The TNF-a/TNF-a Receptor System

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Tumor necrosis factor α (TNF-α) is a type II transmembrane protein of 26 kDa that can be cleaved by the metalloprotease TNF-a-converting enzyme (TACE) to a 17 kDa TNF-a soluble form. TNF-α binds to TNF-a receptor 1 and 2 (TNFR1, TNFR2). TNFR1 is expressed on almost all cell types, is activated via both membrane-bound and soluble TNF-a, and is a potent inducer of apoptosis and activation of the transcription factor NF-kB. TNFR2 is expressed only in specific cell types, is predominantly activated by membrane-bound TNF-a, and induces a long-lasting NF-kB activation. Both TNFRs are shed from the cell surface and released into circulation as functional soluble forms that may represent a buffer system that prolong TNF-α biological actions or function as decoys for TNF-α [27]. Effects of TNF-α of potential relevance in DN include expression of adhesion molecules and chemokines [28], citotoxicity and apoptosis/necroptosis of susceptible cells [29, 30], alterations of intraglomerular blood flow and GFR, increased endothelial permeability [31], and induction of oxidative stress [32].

Infiltrating monocytes/macrophages are a major source of TNF-a in the diabetic kidney [33]. Furthermore, mesangial cells [34], podocytes [35], and tubular epithelial cells [36] can also release TNF-α upon stimulation and both hyperglycemia and AGE are potent TNF-a inducers in resident renal cells [37,38]. TNFR1 is expressed by all resident kidney cells, while TNFR2 expression, which is almost undetectable in normal kidneys, raises in pathological conditions, including DN [39]. Studies in experimental diabetes have shown that TNF-α expression is increased in diabetic kidneys [40] in both the glomerulus and the tubulo-interstitium. Furthermore, administration of infliximab, a chimeric monoclonal antibody directed against TNF-a, markedly reduces albuminuria in STZ-induced diabetic rat [41]. Finally, TNF-a, inhibition with a soluble TNFR2 fusion protein (etanercept) improves the early stage of DN in the type 2 diabetic model of the KK-Ay mouse [39]. Taken together these data provide evidence for a role of TNF-a in the pathogenesis of experimental DN.

In the kidney TNF-a can trigger and magnify the inflammatory processes by increasing the expression of adhesion molecules [42] and by inducing the release of both chemokines [43-46], and macrophage colony-stimulating factor [47]. Therefore, TNF-a is a major inducer and driver of renal micro-inflammation. Overexpression of both adhesion molecules and chemokines has also been observed in isolated glomeruli, indicating that TNF-a induces these pro-inflammatory effects by binding to TNFR exposed by resident cells [48].

TNF-a, released by either infiltrating or resident cells, can also directly contribute to the renal damage in DN and in vitro studies on glomerular cells studies have partially clarified the underlying cellular mechanisms. In cultured mesangial cells, TNF-a enhances oxidative stress by inducing ROS production [49], increases cytotoxicity through nitric oxide production [50], and acts synergistically with the prosclerotic cytokine TGF-b1 in promoting deposition of extracellular matrix components by increasing expression of both fibronectin and TIMP-1 [51]. The role of TNF-a in promoting oxidative stress has also been highlighted by a recent study showing that TNF-a activates NADPH oxidase in isolated glomeruli and prompts the local ROS generation via a phosphodiesterase-dependent mechanism [52]. In cultured podocytes, TNF-a lowers nephrin promoter activity leading to reduced nephrin gene expression [53] via activation of the PI3K/Akt pathway [54] and induces a rapid and reversible redistribution and loss of nephrin from the podocyte cell surface [55], probably through a reorganization of actin cytoskeleton and focal adhesions [56]. Of interest, TNF-a also compromises cell viability of podocytes through a decrease in Akt activity and this occurs specifically in podocytes from diabetic db/db mice [57]. These preclinical studies demonstrating the importance of TNF-a in experimental DN have prompted studies in humans to assess the potential relevance of TNF-a as target for therapy and/or clinical biomarker.