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Review

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Novel therapeutic approaches for diabetic nephropathy and retinopathy

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Vera Usuelli, Ennio La Rocca ∗ Division of Transplant Medicine, IRCCS Ospedale San Raffaele, Milan, Italy

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Article history: Received 3 September 2014 Received in revised form 3 October 2014 Accepted 16 October 2014 Available online xxx

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Keywords: Diabetic nephropathy Diabetic retinopathy Type 1 diabetes Type 2 diabetes Hyperglycemia Microvascular complications

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Contents

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Diabetes mellitus is a chronic disease that in the long-term increases the microvascular and macrovascular degenerative complications thus being responsible for a large part of death associated with diabetes. During the years, while preventive care for diabetic patients has improved, the increase in the prevalence of diabetes worldwide is continuous. The detrimental effects of diabetes mellitus result in microvascular diseases, which recognize hyperglycemia as major determinant. A significant number of potential therapeutic targets for the treatment of diabetic microvascular complications have been proposed, but the encouraging results obtained in preclinical studies, have largely failed in clinical trials. Currently, the most successful strategy to prevent microvascular complications of diabetes is the intensive treatment of hyperglycemia or the normalization of glycometabolic control achieved with pancreatic and islet transplantation. In this review, we focus on the novel therapeutic targets to prevent the development and progression of diabetic nephropathy and retinopathy microvascular complications. © 2014 Elsevier Ltd. All rights reserved.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetic retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction Diabetes mellitus (DM) is a chronic disease characterized by hyperglycemia that in the long-term increases the likelihood of developing microvascular and macrovascular degenerative complications and causes an increase of morbidity and mortality [1]. Although preventive care for diabetic patients has improved during the last two decades and the rates of diabetes related complications have declined, a large burden of disease persists because of the continued increase in the prevalence of diabetes worldwide

∗ Corresponding author. Tel.: +39 0226432575; fax: +39 0226433790. E-mail address: [email protected] (E. La Rocca).

[2]. Diabetic complications are influenced by both genetic determinants of individual susceptibility and by independent accelerating factors such as hypertension, hyperhomocysteinemia and left ventricular dysfunction [3–5]. Hyperglycemia must be considered the major determinant of diabetic microvascular diseases, while free fatty acids associated to insulin resistance, must be considered the major determinant of diabetic macrovascular complications [6]. The main biological mechanisms of diabetic complications can be unified by the process of overproduction of superoxide radical oxygen species (ROS), the downstream intracellular signaling pathways and their modulators, which may serve as therapeutic target for the treatment of diabetic complications [6]. Among these targets we should mention the advanced glycation end products (AGEs) and their receptors, glucose transport molecules, nuclear

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Hemodynamic pathway High Pressure, Angiotensin II VEGF, TGF-β

Metabolic pathway Hyperglycemia Glucose lowering

ACE inhibitors, ARBs PKC inhibitors Antioxidants

PKC

Oxidative AGEs Polyol stress

ARIs AGE inhibitors

Activation of intracellular signaling molecules, growth factors and cytokines (e.g.; NFkB, TGF-β, VEGF, IL-6, IL-1β)

VEGF inhibitors

Cellular damage and pathological alterations

Diabetic Nephropathy and Retinopathy Fig. 1. Signaling pathways and common therapeutic approaches for diabetic nephropathy and retinopathy. Abbreviations: AGEs, advanced glycations end products; PKC, protein kinase C; TGF-␤, transforming growth factor beta; IL-6, interleukin-6; VEGF, vascular endothelial growth factor; NF␬B, nuclear factor kappa-light-chain-enhancer of activated B cells; IL-1␤, interleukin-1 beta; ARBs, angiotensin II receptor blockers; ARIs, aldosterone reductase inhibitors; ACE, angiotensin-converting enzyme.

