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Transl Res. 2015 Apr;165(4):512-30. doi: 10.1016/j.trsl.2014.07.010. Epub 2014 Aug 13.

Therapeutic targets for treating fibrotic kidney diseases.

Author information

1
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Department of Internal Medicine, Bundang CHA Medical Center, CHA University School of Medicine, Seongnam, South Korea.
2
Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY.
3
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY. Electronic address: mechoi@med.cornell.edu.

Abstract

Renal fibrosis is the hallmark of virtually all progressive kidney diseases and strongly correlates with the deterioration of kidney function. The renin-angiotensin-aldosterone system blockade is central to the current treatment of patients with chronic kidney disease (CKD) for the renoprotective effects aimed to prevent or slow progression to end-stage renal disease (ESRD). However, the incidence of CKD is still increasing, and there is a critical need for new therapeutics. Here, we review novel strategies targeting various components implicated in the fibrogenic pathway to inhibit or retard the loss of kidney function. We focus, in particular, on antifibrotic approaches that target transforming growth factor (TGF)-β1, a key mediator of kidney fibrosis, and exciting new data on the role of autophagy. Bone morphogenetic protein (BMP)-7 and connective tissue growth factor (CTGF) are highlighted as modulators of profibrotic TGF-β activity. BMP-7 has a protective role against TGF-β1 in kidney fibrosis, whereas CTGF enhances TGF-β-mediated fibrosis. We also discuss recent advances in the development of additional strategies for antifibrotic therapy. These include strategies targeting chemokine pathways via CC chemokine receptors 1 and 2 to modulate the inflammatory response, inhibition of phosphodiesterase to restore nitric oxide-cyclic 3',5'-guanosine monophosphate function, inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 and 4 to suppress reactive oxygen species production, and inhibition of endothelin 1 or tumor necrosis factor α to ameliorate progressive renal fibrosis. Furthermore, a brief overview of some of the biomarkers of kidney fibrosis is currently being explored that may improve the ability to monitor antifibrotic therapies. It is hoped that evidence based on the preclinical and clinical data discussed in this review leads to novel antifibrotic therapies effective in patients with CKD to prevent or delay progression to ESRD.

PMID:
25176603
PMCID:
PMC4326607
DOI:
10.1016/j.trsl.2014.07.010
[Indexed for MEDLINE]
Free PMC Article

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