The role of TNF-α in diabetic nephropathy: Pathogenic and therapeutic implications

Cytokine & Growth Factor Reviews 17 (2006) 441–450 www.elsevier.com/locate/cytogfr

Mini review

The role of TNF-a in diabetic nephropathy: Pathogenic and therapeutic implications Juan F. Navarro a,b,c,*, Carmen Mora-Ferna´ndez b a

Nephrology Service, University Hospital Nuestra Sen˜ora de Candelaria, Ctra. del Rosario 145, 38010 Santa Cruz de Tenerife, Spain b Research Unit, University Hospital Nuestra Sen˜ora de Candelaria, Ctra. del Rosario 145, 38010 Santa Cruz de Tenerife, Spain c Centre of Biological Research, Spanish National Research Council, Serrano 117, 28006 Madrid, Spain

Abstract Diabetes mellitus and its complications are a public health problem. Diabetic nephropathy has become the main cause of renal failure, and furthermore is associated with a dramatic increase in cardiovascular risk. Unfortunately, the mechanisms leading to the development and progression of renal injury in diabetes are not yet fully known. There is now evidence that activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Furthermore, different inflammatory molecules, including pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a), play a critical role in the development of microvascular diabetic complications, including nephropathy. This review discusses the role of TNF-a as a pathogenic factor in renal injury, focusing on diabetic nephropathy, and describes potential treatment strategies based on modulation of TNF-a activity. # 2006 Elsevier Ltd. All rights reserved. Keywords: Tumor necrosis factor-a; Chronic kidney disease; End-stage renal disease; Diabetic nephropathy

1. Introduction Chronic kidney disease (CKD) is emerging in the 21st century as a worldwide public health problem. According to the World Health Report 2002 and Global Burden of Disease project, diseases of the kidney and urinary tract contributes significantly to the global burden of diseases with 850,000 deaths every year and more than 15,000,000 disabilityadjusted life years, although the global incidence and prevalence of CKD is probably underestimated [1]. In a survey published in 2002 including 122 countries, the approximate total number of end-stage renal disease (ESRD) patients on renal replacement therapy (RRT) was over 1.4 million [2]. In the United States in 2003, 360,000 people with ESRD were on RRT, but according to a forecast * Corresponding author at: Servicio de Nefrologı´a, Hospital Nuestra Sen˜ora de Candelaria, Ctra. del Rosario 145, 38010 Santa Cruz de Tenerife, Spain, Tel.: +34 922 602061; fax: +34 922 602349. E-mail address: [email protected] (J.F. Navarro). 1359-6101/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2006.09.011

analysis this number will increased to 650,000 in less than 10 years [3]. Estimations indicate that as many as 2 million patients will require RRT by 2010 [3,4]. This situation is even more worrying if we take into account that patients with ESRD are likely to represent the tip of the iceberg of the entire burden of CKD [5], and therefore, the number of individuals with earlier stages of CKD are likely to exceed by as much as 50-fold of those reaching ESRD. The Third National Health and Nutrition Examination Survey (NHANES III) has estimated that 19 million of the adult American population (11%) has some degree of renal involvement [6]. Furthermore, it is increasingly recognized that the burden of CKD is not limited to its impact on demands for RRT but has major consequences on overall population health. Therefore, CKD, even in stages of minor renal dysfunction, has a significant influence on the global burden of death due to cardiovascular disease, even in general population [7,8]. Chronic diseases are now in pandemic proportions and are the major causes of morbidity and mortality worldwide [9,10],

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and diabetes mellitus, especially type 2 diabetes, has an important place. The global number of individuals with diabetes in 2000 was estimated to be around 170 million worldwide, and projected to more than 350 million in 2030 [11]. Due to this changing disease profile to chronic diseases, we are experiencing a change in the cause of renal insufficiency. Thus, type 2 diabetes is now the major cause of ESRD, both in the developed and the emerging world [12].

