MICROINFLAMMATION IN DN

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Inflammation is characterized by inflammatory cell accrual, increased expression of adhesion molecules, chemokines, and inflammatory cytokines. These features are seen in DN, though they are quite mild as compared with classic inflammatory diseases. Therefore, the low grade inflammation that occurs in DN is termed “microinflammation” to distinguish it from classic inflammation.

In human DN, there is a glomerular infiltration of monocytes/macrophages that is not secondary to fibrosis as it occurs in mild and moderate glomerulosclerosis and recedes as sclerosis progresses [12]. In addition, tubulo-interstitial damage triggers an inflammatory response with mononuclear cell infiltration that is strongly related to disease progression [13]. Studies in experimental diabetes have clarified that macrophage infiltration occurs at an early stage of the disease and correlates with renal injury [14-16]. Deletion of genes encoding proteins crucial in driving renal monocyte recruitment such as the chemokine Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) and the adhesion molecule InterCellular Adhesion Molecule-1 (ICAM-1) prevents the development of kidney injury in experimental diabetes [17, 18]. Moreover, a causal link between macrophages and renal damage has been recently established by demonstrating that macrophage depletion significantly reduces albuminuria, kidney macrophage recruitment, and glomerular histological changes and preserves expression of podocyte proteins, such as nephrin and podocin, important in maintaining glomerular permselectivity [19].

The mechanism whereby macrophages contribute to the renal damage in DN remains elusive; however, activated macrophages are capable of secreting a wide range of potentially cytotoxic products, including proteolytic enzymes and reactive oxygen species (ROS), as well as both proinflammatory [Tumor Necrosis Factor-a (TNF-a), Interferon-g (IFN-g), Interleukin-1 (IL-1)] and prosclerotic [Transforming Growth Factor-b1 (TGF-b1)] cytokines that can contribute to renal cell dysfunction/injury. Consistent with this notion, in vitro studies have shown that mesangial cell exposure to macrophage-conditioned medium increases expression of extracellular matrix components [20], such as fibronectin, collagen type IV, laminin, and Tissue Inhibitor of Metalloproteinases (TIMPS), which inhibits extracellular matrix degradation. In addition, coculture of macrophages and mesangial cells leads to a synergistic increase in fibronectin production by mesangial cells [20]. Studies on cultured podocytes have demonstrated that podocyte exposure to conditioned medium from activated macrophages causes cell shrinkage, disorganization of F-actin microfilaments, loss of cell processes, and downregulation of both nephrin and podocin [21]. The specific factor secreted by macrophages that is responsible for these alterations is often undetermined, but the pro-inflammatory cytokines TNF-a and IL-1 appear to play a predominant role. Finally, the direct physical interaction between monocytes/macrophages and glomerular cells via the adhesion molecule ICAM-1 [22] can amplify the inflammatory process by favouring glomerular monocyte infiltration through chemokine secretion and by enhancing the release of inflammatory cytokines by both cell types.

Besides enhancing renal monocyte recruitment, diabetes also affects the phenotype of macrophages. Infiltrating macrophages can polarize towards either pro-inflammatory M1 macrophages that play a key role in tissue injury or anti-inflammatory M2 macrophages that are important in tissue repair. In experimental diabetes both subsets of macrophages are increased in the diabetic kidney, though M1 macrophages appear predominant [19, 23, 24]. In addition, a recent in vitro study has demonstrated that M1, but not M2, macrophages impair integrity of podocyte exposed to high glucose, leading to enhanced permeability to albumin [19]. Strategies that increase M2 macrophages relative to M1 at sites of kidney injury have been proposed for renal protection [25]. Notably adoptive transfer of M2 macrophages to mice with streptozotocin (STZ)-induced diabetes has been shown to decrease both renal macrophage accumulation and kidney damage [26].

Given the important role of micro-inflammation in the pathogenesis of DN, a large number of inflammatory mediators have been investigated to assess their potential relevance as clinical biomarkers and/or molecular targets in DN. These studies have clarified that some proinflammatory systems not only control infiltration and activation of inflammatory cells and thus indirectly contribute to the kidney damage, but they also have direct deleterious effects on resident kidney cells that occur independently of local monocyte accrual, opening an entirely new scenario in our understanding of the role of inflammatory processes in DN and in our possibility to exploit it for clinical purposes (Figure 1). In this review, we will specifically focus on three of these pro-inflammatory systems: the Tumor Necrosis Factor(TNF)-a/TNF-a receptor system, the Monocyte Chemoattractant Protein-1/CC-chemokine receptor-2 system, and the Endocannabinoid system (ECS) as recent studies have highlighted their potential clinical relevance in DN. TNF-a has long been implicated in the pathogenesis of DN, but recent epidemiological studies suggest that TNF-a receptors may also serve as novel biomarkers of renal function decline. Convincing preclinical data have demonstrated that blockade of the MCP-1/CCR2 system is beneficial in experimental diabetes, but phase I and II trials have only recently provided preliminary evidence of effectiveness and safety in humans. The ECS has been extensively studied in both obese and type 2 diabetic patients because of its important metabolic effects, but a previously unsuspected role of the ECS in DN has been only recently elucidated.