Fig. 6. Summary of novel therapeutic targets in DN. Potentially useful therapeutic principles are depicted in light gray lettering. See text in "Emerging, Novel Therapeutic Targets and Strategies" Section for explanations.

TGF-P in the renal interstitium, and fibroblasts are the primary target. Transcriptional upregulation of C-C chemokines appears to be NF-kB-dependent which, in turn, is activated by proteasomal degradation of its endogenous inhibitor, I-kB. Indeed, inhibition of MCP-1 with 7ND by means of renal overexpression of a 7ND expression plasmid reduces interstitial fibrogenesis (63). Similarly, renal overexpression of IkB with an adenoviral vector reduces the MCP-1 response and the macrophage infiltrate and lessens interstitial fibrosis (64). These experiments provide proof of concept but are perhaps therapeutically not feasable in patients. Prolongation of the half-life of endogenous I-kB with a specific proteasomal inhibitor, bortezomib (PS-341, VelcadeĀ®, Millenium Pharmaceuticals, Cambridge, MA), which is approved for the treatment of multiple myeloma by regulatory agencies, could provide a testable therapeutic avenue for the management of renal interstitial fibrogenesis in DN (Fig. 6) but neither experimental nor clinical data are currently available in this setting (65,66).

Recombinant Human HGF

rhHGF is present in glomerular ultrafiltrate in rats with DN and acts through apical membranes on tubular epithelial cells. As discussed earlier, some of the cells' responses, but not others, suggest contributions to renal fibrogenesis. However, in the renal intersti-tium, rhHGF appears to inhibit profibrogenic TGF-P signals. Cell culture studies indicate that HGF induces the smad transcriptional corepressor snoN and reduces the catabolism of the smad corepressor TGIF (Fig. 6) (67-69). This reduces TGF-P-induced ECM production as well as TGF-P-driven CTGF transcription (70). Systemic administration of rhHGF or of a HGF-expression plasmid ameliorate DN in mice (69,71). Thus, systemi-cally administered rhHGF or (small molecule) HGF agonists may be beneficial in DN (Fig. 6).

Bone Morphogenetic Protein 7

Bone morphogenetic protein (BMP)7 is a member of the TGF-P superfamily of cysteine knot cytokines and plays pivotal roles during renal and eye development. In adult mammalian organisms, expression of BMP7 is retained very selectively and the kidney is among the sites of prominent expression, primarily in selective tubular segments and in glomerular podocytes. In bone, BMP7 promotes osteoblast function, giving rise to the hypothesis that renal BMP7 functions as an osteotrophic hormone. In STZ diabetes in rats, renal BMP7 expression decreases predating other renal pathologies (72). Several experimental observations support the notion that renal BMP7 opposes TGF-P actions and has antifibrogenic activity. In vitro studies demonstrate that coincubation of mesan-gial cells with BMP7 lessens TGF-P-driven expression of ECM-proteins and profibro-genic regulators (73). Its mechanisms of action have been partially delineated and include smad6, which is induced by BMP7 smad5 dependently (Fig. 6). Smad6 reduces effective nuclear translocation of TGF-P-induced smad3/4 complexes without involvement of smad corepressors (74). BMP7 also opposes TGF-P-dependent epithelial-mesenchymal transition in vitro and in vivo (75). Systemic administration of rhBMP7 reduces renal fibrogenesis in rodents with DN (76). At present, there are no studies in humans with diabetic renal disease involving rhHGF or rhBMP7.

TGF-P Receptor Kinase Inhibitors

Given the pivotal contribution of ultrafiltered as well as interstitial TGF-P in renal fibrogenesis in DN, it is no surprise that inhibition of this cytokine such as with neutralizing antibodies ameliorates renal fibrosis (Fig. 6) (77). Small molecule derivatives of imidazole inhibitors of p38 mitogen-activated protein kinase selectively inhibiting the TGF-P-receptor I kinase (activin-like kinase [ALK]-5) have recently been developed and tested in in vitro experiments and found to block many or all actions of TGF-P (78-82). These compounds also inhibit ALK-4 and -7 but not the BMP-activated type-I receptors (ALK-2, -3, or -6). Unfortunately, no in vivo experimental studies with these ALK-5 inhibitors in animal models of renal diseases, especially DN, have yet been published. Because TGF-P knockout mice develop systemic lymphoma-like illnesses with accelerated mortality (indicating a role of this cytokine in immune surveillance), systemic therapy with a global TGF-P antagonist in humans could be risky (83).

CTGF Antagonists

CTGF is induced, although not exclusively, by TGF-P and is involved in the upregu-lation of ECM-expression in several cell types. Moreover, this growth factor also contributes to the phenotype transition of fibroblasts to myofibroblasts. Antisense oligonucleotides that reduce CTGF have been shown to lessen renal fibrogenesis (84). An anti-CTGF human monoclonal antibody is presently examined in phase Ib clinical trials in patients with DN (85).

Imatinib Mesylate

Imatinib mesylate (GleevecĀ®, Novartis, New Hanover, NJ) has been developed for the treatment of Philadelphia* acute myelogenous leukemia expressing B-cell receptor-abl and for tumors that grow c-kit dependently. In addition to these two oncogene products, this compound inhibits abelson and the PDGF-receptor kinase (Fig. 6). There are two reasons why imatinib could be a useful antifibrogenic therapeutic agent in renal diseases such as DN. First, PDGF is an important proliferative agent for renal fibroblasts (35). Second, recent observations indicate a dual function of TGF-P in (renal) fibroblasts. TGF-P-dependent fibroblast proliferation utilizes the ableson nonreceptor tyrosine kinase (c-abl) but other fibrogenic functions of this cytokine such as promoting transition to myofibroblasts and upregulation of matrix expression in these latter cells appears to be mainly smad3-dependent (50). In vivo studies in a rat model demonstrate that imatinib ameliorates TGF-P-driven renal interstitial fibrosis by reducing fibroblast proliferation (50,51). Thus, although data in DN in humans are not available, imatinib mesylate or newer drugs with similar functions could be useful in the therapy of DN pending further (especially human) studies (86).

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