2. Diabetes mellitus: an autoimmune-inflammatory disorder An exciting hypothesis proposed at the end of 1990s suggested that activation of the innate immune system and chronic low-grade inflammation are closely involved in the pathogenesis of type 2 diabetes [13,14]. In this model, the innate immune system modulates the effects of many factors including genes, ethnicity, foetal programming, nutrition and age upon the later development of metabolic sequelae associated with insulin resistance. The hypothesis suggests that long-term innate immune system activation, resulting in chronic inflammation, elicits disease instead of repair in individuals who develop type 2 diabetes. Studies in non-diabetic subjects, in individuals with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), in type 2 diabetic patients, as well as in the general population, have shown that markers of inflammation, acutephase reactants and pro-inflammatory cytokines, including Creactive protein (CRP), sialic acid, tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), are positively correlated with measures of insulin resistance [15–18]. Furthermore, diabetic patients show elevated levels of inflammatory parameters compared with non-diabetic subjects [18–20]. Moreover, diverse prospective studies, including the Atherosclerosis Risk in Communities (ARIC) study [21], the Cardiovascular Health Study [22], the U.S. Women’s Health Study [23], the U.S. Insulin Resistance and Atherosclerosis Study [24] or the European Prospective Investigation into Cancer and Nutrition (EPIC)-Postdam Study [25], strongly support the notion that chronic low-grade inflammation plays a determinant contributory role in the genesis of type 2 diabetes. Therefore, there is now clear evidence that inflammatory markers, acute-phase reactants and proinflammatory cytokines are strongly associated with the risk of developing type 2 diabetes. The realization of this new pathogenic perspective of type 2 diabetes leads us to question whether inflammation and pro-inflammatory cytokines play a role in the development of diabetic complications.

3. Diabetic nephropathy: a pro-inflammatory cytokine-associated disease Despite improvements in our knowledge of the pathogenesis of diabetic nephropathy (DN), the intimate

mechanisms leading from chronic hyperglycaemia to renal lesion are complex and not yet fully known. In 1991, Hasegawa et al. [26] suggested for the first time that the proinflammatory cytokines TNF-a and interleukin-1 (IL-1) could significantly contribute to the pathogenesis of DN. After this initial study, other experimental works demonstrated that in the kidney, both blood-borne cells (mainly monocytes and macrophages), as well as diverse intrinsic renal cells, synthesize pro-inflammatory cytokines [27–31], which may play a significant role in the development of renal injury in type 2 diabetes. Distinct from their role as mediators of immunological reactions and inflammatory processes, TNF-a and IL-1 have been associated with significant direct renal effects. IL-1 stimulates mesangial cell proliferation and extracellular matrix synthesis, which would lead to expansion of the mesangium and thickening of the glomerular basement membranes (GBM), a critical lesion of diabetic glomerulopathy. Furthermore, IL-1 has been involved in the development of intraglomerular microcirculatory abnormalities related to the stimulation of prostaglandin synthesis by mesangial cells. Finally, IL-1 induces endothelial procoagulant activity and also increases endothelial permeability [32–34]. IL-6 has been related to increased GBM width [35]. Furthermore, IL-6 enhances fibronectin expression, affects extracellular matrix dynamics at both mesangial and podocyte levels, stimulates mesangial cell proliferation, and increases endothelial permeability [35,36]. IL-18 has been demonstrated to be independently associated with urinary albumin excretion rate in type 2 diabetic subjects [37]. The intrinsic renal effects of IL-18 related renal lesion in DM are not known, although this cytokine has been involved in local inflammatory, immune and immunopathological reactions in renal parenchyma [38,39]. With regard to TNF-a, most attention has been paid to the involvement of this cytokine in the development of renal injury in human disease, including DN.

