Current Pharmaceutical Design - Volume 10, Issue 27, 2004

This issue of Current Pharmaceutical Design, for which I have the great pleasure to be Executive Guest Editor, addresses topical issues relating to the pathogenesis and treatment of the diabetic microvascular complications, retinopathy and nephropathy. Wilkinson-Berka and Fletcher [1] discuss the role of the renin-angiotensin and kallikrein-kinin systems in vascular and neuroglial dysfunction in diabetic retinopathy. Evidence from both experimental and clinical studies indicates that these systems are disturbed in diabetic retinopathy and may be potential therapeutic targets. Wilkinson-Berka [2] then explores the importance of the vasoactive factors, vascular endothelial growth factor, cyclooxygenase-2 and nitric oxide in diabetic retinopathy, and how these factors may interact to stimulate pathology in ischemic-induced retinopathies. Stitt et al. [3] then addresses the importance of advanced glycation end-products in the development of diabetic retinopathy. The mode of action of these agents and the implications for their inhibition as a treatment strategy is reviewed. Forbes et al. [4] extends the discussion of advanced glycation end-products to review the role of these agents in diabetic nephropathy. The efficacy of various types of inhibitors is explored and their interactions with the renin-angiotensin system. Kelly et al. [5] continues with the theme of diabetic nephropathy and discusses the important role of vasoactive factors. It is well established that blockade of angiotensin II is renoprotective, however, other novel factors such as urotensin may also be pathogenic. Flyvbjerg et al. [6] examines experimental and clinical evidence that growth hormone, insulin-like growth factor and vascular endothelial growth factor are causative factors in the pathogenesis of diabetic nephropathy. The interplay between each system is discussed and well-known and potential therapeutic strategies targeting these systems. Jenkins et al. [7] reviews evidence that dyslipoproteinaemia contributes to the development of diabetic nephropathy and retinopathy. Lipoprotein metabolism in Type 1 and Type 2 diabetes is reviewed, and the recognition and treatment of lipoprotein-related risk factors as a treatment strategy for the high complication risk diabetic patient. Given the excellence of reviews contained in this issue, I hope that the readers of Current Pharmaceutical Design will find this issue useful for updating their knowledge on the interactions between the many factors involved in the progression of diabetic microvascular complications. The reviews identify the potential for the development of new and improved drugs for the prevention and treatment of both diabetic retinopathy and nephropathy.

The renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) are complex pathways linked by a number of molecules that participate in both systems. Apart from modulating a variety of normal physiological processes, both the RAS and KKS are up-regulated following tissue injury where they influence vascular function, inflammation, cell growth and differentiation and angiogenesis. The RAS exerts its effects by the generation of a family of bioactive angiotensin peptides in which angiotensin II (ANG II) and the angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptors are most well characterised. In the KKS, bradykinin (BK) and kallidin and their carboxypeptidase metabolites, des-Arg9-BK and des-Arg10-kallidin, are the effector peptides exerting their actions via BK type 1 (BK-B1) and BK type 2 (BK-B2) receptors. Emerging evidence suggests that an ocular RAS is activated in diabetic retinopathy and may contribute to progressive alterations to retinal cells such as pericytes, endothelial cells, neurons and glia. Less well studied is the retinal KKS, however recent studies indicate effects on retinal electrophysiology and angiogenesis. The pathogenetic actions of the RAS and KKS in many tissues and possibly the diabetic retina are mediated by specific growth factors such as vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF). This review will examine the roles of the RAS and KKS in both retinal vascular and neuro-glial dysfunction in diabetic retinopathy, and the potential of blockade of these systems for the prevention and treatment of this serious diabetic complication.

The pathogenetic agents involved in the development of diabetic retinopathy are diverse. In the setting of hyperglycaemia and retinal hypoxia a number of vasoactive factors may interact to promote pathology in a variety of cell types including the microvasculature, neurons and glia. Vascular endothelial growth factor (VEGF) is universally accepted as a primary factor in the regulation of vessel patency in vascular networks throughout the body and including the retina. There is considerable evidence that the VEGF system in disturbed early in diabetes and interacts with other pathways and vasoactive factors to stimulate breakdown of the blood retinal barrier (BRB) and eventually promote angiogenesis, the hallmark feature of proliferative diabetic retinopathy (PDR). There is a distinct relationship between VEGF and the prostaglandin-cyclooxygenase system. Prostaglandins influence retinal blood flow, are important in inflammation and are also pro-angiogenic. Recent evidence suggests that cyclooxygenase-2 (COX-2) modulates angiogenesis by interacting with the VEGF system. Like prostaglandins, nitric oxide (NO) is a vasodilator and is implicated in VEGF mediated vascular permeability and angiogenesis. Emerging evidence indicates that COX-2 also interacts with NO and that these two systems have reciprocal effects on each other. There is little doubt that the interactions between these three vasoactive systems are complex and requires further study in the context of retinal vascular permeability, angiogenesis and neurodegeneration. This review will explore experimental and clinical evidence that VEGF, COX-2 and NO promote retinal pathology in diabetes and other ischemic-induced retinopathies.

