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 anti-fibrotic 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 pro-fibrotic 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 anti-fibrotic therapy. These include strategies targeting chemokine pathways via CC chemokine receptor 1 and 2 to modulate the inflammatory response, inhibition of phosphodiesterase to restore nitric oxide (NO)-cyclic 3′,5′ guanosine monophosphate (cGMP) function, inhibition of NADPH oxidase 1 (Nox1) and 4 (Nox4) to suppress reactive oxygen species production, as well as 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 currently being explored that may improve the ability to monitor anti-fibrotic therapies. It is hoped that evidence based on the preclinical and clinical data discussed in this review leads to novel anti-fibrotic therapies effective in patients with CKD to prevent or delay progression to ESRD.

TGF-β signaling in the kidney: profibrotic and protective effects

“…TGF-␤1 is the most extensively studied prototype member of the TGF-␤ superfamily in the context of fibrosis. TGF-␤1 is well known as a central mediator of renal fibrosis and has long been considered to play potent roles in the progression of CKD (7,17,48). Increased expression of TGF-␤1 mRNA and protein is seen in patients with fibrotic kidney diseases, including IgA nephropathy, focal and segmental glomerulonephritis, lupus nephritis, and diabetic and human immunodeficiency virus-associated nephropathy (5).…”

“…BMP-7 is a TGF-␤ superfamily member that has been shown to play a protective role in renal fibrosis through anti-inflammatory, antioxidative, and antifibrotic effects by counteracting the effects of TGF-␤1 (100). The BMP-7 signaling pathway and its role in fibrosis have been the subject of several recent reviews (6,48,71). In murine mesangial cells, BMP-7 decreases Smad3 accumulation and inhibits the transcriptional upregulation of Smad3 targets such as PAI-1, thereby suppresses the profibrotic effects of TGF-␤1 (93).…”

“…Interestingly, despite the established proinflammatory role, TGF-␤1 also possesses anti-inflammatory effects (49). Its anti-inflammatory properties are evidenced by findings that targeted deletion of the TGF-␤1 gene results in profound multifocal inflammatory disease in mice (48,83). Tgf-␤1-null mice develop a rapid wasting syndrome and early death by 3-4 wk of age and display excessive inflammatory responses with massive infiltration of lymphocytes and macrophages in many organs (45).…”

Oxymatrine inhibits renal fibrosis of obstructive nephropathy by downregulating the TGF-β1-Smad3 pathway

“…TGF-b1 has been considered as a powerful mediator in the pathogenesis of renal fibrosis. 17 The activation of TGF-b1 can increase the production of ECM, as well as suppress its degradation. In addition, TGF-b1 can activate myofibroblasts by activating resident fibroblasts, 18 inducing epithelial-to-mesenchymal transition 19 or endothelial-to-mesenchymal transition, 20 and initiating inflammatory responses.…”

Make Precision Medicine Work for Chronic Kidney Disease

“…Clinical trials of pirfenidone in CKD have been performed in patients with focal segmental glomerulosclerosis and DN. The results suggested that pirfenidone might be an effective agent to slow renal function decline in CKD [40] . In addition, the inhibition of TGF-β signaling by Smad7, bone morphogenetic protein-7 agonists, connective tissue growth factor inhibitors, in vivo delivery of small interfering RNA, as well as all other molecules and pathways in Figure 2 could be potential therapeutic targets to inhibit or slow the progressive loss of kidney function in patients with CKD.…”