Fibrogenesis in kidney transplantation: potential targets for prevention and therapy

Abstract

Kidney allograft fibrosis results from a reactive process mediated by humoral and cellular events and the activation of transforming growth factor beta1. It is a process that involves both parenchymal and graft infiltrating cells and can lead to organ failure if injury persists or if the response to injury is excessive. In this review, we will address the role of preventive and therapeutic strategies that target kidney allograft fibrogenesis. We conclude that in addition to preventive strategies, therapies based on bone morphogenetic protein 7, hepatocyte growth factor, connective tissue growth factor, and pirfenidone have shown promising results in preclinical studies. Clinical trials are needed to examine the effect of these therapies on long-term outcomes.

Figure 1. Biological pathways involved in allograft fibrosis

Figure 1 is a simplified cartoon representing the biological pathways involved in kidney allograft fibrogenesis. Fibrosis results from antigen-dependent and antigen-independent mechanisms that primarily trigger TGF-β1 in graft infiltrating and parenchymal cells. These triggers include acute rejection, infections, ischemia-reperfusion injury, oxidative stress and calcineurin inhibitors. Adhesion molecules and chemokines play an important role at this level. In turn, TGF-β1 switches on the signaling pathways that will result in the activation of myofibroblasts. In theory, the source of interstitial myofibroblasts includes resident fibroblasts, epithelial-to-mesenchymal transition (EMT), bone marrow derived cells, endothelial cells and pericytes. However, as suggested by the “?” more evidence is needed to support the last three mechanisms in kidney transplantation.

Figure 2. Molecules and signaling targets for the treatment of fibrosis in kidney allografts

Figure 2 is a schematic representation of the molecular pathways involved in kidney allograft fibrogenesis with related preventive and therapeutic strategies. TGF-β1 activates downstream profibrotic signaling pathways that include Smad, small GTPase Ras/Rho and mitogen-activated protein kinase (MEK) pathways. The activation of these pathways will result in a cascade of events culminating in phenotypic changes consistent with epithelial-to-mesenchymal transition (EMT) and fibrosis. During EMT tubular epithelial cells are transformed into myofibroblasts in a stepwise fashion (yellow box). The process is characterized by a loss of cell-cell adhesion and E-cadherin expression (a), de novo α-smooth muscle actin (α-SMA) expression and actin reorganization in inured cells (b), tubular basement membrane disruption and cell migration (c) with fibroblast invasion and production of profibrotic molecules including collagen and fibronectin (d). CTGF can induce EMT by inhibiting BMP-7 or activating hypoxia-inducible genes including HIF-1α and VEGF. VEGF may result in renal injury and fibrosis in the absence of nitric oxide (NO). Pirfenidone (PFD) and HGF can inhibit fibrogenesis by downregulating TGF-β1 expression. BMP-7 counterbalances the profibrotic effects of TGF-β1 by activating regulatory Smads 1, 5 and 8.