4. TNF-a and renal injury Human TNF-a is synthesized primarily by monocytes/ macrophages [40], although intrinsic resident renal cells, such as endothelial, mesangial, glomerular and tubular epithelial cells, are also able to synthesize this cytokine [27– 31]. The synthesis of TNF-a starts with the activation of the TNF-a gene, which leads to the production of a protein with 233 amino acids. This precursor is a 26 kDa membraneassociated form which exists as an integral transmembrane protein with the carboxy-terminus extracellular, that either serves as precursor for the mature TNF-a (a 157 amino acid protein with a molecular mass of 17 kDa), or binds without processing to the TNF-a receptors via cell-to-cell contacts. The multiple actions of TNF-a are mediated by specific cell surface receptors. Two types of receptors have been described: an ephithelial cell-type receptor (TNF-R1) and

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a myeloid cell-type receptor (TNF-R2) [40]. Binding of TNF-a to its receptors activates a number of signal transduction pathways that result in the expression of a variety of transcription factors, cytokines, growth factors, receptors, cell adhesion molecules, mediators of inflammatory processes, acute-phase proteins and major histocompatibility complex proteins [41]. Furthermore, the binding of TNF-a to a cell surface receptor results in intracellular metabolic changes that mediate apoptotic and necrotic cell death [42,43]. The role of TNF-a in mediating renal and glomerular lesion was not elucidated until 1989, when Bertani and associates observed that the infusion of human recombinant TNF-a into rabbits induced the presence of inflammatory cells in the glomerular capillaries, with the prominent findings of glomerular endothelial damage, polymorphonuclear cell accumulation and fibrin deposition within the capillary lumen [44]. Since then, diverse studies have demonstrated that this cytokine, through a broad of bioactivities, may promote significant actions in the kidney with the development of renal injury (Table 1) [45]. 4.1. Hemodynamic alterations TNF-a has been implicated in the intraglomerular hemodynamic disbalance between vasodilatory and vasoconstrictive mediators. This cytokine has been demonstrated to stimulate the production of vasodilatory substances, including adenosine, nitric oxide and prostaglandins (PG) [45–48]. In addition, TNF-a stimulates the mesangial production of vasoconstrictive mediators, including platelet activating factor [49], endothelin-1 [50,51], and also prostaglandins [52]. Synthesis of PGE2, PGI2 and PGF2a is altered by the effect of TNF-a on the production of Table 1 Renal effects of TNF-a Cell contraction Increment of tubular sodium reabsorption Increment of renal protein content and glomerular volume Inhibition of endothelium-dependent relaxation Reduction of glomerular blood flow and glomerular filtration rate Disruption of glomerular permeability barrier Increment of albumin permeability Stimulation of plasminogen-activator inhibitor type-1 tissue factor production Downregulation of tissue factor pathway inhibitor mRNA Reduction of thrombomodulin expression Stimulation of polymorphonuclear leukocytes and monocytes recruitment Stimulation of adhesion molecules expression Stimulation of synthesis and release of chemokines/cytokines/growth factors: MCP-1, RANTES, IP-10, IL-6, IL-8, fibronectin, PDGF, NGF Induction of major histocompatibility complex antigen expression Stimulation of the production of diverse pro-inflammatory and hemodynamic mediators: complement components, reactive oxygen species, nitric oxide, adenosine, plateled activating factor, prostaglandins Proliferation, cytotoxicity and regulation of cell death related genes Induction of apoptosis