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factor kappa-light-chain-enhancer of activated B cells (NF␬B), protein kinase C (PKC), inflammatory molecules such as adipokines, chemokines, adhesion molecules and pro-inflammatory cytokines [6,7]. Furthermore, pro-fibrotic molecules as epidermal growth factor, vascular endothelial growth factor (VEGF), connective tissue growth factors (CTGF) and the transforming growth factor beta (TGF-␤), which are considered to potentiate the morphological alterations related to diabetic complications have also been studied [7]. In recent times, epigenetic alterations, including histone, methylation and microRNAs have demonstrated their potential role as novel therapeutic targets in the area of diabetic complications [8]. An elevated number of new potential agents are the focus of clinical trials or are in pre-clinical investigations. We focus here on a novel therapeutic approaches to prevent the development and progression of diabetic nephropathy and retinopathy microvascular complications [9] (Fig. 1).

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Diabetic nephropathy

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Diabetic nephropathy (DN) is a leading cause of end stage renal disease and it seems to occur as a result of an interaction among inflammatory, metabolic and hemodynamic factors [10] (Fig. 1). The progression to end stage renal disease, favored by hyperglycemia and hypertension, is characterized by microalbuminuria and macroalbuminuria. Typically these factors induce structural abnormalities of the glomerulus, tubular epithelial cells, interstitial fibroblasts and vascular endothelial cells [11]. Over the past decade, there have been important advances in understanding the pathogenesis of diabetic nephropathy, with particular focus on inflammatory status and oxidative stress. Glucose-dependent pathways, such as advanced glycation, play an important role in the development of diabetic renal disease [12]. In addition, the accumulation of extracellular matrix seems to be the consequence of pro-sclerotic action of growth factors, including TGF-␤ and CTGF [13]. It is also increasingly clear that angiotensin II can enhance AGEs accumulation in the kidney and AGEs can directly modulate expression of key components of the renin-angiotensin system

(RAS). Thus, it seems that metabolic and hemodynamic stimuli, triggered by diabetes, interact to increase injury and the progression of renal damage [14]. Furthermore, as observed in type 1 diabetes (T1D), the onset of nephropathy is associate with inflammatory cells infiltration and increase of C-reactive protein and inflammatory cytokines such as interleukin-1 beta (IL-1␤) and vascular cell adhesion molecule 1 [15]. In addition, in type 2 diabetes (T2D), the development of nephropathy is associated with the activation of CD8+ T cells and with the increase of interleukin-6 (IL-6) [7,16,17]. Systemic control Several large cohort studies have shown the efficacy of strict glycemic control treatment on the development of DN. In particular two studies, the Diabetes Control and Complications Trial (DCCT) [18] and the Epidemiology of Diabetes Interventions and Complications (EDIC) [19], resulted in clinically important, long-lasting reductions in incidence of kidney disease. In these studies, intensive diabetes therapy in T1D patients reduced the risks of microalbuminuria, macroalbuminuria and impaired glomerular filtration rate (GFR) [18,19]. Studies performed in pancreas-transplanted patients as well as in Langherans islet transplant recipients, confirmed that strict glycemic control might slow the rate of kidney damage, even if overt proteinuria has developed [20]. The efficacy of prolonged euglycemia on diabetic nephropathy has been further demonstrated in T1D patient recipients who received pancreas transplantation alone [21]. When compared with a control group treated with conventional insulin therapy at a five years follow up, these with recipients of pancreas transplantation showed histological changes associated with DN (e.g.; increased mesangial and glomerular volume). After 10 years of successful pancreas transplantation, significant reductions were observed in the thickness of the glomerular basement membranes and of the mesangial fractional volume [21]. Antihypertensive drugs that interrupt the RAS, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are currently considered first-line treatments for DN [22]. Reduction of blood pressure

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with RAS inhibition is able to prevent or delay nephropathy in microalbuminuric or proteinuric T1D and T2D patients [23]. The treatment with RAS inhibition in normotensive and normoalbuminuric T1D patients is ineffective in preventing microalbuminuria [23]. Identification of new components of this pathway, such as angiotensin-converting enzyme-2 (ACE2), suggested the existence of a complex interaction between the vasoconstrictor and vasodilator arms of the RAS [24]. Indeed, it seems that an alteration in one component, such as ACE2, can influence the renal response to agents such as ACE inhibitors [24].

