Microvascular complications of diabetes

Endocrinol Metab Clin N Am 33 (2004) 215–238

Microvascular complications of diabetes Zhiheng He, MD, PhD, George L. King, MD Section on Vascular Cell Biology and Complications, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA

Microvascular complications in diabetes contribute to pathologic and functional changes in many tissues, including eye, heart, kidney, skin, and neuronal tissues. Based on the tissues affected, these changes are traditionally known as diabetic retinopathy, nephropathy, and neuropathy, respectively. In addition to these classic complications, pathologic changes in the microvessels of the myocardium reduce cardiac contractility, and ventricular dysfunction is often observed in diabetic patients. The development and progression of microvascular complications is associated closely with chronic hyperglycemia, a relationship supported by numerous clinical studies, such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study [1,2]. Tight glycemic control is by far the most effective approach in the prevention of diabetic vascular complications. Even if satisfactory euglycemic control is not achieved, several theories of the pathogenesis of microvascular complications of diabetes have been proposed, providing feasible targets for specific interventions to prevent the development of diabetic complications. The authors begin this article, which discusses the theories of pathogenesis, by describing typical microvascular pathologies found in diabetes.

Vascular changes in diabetes Some typical pathologic changes in the vasculature occur before the onset of overt diabetes. Basement membrane thickening is common in retinopathy, nephropathy, and neuropathy, and might be a direct consequence of the expression and deposition of extracellular matrix (ECM) proteins in the vasculature. ECM components, such as collagen types I, III, IV, and VI; fibronectin; and laminin, are all increased in the vessels in retina, kidney, and neurovascular tissues in patients with diabetes [3,4]. Other pathologic changes E-mail address: [email protected] (G.L. King). 0889-8529/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ecl.2003.12.003

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include the altered proliferation and death of vascular cells in a cell type– dependent and tissue-specific fashion. For example, retinal pericyte death is an early sign of retinopathy, whereas an increased proliferation of retinal endothelial cells is observed at the sites of pericyte loss, resulting in microaneurysm. Active endothelial cell proliferation is associated with pathologic angiogenesis in proliferative diabetic retinopathy [5]. Tissue specificity can be reflected by the comparison between retinal and myocardium tissues in patients with diabetes. In contrast to the increased proliferation of endothelial cells and angiogenesis in the retinal tissue, diabetic myocardium has reduced endothelial cell staining, suggestive of reduced cell growth [6]. In addition to these structural changes, gene expression for vascular tone mediators, such as endothelin-1 (ET-1) and prostacyclins, is also regulated to induce hemodynamic abnormalities in diabetic patients. Retinopathy Diabetic retinopathy is characterized by several common and unique features, including thickening of vascular basement membrane, pericyte death, microaneurysms, vascular occlusion, and pathologic neovascularization, that advance to retinal hemorrhage, retinal detachment, and vision loss [5,7]. Severity and duration of hyperglycemia are linked directly to pathologic changes and cause vascular dysfunction, such as retinal angiogenesis and vascular permeability [8–10]. Loss of pericytes is one of the earliest specific findings in diabetic retinopathy and the sites of pericyte loss are often associated with microaneurysm formation and vascular obstruction [5]. These changes result in retinal hypoxia, which increases the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF), that in turn promote neovascularization [5]. Nephropathy Diabetic nephropathy is the leading cause of end-stage renal disease worldwide [11,12] and is manifested by early hemodynamic changes, glomerular hyperfiltration, mesangial expansion, glomerular hypertrophy, and thickening of glomerular basement membrane that ultimately progress to glomerulosclerosis and renal insufficiency. These pathologic changes may be caused by multiple mechanisms, including the accumulation of advanced glycation end-products (AGEs), enhanced oxidative stress, activation of protein kinase C (PKC), and altered expression and action of growth factors and vasoactive mediators in the glomerular tissues [13]. Furthermore, suppression of AGE formation and action [13], oxidative stress [14], and PKC activation [15,16] all protect against the development of diabetic nephropathy in patients and experimental animals [13]. Profibrotic factors transforming growth factor-b1 (TGF-b1) and connective tissue growth factor

