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Emerging strategies to disrupt the central TGF-β axis in kidney fibrosis
Michael Rauchman1, David Griggs2
1Division of Nephrology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri; VA St. Louis Health Care System, Saint Louis, Missouri.
Abstract:
Chronic kidney disease (CKD) affects more than 20 million people in the United States and the global burden of this disorder is increasing. Many affected individuals will progress to end stage kidney disease necessitating dialysis or transplantation. CKD is also a major independent contributor to the risk of cardiovascular morbidity and mortality. Tubulointerstitial fibrosis is a final common pathway for most causes of progressive CKD. Currently, there are no clinically available therapies targeting fibrosis that can slow the decline in kidney function. Although it has long been known that TGF-β signaling is a critical mediator of kidney fibrosis, translating this knowledge to the clinic has been challenging. In this review, we highlight some recent insights into the mechanisms of TGF-β signaling that target activation of this cytokine at the site of injury or selectively inhibit pro-fibrotic gene expression. Molecules directed at these targets hold the promise of attaining therapeutic efficacy while limiting toxicity seen with global inhibition of TGF-β. Kidney injury has profound epigenetic effects leading to altered expression of more than a thousand genes. We discuss how drugs targeting epigenetic modifications, some of which are in use for cancer therapy, have the potential to reprogram gene regulatory networks to favor adaptive repair and prevent fibrosis. The lack of reliable biomarkers of kidney fibrosis is a major limitation in designing clinical trials for testing CKD treatments. We conclude by reviewing recent advances in fibrosis biomarker development.
Insights
New therapeutic strategies for chronic kidney disease (CKD) focus on targeting transforming growth factor-beta (TGF-β) signaling and epigenetic modifications to prevent kidney fibrosis and improve patient outcomes.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Chronic kidney disease (CKD) affects millions globally, often progressing to end-stage renal disease and increasing cardiovascular risk.
- Tubulointerstitial fibrosis is a common pathway in progressive CKD, with no current therapies to slow kidney function decline.
- Transforming growth factor-beta (TGF-β) signaling is a known mediator of kidney fibrosis, but clinical translation remains challenging.
Purpose of the Study:
- To review recent advancements in understanding TGF-β signaling mechanisms for targeted kidney fibrosis therapy.
- To explore the potential of epigenetic drugs in reprogramming gene expression for kidney repair.
- To discuss the development of reliable biomarkers for kidney fibrosis in clinical trials.
Main Methods:
- Review of recent literature on TGF-β signaling pathways in kidney fibrosis.
- Analysis of epigenetic modifications and their therapeutic potential in kidney injury.
- Examination of emerging biomarkers for assessing kidney fibrosis.
Main Results:
- Targeting TGF-β activation at injury sites or selective inhibition of pro-fibrotic genes shows promise for therapeutic efficacy with reduced toxicity.
- Epigenetic drugs, including those used in cancer therapy, may reprogram gene networks to promote kidney repair and prevent fibrosis.
- Advances in biomarker development are crucial for overcoming limitations in clinical trial design for CKD treatments.
Conclusions:
- Novel therapeutic approaches targeting specific TGF-β pathways and epigenetic modifications offer potential for treating kidney fibrosis.
- Development of reliable fibrosis biomarkers is essential for advancing clinical trials and therapeutic strategies in CKD.
- Future research should focus on translating these mechanistic insights into effective clinical interventions for CKD patients.
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