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phospholipase A2, which regulates the availability of arachidonic acid [53], and of cyclooxigenase, that converts arachidonate to PGH2 [52]. Furthermore, TNF-a is able to inhibit the endothelium-dependent relaxation [54], as well as to induce the contraction of mesangial cells in a time- and dose-dependent manner [55,56]. These effects favour the balance towards vasoconstriction, resulting in reductions of glomerular blood flow and glomerular filtration rate. 4.2. Disruption of glomerular permeability barrier Initial studies showed that TNF-a is cytotoxic to glomerular, mesangial and epithelial cells, and it is able to induce direct renal damage [44]. McCarthy et al. [57] demonstrated a direct effect of TNF-a on the protein permeability barrier of the glomerulus that is independent of alterations in hemodynamic factors or effects of recruited inflammatory cells. In that study, TNF-a significantly increased the albumin permeability of isolated rat glomeruli, whereas coincubation of glomeruli with anti-TNF-a antibodies abolished this effect, demonstrating that the effect was specific to TNF-a. In addition, superoxide dismutase, a scavenger of superoxide, abolished the TNF-amediated increase in albumin permeability, whereas scavengers of hydrogen peroxide or hydroxyl radical did not alter the effect of TNF-a on albumin permeability, indicating that the reactive oxygen specie superoxide may play an important role as mediator of this effect. 4.3. Procoagulant effects Electron microscopy analysis in the study by Bertani et al. [44] showed a dose-dependent glomerular endothelial cell damage in animals given TNF-a with fibrin-like material in the capillary lumens. TNF-a has a strong procoagulant effect [58] through several mechanisms. This cytokine stimulates the mesangial production of plasminogen-activator inhibitor type-1 tissue factor [59], as well as the synthesis and release of tissue factor by mesangial [60] and endothelial cells [61]. In addition, TNF-a is also able to down-regulate the tissue factor pathway inhibitor mRNA [62] and reduce the glomerular expression of thrombomodulin, a constitutive anticoagulant glycoprotein of the cell surface membrane [63]. 4.4. Recruitment of infiltrating cells into the kidney TNF-a recruits polymorphonuclear leukocytes and monocytes to the kidney and enhances their adhesion to glomerular cells. This cytokine activates mesangial cells with the production of chemoattractants for neutrophils, such as interlukin-8 (IL-8) and interferon-inducible protein10 [64,65], as well as for monocytes, including monocyte chemoattractant protein-1 and colony-stimulating factor-1 [66]. Besides the induction of chemoattractants, TNF-a stimulates the expression of intercellular adhesion molecule-

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1 (ICAM-1) on mesangial cells [67], as well as the biosynthesis and surface expression of ligands for L-selectin on glomerular endothelial cells [68]. This promotes the rapid adhesion of neutrophils and monocytes to these renal cells, which is blunted by blockade of TNF-a [69]. In addition to the infiltration of glomerular structures, TNF-a may be important in mediating infiltration of the interstitium by blood-borne cells. In vitro studies have shown that exposure of tubular epithelial cells to this cytokine also increased the synthesis and secretion of IL-8 [70] and ICAM-1 [71]. 4.5. Induction of apoptosis TNF-a induces cellular apoptosis, a process by which cells undergo programmed non-necrotic cellular death, in many cells, including renal epithelial cells [72]. This process is triggered by the binding of TNF-a to either its TNF-R1, which determines the specific interaction of the TNF-R1associated death (TRADD) domain with the death domain of the TNF-R1 [73]. Similarly, TNF-a may also binds to a similar membrane receptor, Fas, which triggers the cytoplasmic protein Fas-associated death domain (FADD) to interact specifically with the death domain of Fas [74]. These proteins, TRADD and FADD, activate the receptor interacting protein, a protein kinase that activates intranuclear endonucleases, which cleave nuclear DNA and trigger cellular apoptosis [75–77]. In a recent study, Vasylyeva et al. showed that TNF-a-induced mesangial cells apoptosis may be mediated by insulin-like growth factor binding protein-3, describing therefore a new mechanisms of TNF-a-induced apoptosis [78].

5. TNF-a in renal disease and diabetic nephropathy Great advances have been made in understanding the pathogenesis of renal damage in different entities, with in vitro, experimental and clinical studies implicating TNF-a as an important mediator in the development of renal diseases (Table 2) [79]. Significantly elevated concentrations of TNF-a have been found in the supernatant of in vitro cultures of isolated glomeruli from different renal diseases, including experimental focal and segmental glomerulosclerosis, nephrotoxic serum nephritis, passive autologous anti-GBM glomerulonephritis, and rapidly progressive crescentic glomerulonephritis. Furthermore, an increased in situ renal expression of this cytokine has been documented in immune complex glomerulonephritis, murine lupus nephritis and aminoglucoside nephrosis. These in vitro and experimental data parallel the results obtained in clinical studies. Thus, an overexpression of TNF-a has been demonstrated in kidney specimens from patients with various renal disorders, such as acute allograft rejection of renal transplant, ANCA-positive systemic vasculitis, and mesangial IgA nephropathy [79]. Apart from the findings of those studies, the demonstration that blocking