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(CTGF) are increased in diabetic kidneys and likely cause the accumulation of ECM proteins and induction of mesangial expansion [13]. This upregulation of gene expression has been shown to follow the accumulation of AGEs, increased oxidative stress, and the activation of PKC. In addition, the activation of vasoactive mediators such as ET-1 and angiotensin pathways is reported to increase in diabetic glomerular tissues [13] and their inhibition clearly protects against diabetic nephropathy [13]. Neuropathy There are many types of diabetic neuropathy (peripheral polyneuropathy is the major form), characterized by distal, symmetrical sensory loss or sensorimotor dysfunction that often affects distal lower limbs [17]. Several pathologic changes are noted, including the loss of nerve fibers, paranodal or segmental demyelination, axonal thickening, and endoneuronal capillary narrowing [18]. Hyperglycemia and other metabolic derangement may damage neurons and nerve parenchyma [19]. In addition, abnormalities in neurovascular blood flow may cause ischemic-neuronal damage [19]. Biochemical changes akin to those seen in retinopathy and nephropathy (eg, activation of PKC, enhanced oxidative stress, formation of AGEs in neuronal tissues, and altered expression of neurotrophic factors such as nerve growth factor and insulin-like growth factors–1) have been suggested to contribute to the pathogenesis of diabetic neuropathy [17,20]. The vascular etiology of diabetic neuropathies is supported by multiple abnormalities in the neurovasculature, including the deposition of AGEs in the perineuronal vascular wall, basement thickening, endothelial cell swelling, loss of pericytes, reduced endothelial nitric oxide activity, capillary occlusion [17], and degeneration of blood vessels supplying neuronal tissues [21]. These changes eventually contribute to a hyperglycemia-induced decrease in neurovascular flow and subsequent hypoxic-ischemic damage [22]. Transfer of VEGF to neuronal tissue in experimental diabetic animal models has been reported to restore blood flow in neuronal tissues and rectify the conductivity of nerves that were impaired in diabetic states [21], affirming the microvascular pathology nature of diabetic neuropathy. Reduced cardiac angiogenesis and collateral formation Patients with diabetes have a higher risk of developing myocardial infarction and subsequent heart failure [23–27], which is the leading cause of mortality in types 1 and 2 diabetes mellitus [28–30]. In animal studies, myocardial infarct size is increased in diabetic rats [31], supporting a close link between diabetes and reduced myocardium vascular supply that may be caused by impaired cardiac angiogenesis and collateral vessel formation [32,33]. Morphometric evaluation of myocardium from patients with ischemic heart disease with or without diabetes, as well as from healthy

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hearts, revealed a dramatic decrease in the capillary/myofiber ratio in diabetic patients suffering from ischemic heart disease compared with healthy myocardial tissues; this ratio was increased in ischemic heart disease patients without diabetes [6]. This observation implies that ischemia-induced reactive angiogenesis is decreased in diabetic states and therefore renders diabetic hearts more susceptible to ischemic insult. Similar observations have been reported in animal models of diabetes as well [34,35]. The reduced expression profile of VEGF in myocardium from patients and rats with diabetes and insulin resistance [36] is consistent with this finding and suggests a crucial role for angiogenic factors such as VEGF in the maintenance of cardiac microvascular homeostasis [37].

Pathogenesis of diabetic microvascular complications Research on diabetic vascular complications using molecular and cellular biology approaches has advanced greatly our understanding of the pathogenesis of the formidable complications of diabetes and makes it possible to design interventional strategies based on these mechanisms. Several theories have been proposed based on results from experimental and clinical studies, including (1) generation of reactive oxygen species and oxidative stress, (2) activation of polyol pathway, (3) formation of AGEs, (4) induction of flux through the hexosamine pathway, (5) activation of PKC, and (6) altered expression and action of growth factors. See later discussion for more information about these theories of pathogenesis of microvascular complications. Oxidative stress–induced vascular pathology in diabetes Hyperglycemia in diabetic states can induce increased formation of reactive oxygen species and oxidative stress (Fig. 1). This induction is mediated by multiple mechanisms, such as enhanced activity of the mitochondrial respiratory pathway, alteration of cellular redox states, uncoupling of endothelial nitric oxide (eNOS) activity, and reduction of endogenous antioxidant defenses. Increased activity in the mitochondrial respiratory chain in response to glycolysis and tricarboxylic acid cycle results in the accumulation of reducing protons, which drives the formation of superoxide anions [38]. Vascular cells cultured in media containing high levels of D-glucose generate large amounts of superoxides that can be prevented by reagents that reduce mitochondrial membrane proton gradients (eg, overexpression of uncoupling protein-1 or inhibitors targeting respiratory chain complex II) [39,40]. These findings support a key role for mitochondrialoriginated reactive oxygen species formation in diabetes. Hyperglycemia causes a host of biochemical changes, such as increased activity of polyol pathway, AGE formation, and activation of PKC pathway. These changes can result in the production of reactive oxygen species and