Diabetic retinopathy remains the most common microvascular complication suffered by diabetic patients and is the leading cause of registerable blindness in the working population of developed countries. The clinicopathological lesions of diabetic retinopathy have been well characterised and although a multitude of pathogenic mechanisms have been proposed, the underlying dysfunctional biochemical and molecular pathways that lead to initiation and progression of this complication remain largely unresolved. There is little doubt that the pathogenesis of diabetic retinopathy is highly complex and there is a pressing need to establish new therapeutic regimens that can effectively prevent or limit retinal microvascular cell dysfunction and death which is characteristic of the vasodegenerative stages of diabetic retinopathy. The formation and accumulation of advanced glycation endproducts (AGEs) and / or advanced lipoxidation endproducts (ALEs) are among several pathogenic mechanisms that may contribute to diabetic retinopathy. AGEs / ALEs can form on the amino groups of proteins, lipids and DNA through a number of complex pathways including non-enzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. These reactions not only modify the structure and function of proteins, but also cause intra-molecular and intermolecular cross-link formation. AGEs / ALEs are known to accumulate in the diabetic retina where they may have important effects on retinal vascular cell function, as determined by a growing number of in vitro and in vivo studies. Evidence now points towards a pathogenic role for advanced glycation / lipoxidation in the initiation and progression of diabetic retinopathy and this review will examine the current state of knowledge of AGE / ALE-related pathology in the diabetic retina at a cellular and molecular level. It will also outline how recent pharmaceutical strategies to inhibit AGE / ALE formation or limit their pathogenic influence during chronic hyperglycaemia may play a significant role in the treatment of diabetic retinopathy.

Advanced glycation end products (AGEs) in diabetic nephropathy have been extensively researched over the last decade and are now firmly established as major players in this disease. The enigma remains the search for the ideal AGE inhibition therapy, which is a great challenge in the context of the structural diversity inherent to AGE chemistry. Certainly, there is a requirement to standardize measurements of circulating and tissue levels of AGEs and to characterize the pathogenic potential of specific AGE moieties. In order to develop more effective, targeted approaches to combat diabetic nephropathy, the mechanisms of action of selective AGE inhibitors and the inter-relationships of advanced glycation with other pathogenic pathways must be addressed.

Ongoing investigation into the relationship between the renin-angiotensin system (RAS) and the progression of diabetic renal disease has persisted for the past two decades. Experimental and clinical evidence suggests that the RAS has a pathogenic role, induced by its haemodynamic and non-haemodynamic mechanisms. The discovery of a local intrarenal RAS provides a rationale for investigating the components of RAS, specifically Angiotensin II (AngII) in the diabetic setting. AngII has multiple effects, including activating intracellular second messengers, transcription factors, extracellular matrix protein and also growth factors and cytokines, which lead to many of the structural and functional changes in the diabetic kidney. The beneficial effects afforded by RAS blockade further implicate AngII in the progression of diabetic nephropathy. Although AngII is a common suspect in the pathogenesis of diabetic nephropathy RAS blockade does not prevent patients from progressing to end stage renal disease. Evaluating other vasoactive factors, which have similar and distinct functions to AngII, will assist in understanding their potential role in the pathogenesis of diabetic nephropathy. A large number of researchers are studying vasoactive factors, however, the case for their role in diabetic nephropathy is inconclusive. Further investigation into the effects of inhibiting vasoactive compounds, including endothelin, urotensin II and vasopeptidases, together with inhibiting RAS, may provide another therapeutic avenue for treating diabetic nephropathy.

At present, diabetic kidney disease affects about 15-25 % of patients with type 1 diabetes (T1D) and 30-40 % of patients with type 2 diabetes (T2D). Several decades of extensive research have elucidated various pathways to be implicated in the development of diabetic kidney disease. These include metabolic factors beyond blood glucose (e.g. advanced glycation endproducts (AGEs)), haemodynamic factors (e.g. the renin angiotensin system (RAS)), intracellular signaling molecule proteins (e.g. protein kinase C (PKC)) and growth factors / cytokines (e.g. growth hormone (GH), insulin-like growth factors (IGFs), transforming growth factor ß (TGF-ß) and vascular endothelial growth factor (VEGF)). This review focusses on the role of three of these growth factors, i.e. GH, IGFs and VEGF. A brief discussion of each system is followed by description of its expression in the normal kidney. Then, for each system, in vitro, experimental and clinical evidence addressing the role of the system in diabetic kidney disease is presented. The interplay of each system to other potential pathways will also be adressed. Finally, well-known and potential therapeutic strategies targeting the GH / IGF and VEGF systems in a specific or indirect way will discussed.

