Molecular Basis

There are sequential pathological steps during the establishment of DN (1,3). In these, multifunctional activities driven via HGF/c-Met coupling are needed to induce protective, regenerative and antifibrotic functions. A possible main sequence of events is as follows:

1. HGF initially targets glomerular cells and reduces hyperfiltration;

2. albuminuria is then attenuated, possibly associated with podocyte protection;

3. suppression of albuminuria leads to inhibiting MCP-1 expression and reduction in the number of macrophages (a major source of TGF-P1); and

4. as a result, renal TGF-P levels decline then interstitial myofibroblastosis and fibrosis are inhibited.

TGF-P and HGF are counteracting in many multipotent biological actions. TGF-P induces growth arrest and/or apoptosis in epithelial and endothelial cells, and HGF

exhibits mitogenic and anti-apoptotic activities in these same cell types (98-100). HGF-induced regenerative responses are inhibited by TGF-P, and vice versa in cases of TGF-P-mediated fibrogenic events (72,98-101). HGF stimulates or induces proteases involved in the breakdown of ECMs in several types of cells, including MTl-matrix metalloproteases (MMPs), uPA, and MMPs (75,102-104). In contrast, TGF-P stimulates the synthesis of ECM and the production of inhibitors of proteases involved in ECM breakdown (68). Consistently, HGF increases the expression of MMP-9, whereas HGF decreases the expression of tissue inhibitors of matrix metalloproteinase (TIMP)-1 and TIMP-2 in proximal tubular cells (75,104). Together, we predict that such a balance between HGF vs TGF-P regulates a threshold to inhibit or foster renal tissue fibrosis (Fig. 7B). Thus, administration of HGF is a pathogenesis-based therapy for DN and other CRDs.

It is noteworthy that administration of exogenous HGF leads to restoration of endogenous HGF production (18,71), associated with suppressed TGF-Pj levels. In fact, exogenous HGF is capable of enhancing HGF production in an auto-inductive manner (82,89,105). Considering that endogenous HGF is essential to minimize renal fibrogenesis in CRDs (18,71,75), restoration of HGF production by exogenous HGF also participates in the attenuation of renal fibrosis. For example, blockade of Ang-II action with an Ang-II receptor antagonist delays progression of renal fibrosis, and this is associated with the increase in HGF production (106). More importantly, HGF and Ang-II receptor antagonist synergistically improved renal fibrosis in a model of UUO (107). These findings mean that restoration of the pathologically suppressed HGF production or its exogenous administration can be a sound strategy for treating CRDs.

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