Table 2 Renal diseases with pathogenic participation of TNF-a Nephrotoxic nephritis Lupus nephritis Immune complex proliferative nephritis Crescentic glomerulonephritis Anti-neutrophil cytoplasmic antibodies-positive glomerulonephritis Anti-glomerular basement membrane glomerulonephritis IgA nephropathy Mesangial proliferative glomerulonephritis Membranous nephropathy Focal and segmental glomerulosclerosis Sytemic vasculitis Adryamicin nephrosis Puromycin nephrosis Aminoglucoside nephrosis Acute renal allograft rejection Diabetic nephropathy

TNF-a activity by using neutralizing antibodies, soluble forms of TNF-a receptors or antagonists regulatory proteins, results in the prevention of the renal harmful effects of this factor gives definitive support to the critical participation of TNF-a in the pathophysiological mechanisms of renal disease [26,80–82]. Concerning DN, initial in vitro studies showed that peritoneal macrophages incubated with GBM from diabetic rats produced significantly greater amounts of TNF-a and IL-1 than macrophages incubated with GBM from nondiabetic normal animals [26]. Nakamura et al. [28] demonstrated that TNF-a mRNA levels in the glomeruli of diabetic rats increased by 2-fold after 4 weeks of diabetes, 3-fold after 12 weeks, and 4.2-fold after 24 weeks. Sugimoto et al. [29] reported a significant rise in expression of TNF-a in streptozotocin-induced diabetic rat glomeruli after 26 weeks of diabetes induction, with a further increase after 51 weeks. Our group has recently shown in an experimental model of DN that after 8 weeks of the onset of diabetes urinary TNF-a excretion was significantly enhanced in diabetic rats compared with control animals, and furthermore, that renal mRNA expression for this cytokine was also increased by 2.5-fold in diabetic animals [83]. More important, in that study urinary albumin excretion, the earliest clinical marker of DN and one of the most important factors in the progression to ESRD, significantly correlated with renal cortical mRNA levels and urinary TNF-a concentration [83]. Apart from these data on the association between TNF-a and albuminuria, other studies have demonstrated a significant role of this cytokine in the development of renal hypertrophy and hyperfunction, the principal renal alterations that occur during the initial stage of DN [84,85]. Renal enlargement is very common in diabetic patients and may predict progression to overt nephropathy [84,86], whereas sodium retention is a manifestation of renal hyperfunction observed in diabetic patients before the onset of albuminuria, which contributes to organ hypertrophy [84,87]. The results of the studies by DiPetrillo et al. [84] showed that