Risk factors for the microvascular complications (nephropathy and retinopathy) of Type 1 and Type 2 diabetes mellitus and the associated accelerated atherosclerosis include: age, diabetes duration, genetic factors, hyperglycaemia, hypertension, smoking, inflammation, glycation and oxidative stress and dyslipoproteinaemia. Hypertriglyceridaemia, low HDL and small dense LDL are common features of Type 2 diabetes and Type 1 diabetes with poor glycaemic control or renal complications. With the expansion of knowledge and of clinical and research laboratory tools, a broader definition of 'lipid' abnormalities in diabetes is appropriate. Dyslipoproteinaemia encompasses alterations in lipid levels, lipoprotein subclass distribution, composition (including modifications such as non-enzymatic glycation and oxidative damage), lipoprotein-related enzymes, and receptor interactions and subsequent cell signaling. Alterations occur in all lipoprotein classes; chylomicrons, VLDL, LDL, HDL, and Lp(a). There is also emerging evidence implicating lipoprotein related genotypes in the development of diabetic nephropathy and retinopathy. Lipoprotein related mechanisms associated with damage to the cardiovascular system may also be relevant to damage to the renal and ocular microvasculature. Adverse tissue effects are mediated by both alterations in lipoprotein function and adverse cellular responses. Recognition and treatment of lipoprotein-related risk factors, supported by an increasing array of assays and therapeutic agents, may facilitate early recognition and treatment of high complication risk diabetic patients. Further clinical and basic research, including intervention trials, is warranted to guide clinical practice. Optimal lipoprotein management, as part of a multifaceted approach to diabetes care, may reduce the excessive personal and economic burden of microvascular complications and the related accelerated atherosclerosis.

The modern pharmaceutical industry based on synthetic chemistry severed the historical connection between plants, food and medicines. The growing costs of discovering new chemical entity-based drugs through high throughput screening methods may yet again reconnect plants and human health at a new level of technological sophistication. Multicomponent botanical therapeutics that comprise functional foods, dietary supplements and botanical drugs hold several advantages over conventional drugs that may earn them a more prominent place in the medicine of the future. They can deliver mixtures of multi-functional molecules with potentiating and synergistic effects and pleiotropic targeting at a reasonable cost and with fewer regulatory constraints. They are well suited for long-term disease prevention in an era of genetic testing and increased life expectancy. They also provide additional vehicles for delivering health and wellness. Technologies that address the needs of discovery, development and manufacturing of multi-component botanical therapeutics are emerging. They include computational and bioinformatics approaches, cell based gene expression and high-content screening systems, and phytochemical elicitation and unique plant cultivation / extraction methods designed to optimize the production of bioactives, standardize overall extract composition and assure batch-to-batch product consistency. Nevertheless, multi-component botanical therapeutics carry risks associated with potential interactions with conventional drugs and adverse reactions, which are difficult to detect and diagnose. They face problems of acceptance by the medical community and pharmaceutical industry, safety and efficacy validation, poor standardization and quality control, and difficulties in identifying active ingredients and determining their complex mode(s) of action. Solving these problems will accelerate the merger of grocery stores with pharmacies and agriculture with chemical manufacturing and provide physicians and patients with broader and more individualized choices for disease prevention and treatment.

Eph receptors are a unique family of receptor tyrosine kinases (RTK) that play critical roles in embryonic patterning, neuronal targeting, and vascular development during embryogenesis. In adults, Eph RTKs and their ligands, the ephrins, are frequently overexpressed in a variety of cancers and tumor cell lines, including breast, prostate, non-small cell lung and colon cancers, melanomas, and neuroblastomas. Unlike traditional oncogenes that often function only in tumor cells, recent data show that Eph receptors mediate cell-cell interaction both in tumor cells and in tumor microenvironment, namely the tumor stroma and tumor vasculature. As such, Eph RTKs represent attractive potential targets for drug design, as targeting these molecules could attack several aspects of tumor progression simultaneously. This review will focus on recent advances in dissecting the role of Eph RTKs in tumor cells, tumor angiogenesis, and possible contribution to trafficking of inflammatory cells in cancer.