Therapeutic targets for treating fibrotic kidney diseases

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.

Fig. 1. TGF-β1 signaling via Smad and non-Smad pathways

Initiation of the TGF-β signaling cascade occurs upon ligand binding to TβRII and subsequent TβRI-TβRII hetero-tetrameric complex formation. The canonical Smad pathway involves activation of Smad2/3 through recruitment and phosphorylation by activated TβRI, and requires kinase activity of TβRI. TGF-β1 also activates various non-Smad pathways, including TAK1 and subsequently activates several downstream signaling cascades, including MKK4/7–JNK, MKK3/6–p38 MAPK, and nuclear factor-kappa B (NF-κB)-inducing kinase-IκB kinase. TGF-β1, transforming growth factor-β1; TβRI, TGF-β type I receptor; TβRII, TGF-β type 2 receptor; TAK1, TGF-β-activated kinase 1; TAB1, TAK1-binding protein 1; MKK, mitogen-activated protein kinase kinase; JNK, c-Jun N-terminal kinase.

Fig. 2. Opposing roles of TGF-β1 and BMP-7 signaling pathways

Similar to other members of the TGF-β superfamily, BMP-7 signals via heteromeric interactions of BMP receptors type I (BMPRI) and type II (BMPRII) to activate its R-Smads, Smad1/5/8. Phosphorylated R-Smads form complexes with common signalling component Smad4, which then translocate into the nucleus to regulate transcription of their target genes. Smad6 is an inhibitory Smad that is induced by BMPs and inhibits both TGF-β and BMP signaling. BMP, bone morphogenic protein; BMPR, BMP receptor; TGF-β1, transforming growth factor-β1; TβR, TGF-β receptor.

Fig. 3. A schematic overview of structure of CTGF and factors interacting with CTGF

BMP, bone morphogenic protein; Cys-knot, cystine knot; ECM, extracellular matrix ; HSPG, heparan sulfate proteoglycan; IGF-1, insulin like growth factor-1; LRP, lipoprotein receptor–related protein; TGF-β1, transforming growth factor-β1; VEGF, vascular endothelial growth factor ; vWF, von Willebrand factor.