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diabetic rats exhibited augmented urinary TNF-a excretion, sodium retention, and renal hypertrophy. Importantly, administration of the anti-TNF-a agent TNFR:Fc, a soluble TNF-a receptor fusion protein, significantly decreased urinary TNF-a concentrations and prevented sodium retention as well as renal hypertrophy. These findings indicate that enhanced TNF-a synthesis and release are critical factors underlying the development of early pathological alterations during DN, including sodium retention and renal hypertrophy. The mechanisms of TNF-a-induced sodium retention during diabetes are not totally clear. However, this cytokine has been suggested as a regulating factor that affects transport process of tubular epithelium as shown by its stimulatory effect on sodium-dependent solute uptake in cultured mouse proximal tubule cells [88]. Furthermore, several data suggest that enhanced tubular sodium transport underlies sodium retention in response to elevated TNF-a since: (1) TNF-a was markedly increased in urine of diabetic rats, but it was not detectable in control and TNFR:Fc treated diabetic rats, suggesting that the action of this cytokine were mediated from the lumen of the nephron; (2) in spite of similar sodium and water intake and urine output, administration of TNFR:Fc-induced urinary sodium output during diabetes compared to untreated rats, implying that tubular sodium transport is inhibited by TNFR:Fc; (3) sodium uptake in distal tubule cells isolated from diabetic rats was directly stimulated by TNF-a [84]. DiPetrillo et al. demonstrated that increased urinary TNFa excretion precedes the development of proteinuria [84]. In that study, on day 10 after the onset of diabetes sodium retention was established, but none of the diabetic rats displayed microalbuminuria. On day 20 after induction of diabetes, when all the eight diabetic rats exhibited significant renal hypertrophy, only two out of them showed microalbuminuria, whereas the remaining diabetic rats were normoalbuiminuric. Another recent study has shown relevant observations concerning the temporal relationship between TNF-a and urinary albumin excretion. Kalantarina et al. [89] examined TNF-a in the serum, urine and renal interstitial fluids of concious rats before and early after induction of diabetes and analysed its correlation with urinary albumin excretion. This study demonstrated a significant rise in the urinary and renal interstitial fluid concentrations of TNF-a as early as 3 days after induction of diabetes without evidence of cellular infiltrates of either cortex or medulla, whereas almost 2 weeks after the rise in renal cortical and urinary TNF-a levels, the diabetic animals showed an increase in urinary albumin excretion. The urinary and renal interstitial fluid concentrations of TNF-a were directly correlated with albuminuria. Furthermore, shortly after the rise in urinary albumin excretion, urinary TNF-a concentration showed a further significant increase, suggesting a stimulatory effect for albuminuria on the production of renal TNF-a. In addition to experimental investigations, clinical studies have found a direct and significant association

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between serum TNF-a and urinary protein excretion in diabetic patients with normal renal function and microalbuminuria, as well as in diabetic subjects with overt nephropathy and renal insufficiency [19,90]. On the other hand, serum and urinary TNF-a levels are also elevated in diabetic patients with increased urinary albumin excretion, and furthermore, there is a significant rise of urinary TNF-a excretion as DN progressed [19,92]. Moreover, multivariate analysis showed a significant and independent relationship between urinary TNF-a and clinical markers of glomerular as well as tubulointerstitial damage in patients with DN [19,91]. Interestingly, in these studies a significant correlation between serum and urinary concentrations of TNF-a was not found, strongly suggesting an intrarenal production of this cytokine [19,91]. Although TNF-a appears to be a critical mediator of DN, the source and stimuli of renal TNF-a production remains to be definitively elucidated. In addition to monocytes and macrophages, diverse intrinsic renal cells, including endothelial, mesangial, glomerular and tubular epithelial cells, have been demonstrated to be able to synthesize and release this cytokine [27–31], and therefore, TNF-a could subsequently exerts its pleiotropic biological activities on different renal structures in a paracrine or autocrine manner. Concerning the factors that stimulate TNF-a synthesis by renal cells, advanced glycation endproducts (AGE) and angiotensin II (Ang II) deserve further interest. Glucose and other reducing sugars react spontaneously with a wide spectrum of proteins and lipids to initiate a posttranslational, non-enzymatic modification process called advanced glycation which yields a heterogeneous group of irreversible adducts called AGE [93]. These substances binding to specific cell surface receptors (RAGE) of the immunoglobulin superfamily identified on several cell types, including renal cells [94,95]. Interaction between AGE-ligands and these specific receptors, which has been implicated in the development and progression of DN [96], induce a range of biologically important responses, including TNF-a synthesis and secretion [97,98]. Finally, Ang II, the principal effector of the rennin–angiotensin system, has been implicated in the development and progression of DN. Ang II promotes proteinuria and accelerates the decline in renal function in diabetes through hemodynamic as well as non-hemodynamic effects [99]. Within these non-hemodynamic actions, it is now clear that Ang II has important effects on pro-inflammatory cytokines, including TNF-a. Initial in vitro studies showed that human peripheral blood monocytes were able to produce TNF-a when challenged with Ang II [100]. Similarly, Ferreri et al. [101] demonstrated that Ang II, when incubated with freshly isolated medullary thick ascending limb tubules, promoted accumulation of TNF-a mRNA and enhanced the production of this cytokine. Ruiz-Ortega et al. [102] showed that in vivo Ang II infusion caused elevated renal expression of TNF-a (gene and protein levels), with TNF-a positive cells being observed in glomeruli, tubules and vessels. Finally, in a