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Fig. 1. Induction of reactive oxygen species (ROS) formation and oxidative stress in the development of diabetic microvascular complications.

oxidative stress. Flux through the polyol pathway will alter cellular redox, enhancing oxidative stress. AGEs have been shown to cause tissue factor generation through the activation of nicotinamide adenine dinucleotide phosphate (NADP) oxidase [41], a key enzyme for reactive oxygen species formation. In cultured vascular cells, hyperglycemia and increased circulating free fatty acid induce the activation of NADP oxidase and reactive oxygen species formation through a PKC-dependent pathway [42], supporting a crucial role for PKC in oxidative stress. Uncoupling of eNOS caused by the deficiency of substrate or cofactors also may contribute to reactive oxygen species generation [43]. Lastly, there are abundant endogenous antioxidants that constitute a defense against this type of oxidative stress. Several studies in diabetes cases have demonstrated reduced levels of these antioxidants such as glutathione [44], vitamin C [45], and vitamin E [46]. This may not be the major source of oxidative stress in patients with diabetes, however, because several other studies have failed to confirm these findings [47,48]. Oxidative stress may contribute to multiple forms of diabetic vascular damage, including endothelial dysfunction, vascular leakage, leukocyte adhesion, cellular apoptosis, and altered vasomotor tone [19,38]. These effects are regulated through the induction of cellular DNA damage [49,50] following the activation of poly(ADP-ribose) polymerase [51]. Oxidative stress is also known to impair vasodilation by uncoupling eNOS activity. Although oxidative stress can follow interactions between AGEs and receptor for AGEs (RAGE), it can also activate multiple pathways, including AGE-RAGE, PKC, and aldose reductase pathways, inducing vascular cell damage in diabetic states [39]. Endothelial cell culture studies show that

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suppression of mitochondrial superoxide formation could inhibit hyperglycemia-induced AGE formation, activation of PKC, and sorbitol formation [39], suggesting a profound network of interactions among mechanisms used by hyperglycemia to mediate its adverse effects. Application of antioxidants has been shown to be beneficial in preventing diabetic microvascular complications. Antioxidants such as vitamin C, d-atocopherol (Vitamin E), and lipoic acid can prevent part of the vascular pathologic changes seen in diabetic retinopathy [52,53], neuropathy [54,55], and nephropathy [56]. Clinical assessments of antioxidants in the prevention of diabetic vascular complications, however, have yielded inconclusive results. Several pilot trials involving a small number of patients showed beneficial effects of antioxidants. For example, combined use of vitamins C and E reduced urinary albumin excretion rate [57]. Vitamin E at dosages of 1800 IU/d or higher was effective in reducing hemodynamic abnormalities in the retina and preserving renal function [58]. Despite these initial positive results, the Heart Outcome Prevention Evaluation [59] and Microalbuminuria, Cardiovascular and Renal Outcomes–Heart Outcomes Prevention Evaluation [60] studies demonstrated that vitamin E at a dosage of 400 IU/d failed to prevent diabetic nephropathy and cardiovascular events. In contrast, vitamin E at high dosage (1800 IU/d) could suppress the activation of diagylcerol (DAG)-PKC [61] and rectify retinal abnormalities [58]. These findings suggest other roles for antioxidants and further obscure the role of oxidative stress in the pathogenesis of diabetic microvascular complications. Enhanced oxidative stress may have supportive effects instead of playing a leading role in the development of vascular complications. Achieving satisfactory effects with antioxidants may require additional studies using combinations of therapeutic regimens. Activation of aldose reductase (polyol) pathway in diabetes In diabetic states, the polyol pathway is activated to reduce glucose to sorbitol that can be further oxidized to fructose. This process is mediated by aldose reductase and sorbitol dehydrogenase [19,38]. The increased activity of the polyol pathway has been suggested to cause vascular pathologies by osmotic damage, induction of oxidative stress, and reduced Na+,K+ATPase activity. Aldose reductase and sorbitol dehydrogenase use NADP and oxidized nicotinamide adenine dinucleotide (NAD+) as cofactors for their actions, and generate oxidized NADP (NADP+) and reduced NAD (NADH) as byproducts. The altered NADP+/reduced NADP and NADH/ NAD+ ratios change the intracellular redox balance and initiate a host of biochemical events that do not favor vascular homeostasis (eg, the reduced production of nitric oxide [62], oxidative stress, and down-regulation of Na+,K+-ATPase activity) [38]. In animal studies, inhibitors of aldose reductase prevent some abnormalities in diabetic retinopathy [63,64], nephropathy [65], and neuropathy [66,67]. These results are inconclusive,