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After many experimental studies performed in rodent models and based on many lines of evidence, different antioxidants and anti-inflammatory drugs have been proposed as therapy for DN [7] (Fig. 1). The results obtained from studies where antioxidants were used as therapeutics to treat DN, remain controversial or unknown. While in T1D patients who received high doses (1800 IU/day) of vitamin E an improvement of renal function has been demonstrated [25], in patients with microalbuminuria included in the Heart Outcomes Prevention Evaluation (HOPE), vitamin E supplementation (400 IU/day) did not significantly lower decrease the risk for cardiovascular outcome [26]. Different factors, including renal function, may have influenced the results of the HOPE study. Oxidative stress has an important role in the pathophysiological process of uremia and its complications, including cardiovascular disease. However, it is not clear how early oxidative stress develops during the progression of chronic kidney disease (CKD). In a recent study, performed in patients with CKD stages 1 to 4 [27]; oxidative stress appears to increase as CKD progresses and correlates significantly with renal function. The results reported suggest that larger studies using more appropriate markers to assess the timing and complex interplay of oxidative stress and other risk factors during the progression of CKD should be planned [27]. In a phase III clinical trial, bardoxolone methyl, which interacts with cysteine residues on to Kelch-like ECH-associated protein 1, allowing nuclear factor erythroid derived 2 translocation to the nucleus leading to anti-inflammatory effects, appears to have beneficial effects in DN as compared to placebo after 52 weeks of treatment [28]. However, this trial was stopped because of a higher mortality in the treated group. Bardoxolone methyl significantly increased the estimated GFR, but also increased blood pressure and proteinuria in treated subjects. In addition, it significantly increased the rate of cardiovascular events [28]. Extensive studies in diabetic animals suggest that inflammation could cause glomerulosclerosis, tubular atrophy and fibrosis. Thus, based on these lines of evidence, administration of anti-inflammatory compounds may represent a potential treatment of DN [7] (Fig. 1). A variety of antiinflammatory and metabolic agents have been studied with the intent of treating DN, including inhibitors of chemokines, such as monocyte-chemoattractant protein-1 (MCP-1/CCL2), aspirin and cyclooxygense-2 inhibitors (COX-2), 3-hydroxy-3-methyglutaryl CoA (HMG-CoA) reductase inhibitors, endothelin receptors antagonist, PKC inhibitors, fenofibrate, pyridoxamine, dihydrochloride and pentoxifylline [7]. Up to now, there are insufficient data on any of these agents to advocate their therapeutic use for DN, but among them, the most significant data available, including a meta-analysis, demonstrated that pentoxifylline could decrease albuminuria and may have a similar antiproteinuric effect as ACE inhibitors [29]. Furthermore, in a phase II clinical trial it was shown that ruboxistaurin, a PKC␤ isoform selective inhibitor, significantly decreased albuminuria and maintained a stable GFR [30]. Different studies, showed that hyperglycemia activates PKC␤ isoforms, which enhance angiotensin II toxic effect in glomerular endothelial cells [31] and PKC␦, which induce podocyte apoptosis

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[32]. In addition, it has been reported that rapamycin ameliorates podocyte injury and delays the progression of DN, which may be related to the promotion of podocyte autophagy and inhibition of podocyte apoptosis [33]. As a result, some investigators are suggesting the administration of rapamycin in DN to take advantage of its anti-inflammatory properties. Rapamycin significantly reduces the influx of inflammatory cells, including monocytes and macrophages, associated with mesangial expansion or glomerular basement thickness [34]. However in humans, rapamycin has been frequently associated with nephrotoxic effects, particularly in combination with other drugs (e.g.; FK506) [35]. Recent studies have explored potential molecular and biochemical mechanisms that may be responsible for the progression of renal lesions in diabetes, including podocytes. Podocytes injury and resulting albuminuria are hallmarks of DN, in vitro, the glucose related phosphatidylinositol 3 kinase-dependent upregulation of B7-1 in podocytes and the ectopic expression of B7-1 in podocytes, increased apoptosis and induced disruption of the cytoskeleton that were reversed by the B7-1 inhibitor Cytotoxic T-Lymphocyte Antigen 4 (CTLA4-Ig) [36]. B7-1 Podocyte expression was also induced in vivo in two murine models of DN and treatment with CTLA4-Ig prevented the increase of urinary albumin excretion and improved renal morphological features in these animals [36]. Taken together, these results identify B7-1 inhibition as a potential therapeutic strategy for the prevention or treatment of DN [36,37]. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes, strongly they argue that uric acid lowering should be tested as one such novel intervention [38]. A five years trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D patients at elevated risk of renal function impairment, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes [38]. Finally, it should be mentioned that aldosterone antagonists appear to reduce proteinuria when used alone and to a have additive effect on proteinuria when used in association with ACE inhibitors or with ARBs in T1D as well as in T2D patients [39] (Fig. 1). However, a note of caution should be made regarding the importance of close monitoring of plasma potassium concentration to avoid severe hyperkalemia during aldosterone blockade. Studies are needed to establish the long-term beneficial clinical effects of aldosterone blockade and its side effects [40]. Different short-term studies suggest that a low dose of spironolactone alone (regular dose: 25 mg daily) or in addition to other antihypertensive treatments, including ACE inhibitors and/or ARBs, is well tolerated in T2D patients with kidney disease [41].