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recent study, Siragy et al. [103] reported the chronic in vivo measurement of renal tissue recovery of Ang II and TNF-a over an extended time course in a concious rat model of diabetes. The results of that work demonstrated that increased levels of Ang II and consequent stimulation of the Ang II type 1 receptor increase the renal content of TNFa in diabetes, which was prevented by the administration of valsartan, an Ang II receptor blocker.

6. Modulation of TNF-a: a therapeutic opportunity in diabetic nephropathy Control of classical deleterious factors in the diabetic patient, such as hyperglucemia and elevated blood pressure, has been demonstrated to be critical in preventing the development and progression of DN. In spite of the improvement of these therapeutic strategies, current treatment of DN is suboptimal, being necessary innovative approaches with novel therapies [104]. In this context, the new perspective of DN as a disease with an important participation of inflammatory processes will offer the rationale for the development of new therapeutic targets based on the modulation of inflammatory molecules, including modulation of TNF-a synthesis and activity. Specific TNF-a antagonism has demonstrated beneficial effects in experimental glomerular disease. The administration of anti-TNF-a antibodies decreased proteinuria and the histological lesions in rats with the accelerated autologous nephrotoxic serum nephritis [105]. The use of the TNF-a inhibitor SKF86002 markedly reduced glomerular TNF-a production and improved renal function in antiThy-1 mesangial proliferative glomerulonephritis [106]. A suppression of rat anti-GBM glomerulonephritis was seen when blocking the action of TNF-a using a neutralizing antibody or a soluble form of the TNF-a receptor [107,108]. Evidence from studies using specific TNF-a antagonism with anti-TNF-a antibodies or soluble TNF-a receptors in DN is lacking. However, results from studies modulating TNF-a synthesis and activity by the use of pentoxifylline (PTF) are greatly interesting. PTF is a methylxanthine phosphodiesterase inhibitor with significant hemorheological effects (improve erythrocyte deformability and capillary blood circulation) widely used clinically to treat patients with peripheral vascular disease [109]. In addition to its hemorheological properties, PTF possesses a significant anti-TNF-a activity. In 1988, Strieter et al. [110] reported that PTF reduced TNF-a mRNA accumulation and decreased TNF-a gene transcription. Since then, a number of experimental studies both in vitro and in vivo have demonstrated that PTF is able to suppress the synthesis and release of this cytokine [111–114]. The application of this anti-TNF-a activity has been evaluated in the treatment of different renal diseases where this cytokine is involved. Therefore, PTF administration has demonstrated beneficial effects in experimental models of lupus nephritis

[115], crescentic glomerulonephritis [116], mesangial proliferative glomerulonephritis [117] and remnant kidney model [118]. Concerning DN, PTF has shown beneficial effects preventing or attenuating renal injury. Gunduz et al. [119] showed that treatment with PTF of diabetic rats caused a reduction in the renal protein content and in glomerular volume. Studies by DiPetrillo and Gesek [120], as well as by our group [unpublished data], showed that PTF administration ameliorated renal sodium retention and renal hypertrophy. Taken together, these findings demonstrated that therapy with PTF is able to prevent the initial pathological changes associated with DN. In addition, PTF reduced the increased renal TNF-a expression, synthesis and excretion during experimental diabetes, changes significantly and directly associated with a decrease of urinary albumin excretion. Finally, together with these experimental works, results from clinical studies support the potential efficacy of PTF as a therapeutic agent for DN. Early studies by Solerte et al. showed that, independently of the degree of metabolic control, there was a marked reduction of urinary albumin excretion rate and proteinuria in type 1 and type 2 diabetic patients treated with PTF [121,122]. These initial findings were confirmed by other authors, showing that PTF reduces urinary protein excretion in diabetic subjects, both with normal renal function [123,124] and renal insufficiency [90]. In addition, recent prospective trials in diabetic patients with nephropathy have demonstrated that addition of PTF to blockers of the rennin–angiotensin system, ACE inhibitors [125] as well as ARBs [126], is associated with a significant reduction of urinary albumin excretion. Therefore, diabetic patients with residual albuminuria in spite of long-term blockade of the rennin–angiotensin system may obtain a beneficial additive antialbuminuric effect of PTF, which is significant and directly related to a reduction of urinary TNF-a excretion [126].