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however, because the suppression of polyol pathway did not alter retinopathy and nephropathy in the diabetic canine [68]. In addition, clinical studies using aldose reductase inhibitors, such as sorbinil, failed to prevent diabetic retinopathy and nephropathy [68], although another inhibitor, zenarestat, was shown to improve the nerve conduction and pathology in diabetic peripheral polyneuropathy [69]. Confirming a more definitive role for the polyol pathway in the development of diabetic microvascular complications will require further investigation. Formation of advanced glycation end-products The formation of AGEs can be found in many physiologic or pathologic milieus such as aging, diabetes, and neurodegenerative disorders. In hyperglycemic conditions, irreversible covalent modification and crosslinking of protein by glucose generate multiple end-products such as glyoxal [70], methylglyoxal, and 3-deoxyglucosone [71], collectively known as AGEs. Although many of the glucose-modified structures are found in diabetes, the major forms of AGEs are (carboxymethyl)lysine, pentosidine, and pyralline. In diabetic patients, AGEs can be found in the serum [72] or in glomerular tissue [73], and have been proposed as a marker for predicting later renal insufficiency. Consistent with this hypothesis, AGE deposition can be detected in the glomerular tissues in diabetic rats that eventually develop renal insufficiency [74–77], as well as in retinal tissues [78,79], where it may contribute to pericyte loss [80]. Infusion of AGEs into nondiabetic animals results in pathologic changes similar to those induced by hyperglycemia, such as vascular leakage and reduced nitric oxide–mediated vasodilation [81,82]. Inhibition of AGE formation using pharmacologic inhibitors such as aminoguanidine can prevent some of the pathologic changes observed in nephropathy [83,84] and retinopathy [85] in animal models of diabetes. Glycation of ECM proteins, such as collagen types I and IV and laminin [86,87], can change their function and subsequently alter cell–ECM interactions and the integrity of the ECM [88]. These changes affect the plasticity and vascular tone of blood vessels [38], and disrupt normal vascular cell biology. For example, glycated laminin and type IV collagen display reduced adhesion with endothelial cells, which can change the proliferation and migration phenotype of these cells [88]. AGEs also may interact directly with cell surface proteins, thus activating intracellular signaling pathways to alter vascular cell biology. Many of the cell surface proteins interacting with AGEs have been identified, including RAGE, scavenger receptor class A, AGE-R1 (OST-48), AGE-R2 (80 K-H), and AGE R3 (Galectin-3) [89–94]. These receptors possess diverse biologic functions in the mediation of AGE endocytosis, degradation, and clearance, as well as the activation of intracellular signaling pathways. Evidence shows that AGE receptors are involved in the development of diabetic vascular complications. Renal tissues from diabetic patients revealed