Diabetic retinopathy Diabetic retinopathy (DR) is one of the most common complications of diabetes and it is a leading cause of blindness in people of working age in industrialized countries [42]. The nonproliferative stage of DR includes increased vascular permeability, macular edema and subsequent visual impairment. The proliferative stage of DR is characterized by neovascularization on the retinal surface because of impaired vascular function by capillary occlusion [43]. In this stage, severe visual impairment or even blindness may be caused by bleeding, hemorrhage and subsequent retinal detachment because of the newly formed fragile vessels [44]. The mechanisms whereby elevated blood glucose level causes tissue injury and disease progression in the retina are not fully understood. However, different studies have shown that DR as well as DN is a multi-factorial disease involving multiple pathways, including aldose reductase pathway, oxidative stress, activation of PKC and formation of AGEs [45,46] (Fig. 1). These pathways

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lead to retinal pathological changes by causing osmotic vascular damage, by inducing cell dysfunction and apoptosis through the activation of mitogen-activated protein kinases and oxidation of intracellular components, that result in the release of angiogenic cytokines, and in the breakdown of the vascular junction proteins [46]. Furthermore, it has been demonstrated that retinal inflammation plays a critical role in the pathogenesis of DR. Together with diabetes-induced AGEs formation and impaired endogenous antiinflammatory pathways lead to chronic inflammatory reactions in the retina by persistently inducing expression of inflammatory cytokines, chemokines and recruiting leukocytes [47]. Chronic inflammation is crucial in the pathogenesis of DR because it may cause neurovascular damage and ischemic neovascularization [48]. The current status of novel treatment recommendations for DR explores some possible future therapies. In ongoing trials under investigation are Bevasiranib, Rapamycin (Sirolimus), potential target molecules, in added to VEGF, are angiopoietin-2, tumor necrosis factor alpha, monocyte chemotactic protein-1 and kallicrein-kinin inhibitor [49,50].

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Different studies have led to the recognition of hyperglycemia, hypertension and dyslipidemia as major risk factors for DR and intensive glycemic control, blood pressure control and lipidlowering therapy have shown proven benefits in reducing the incidence and progression of DR [51]. The results from the DCCT showed that, in patients intensively treated, the onset of DR was delayed and the progression of disease was slowed [18]. Furthermore, the positive effect of glucose control initially obtained, seems to persist on DR over many years (metabolic memory), despite a subsequent equivalency of glycated hemoglobin levels among the groups. The results of EDIC study demonstrated that glycemic control should be reached as soon as possible in T1D patients [19]. Good blood pressure control slows down the rate of progression of DR and reduces the risk of vitreous hemorrhage. Diastolic blood pressure may be a better predictor of progression of retinopathy than systolic blood pressure [52]. Elevated levels of serum cholesterol and low-density lipoproteins are considered as independent risk factors for the development of hard exudates [53], which is a major risk factor to develop subfoveal fibrosis. The beneficial role of statins such as atorvastatin (HMG-CoA reductase inhibitor), as an adjunct to standard treatment in patients with diabetic macular edema has been demonstrated [54].

