interstitium, fibroblasts are the principal effectors mediating tubulointerstitial fibrosis. By contrast, the phagocytosis of extracellular matrix and apoptotic cells by macrophages may actually exert a beneficial effect. Interstitial fibroblasts are more heterogeneous than expected, and during renal fibrosis new fibroblasts are derived mainly through epithelial-mesenchymal transition. The intracellular signaling pathways leading to initiation of epithelial-mesenchymal transition remain largely unknown, though recent studies have identified beta-catenin and Smad3 activation of lymphoid enhancer factor, integrin-linked kinase, and small GTPases and mitogen-activated protein kinases as key components. Transforming growth factor-beta is believed to be a critical fibrogenic factor, but recent studies have also focused on transforming growth factor-beta independent pathways as mechanisms of tubulointerstitial fibrosis. As the mechanisms underlying tubulointerstitial fibrosis leading to epithelial-mesenchymal transition have been identified, so have cytokines that efficiently antagonize renal fibrosis, particularly bone morphogenic protein-7 and hepatocyte growth factor.
Summary:
In combination with traditional angiotensin converting enzyme inhibitors, newly identified cytokines may eventually form the basis for new therapeutic strategies aimed at inhibiting the progression of renal disease.
Insights
Tubulointerstitial fibrosis, a cause of kidney disease, involves epithelial-mesenchymal transition. New therapies targeting this process and utilizing cytokines like bone morphogenic protein-7 may halt kidney disease progression.
Area of Science:
- Nephrology
- Cell Biology
- Fibrosis Research
Background:
- Tubulointerstitial fibrosis is a key factor in end-stage renal disease.
- Understanding its mechanisms is crucial for developing new treatments.
- This review highlights epithelial-mesenchymal transition and cellular activation in fibrosis.
Purpose of the Study:
- To review the role of epithelial-mesenchymal transition in tubulointerstitial fibrosis.
- To explore cellular activation as a mechanism in kidney fibrosis.
- To identify potential therapeutic targets for progressive kidney diseases.
Main Methods:
- Literature review of recent studies on tubulointerstitial fibrosis.
- Analysis of cellular and molecular pathways involved in fibrosis.
- Identification of fibrogenic factors and potential antifibrotic agents.
Main Results:
- Interstitial fibroblasts are key effectors, with new fibroblasts arising from epithelial-mesenchymal transition.
- Transforming growth factor-beta and independent pathways contribute to fibrosis.
- Cytokines like bone morphogenic protein-7 and hepatocyte growth factor show antifibrotic potential.
Conclusions:
- Epithelial-mesenchymal transition is a significant mechanism in tubulointerstitial fibrosis.
- Targeting this pathway and utilizing specific cytokines offers therapeutic promise.
- Combined therapies may inhibit the progression of renal disease.