7. Conclusions TNF-a is expressed, synthesized and released, in addition to infiltrating macrophages, by different cells of the kidney, such as endothelial, mesangial, glomerular and tubular epithelial cells, with AGE and Ang II being important stimuli for TNF-a production. The renal effects of this cytokine are diverse and include, in addition to mediate inflammatory reactions, hemodynamic alterations with reduction of glomerular blood flow and filtration rate; damage of the glomerular permeability barrier with the development of albuminuria; procoagulant activity; recruitment of infiltrating cells into the kidney, including polymorphonuclear leukocytes and monocytes; induction of apoptosis. Experimental as well as clinical studies have demonstrated the pathogenic role of TNF-a in the development of renal injury in diverse renal disease, including DN, and the potential benefit of modulating TNF-a activity as a therapeutic target in this condition.

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Acknowledgements The studies by the authors have been supported by Fundacio´n Canaria de Investigacio´n y Salud (FUNCIS), Sociedad Espan˜ola de Nefrologı´a (SEN) and Asociacio´n Cientı´fica para la Investigacio´n Nefrolo´gica (ACINEF).

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Juan Navarro was born in Santa Cruz de Tenerife (Canary Islands, Spain) in 1966 where he graduated in Medicine in 1989 at the University of La Laguna. He specialized in Nephrology from 1991 to 1994 at the Hospital Ramo´n y Cajal, in Madrid. In 1995, he joined the Division of Nephrology at the University Hospital Nuestra Sen˜ora de Candelaria as Staff Nephrologist. He is associate researcher at Research Unit, Hospital Nuestra Sen˜ora de Candelaria (Tenerife) and Biological Research Center, Spanish National Research Council (Madrid).He is assistant professor of Nephrology at the Department of Internal Medicine (University of La Laguna, Tenerife). His research interest focuses on diabetic nephropathy, including experimental works in animal models analysing new mechanisms involved in the pathogenesis of this complication, translational research towards new clinical therapeutic strategies, as well as genomic, proteomic and metabolomic studies. Juan Navarro has published more than 45 original peerreview articles, as well as a number of editorials and reviews in high-impact journals. He is an International Fellow of the American Society of Nephrology since 2006. Juan Navarro won the 2003 ‘‘In˜igo Alvarez de Toledo’’ Spanish Research Award on Clinical Nephrology. In 2006, he won the ‘‘Aula Medica Prize’’ from the Spanish Society of Nephrology. This prize was established to recognize young investigators for excellence in nephrology research. Carmen Mora was born in Madrid in 1966 where she graduated in Medicine in 1991 at the University of Alcala´ de Henares. She is Coordinator of the Intramural Program at the Fundacio´n Canaria de Investigacio´n y Salud (Canarian Health Service). She is associate researcher at Research Unit, Hospital Nuestra Sen˜ora de Candelaria (Tenerife). Her research interest focuses on diabetic nephropathy, including experimental works in animal models analysing new mechanisms involved in the pathogenesis of this complication, translational research towards new clinical therapeutic strategies, as well as genomic, proteomic and metabolomic studies. Carmen Mora has published more than 20 original peer-review articles, as well as a number of editorials and reviews in high-impact journals.