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Although laser photocoagulation and vitrectomy remain the two conventional approaches for macular edema and proliferative DR, a great effort has been made to identify new therapies for DR. The use of RAS inhibitors represent a possible therapeutic approach for DR given that the RAS regulates multiple key factors of inflammation including oxidative stress, AGEs formation and hypertension [47]. A subset of ARBs that possess partial PPAR␥ agonist activity (e.g.; telmisartan and irbesartan), may be more powerful since they will block pro-inflammatory pathways meanwhile enhancing anti-inflammatory pathways [55] (Fig. 1). In addition, the results of different clinical trials demonstrated that in non-hypertensive diabetic patients, the use of candesartan decreases the incidence of DR in T1D patients and favors DR regression in T2D patients with mild retinopathy. Therefore, it is reasonable to suggest the treatment with candesartan for T1D patients, with or without hypertension, at high risk to develop DR and for T2D patients with mild retinopathy [56]. Furthermore, fenofibrate represents a good treatment for T2D patients, with mild and severe non proliferative DR, since, without changing in serum lipids, it decreases the

development of existing DR, thus reducing the need for laser treatment in diabetic macular edema as well as in proliferative DR [57]. Based on this, the benefit on DR demonstrated using fenofibrate and candesartan must be considered an additional value when treating hypertension and dyslipemia in diabetic patients. AntiVEGF therapy represents an advancement in the treatment of DR, since clinical trials have shown beneficial effects of VEGF blockers (pegaptanib, ranibizumab, bevacizumab) in reducing macular edema and causing neovascular regression, particularly when associated with laser photocoagulation [58] (Fig. 1). In spite of this, DR remains a major clinical challenge and the number of patients keeps growing. Laser photocoagulation and anti-VEGF therapy are not always effective and laser therapy can damage retinal neurons which may result in decreases in central vision, vision acuity and impaired night vision [43]. Anti-VEGF therapy requires repeated treatment, but it may impair neuronal and vascular survival function [59]. Unfortunately, anti-VEGF therapy may be associated with a variety of renal pathological complications which may favor proteinuria, hypertension and cardiovascular complications [60].

Conclusion Currently, the most successful strategy to prevent microvascular complications of diabetes is intensive treatment of hyperglycemia and normalization of glycometabolic control achieved with intensive insulin therapy and with islet or pancreas transplantation [35,61–63]. It is likely that insulin pump therapy and artificial pancreas may further decrease the incidence and development of diabetic complications [64]. However, a large burden of diabetic complications persists because of the continued increase in the prevalence of diabetes, and a poor glycemic control in the early periods of disease may have a negative effect on the protection of diabetic complications despite a subsequent improvement of glucose control [19]. A significant number of potential therapeutic targets for the treatment of diabetic complications have been proposed using current rodent model, but the encouraging results obtained in preclinical studies, have failed thus far in clinical trials. A fundamental problem is the difficulty in designing viable clinical trials and identifying which end points should be used as indicators of therapeutic efficacy. In particular, since in diabetic patients renal failure may occur without the presence of albuminuria, urinary albumin excretion is not always accepted as a surrogate marker by regulatory agencies to register drugs. The DN is diverse and may not be completely predicted by clinical parameters [65]. The diagnosis is, for the most part, based on the course of clinical manifestations. Renal biopsy is only performed in patients with atypical presentations. Microalbuminuria has been considered to be a prognostic factor for the progression of DN; however, recent studies showed that patients with microalbuminuria may demonstrate a return to normal [66]. In addition patients with T2D can commonly progress to a significant degree of renal impairment while remaining normoalbuminuric. Therefore, more sensitive and specific markers for predicting the progression of DN may to be necessary in the near future [65]. In addition, the trials require studies that often involve thousands of patients and long followup period. As of DR, a possible future scenario will involve the use of a combination of anti-VEGF agents and laser photocoagulation or anti-angiogenic agents targeting at different steps of the angiogenic cascade. Nevertheless, current treatments for both diabetic nephropathy and retinopathy have not been completely effective in delaying or halting the development of diseases, suggesting that further understanding of the molecular mechanisms underlying the pathogenesis of both diabetic nephropathy and retinopathy are necessary.

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Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.phrs.2014.10.003.

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