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that both messenger RNA (mRNA) and RAGE protein levels were increased in glomeruli in diabetic patients versus healthy control subjects [77]. Overexpression of RAGE in vascular endothelial cells in mice results in characteristic changes of diabetic nephropathy and progressive renal insufficiency under hyperglycemic conditions: exacerbation of nephromegaly, mesangial expansion, albuminuria, glomerular hypertrophy, and sclerosis [95]. RAGE can activate intracellular signal transduction pathways stimulated by AGEs. Such signaling cascades include retrovirus-associated DNA sequence–extracellular signal-regulated kinase 1 and 2 and a stress kinase pathway, which eventually activate nuclear factor-jB, a transcription factor [96–98]. Activation of RAGE also activates proinflammatory programs in vascular tissues [99], p38 mitogen-activated protein kinase cascades, and the Smad pathway independent of TGF-b1 [100]. In addition to their effects on the induction of gene expression for growth factors and proinflammatory cytokines in target cells, AGEs have been shown to induce vascular oxidative stress. AGE-RAGE interactions have been suggested to activate NADP oxidase, generate reactive oxygen species [41], and further interfere with vasodilation by uncoupling it from eNOS activity. Inhibitors that disrupt AGE formation have been developed, including chemical inhibitors that interrupt AGE-mediated cross-linking, such as aminoguanidine [101] and 2-isopropylidenehydrazono-4-oxo-thiazolidin-5ylacetanilide [84]; cross-linker breakers N-phenyl-thiazolium bromide [102], and dimethyl-3-phenacylthiazolium chloride [103,104]; neutralizing antibodies against glycated proteins [105]; antisera against RAGE [81]; soluble recombinant RAGE that blocks AGE-RAGE interactions [106,107]; and lysozyme-linked matrix that captures AGEs [108]. At this time, most of these strategies are still being tested in animal models. Increased flux through hexosamine pathway Overburden of the glycolysis pathway in diabetic states may increase flux through the hexosamine pathway, as illustrated in Fig. 2. Fructose-6phosphate, a glycolysis intermediate, can be catalyzed by glutamine:fructose6-phosphate aminotransferase (GFAT) to glucosamine-6, which eventually forms uridine diphosphate N-acetyl-glucosamine, donor of N-acetylglucosamine (GlcNAC) for the subsequent O-linked glycosylation of target proteins at serine and threonine residues. This alteration is particularly important in the regulation of protein function because the activity of several key intracellular transcriptional factors and enzymes is determined by the phosphorylation states of serine/threonine residues. For example, serine and threonine phosphorylation of the transcription factor Sp1 suppresses its activation. Once Sp1 is competitively glycosylated and has lost these phosphorylation sites, however, as occurs in diabetic patients, it becomes active and initiates the transcription of multiple genes including TGF-a, TGF-b1, plasminogen activator inhibitor 1 (PAI-1) and fibroblast growth

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Fig. 2. Increased activity of hexosamine pathway in diabetes may alter the activity of transcriptional factors and enzymes such as Sp1 and eNOS. These alterations change the spectrum of gene expression and vascular hemodynamic observed in patients with diabetes.

factor 2, all of which participate in vascular remodeling and other pathologies in patients with diabetes. In addition to Sp1, the activity of eNOS is also subject to mutually exclusive phosphorylation and glycosylation modifications at serine1177, a key site that determines its activity. Consistent with this hypothesis, hyperglycemia induces the O-linked glycosylation of eNOS at serine1177 in cultured endothelial cells, and therefore prevents its phosphorylation and suppresses eNOS activity [40,109]. This alteration in eNOS action further contributes to hemodynamic changes observed in patients with diabetes. When vascular cells, including endothelial cells and vascular smooth muscle cells, are cultured in media containing high levels of D-glucose, expression for GFAT and O-GlcNAC transferase (OGTase)—key enzymes in the hexosamine pathway—is increased [110–113]. Examination of biopsy specimens from diabetic humans and rodents confirms the in vivo upregulation of GFAT and OGTase in vascular smooth muscle cells [112,114].

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The mechanisms underlying hyperglycemia-induced activation of hexosamine pathway are still not fully understood. In addition to being an alternative route for diverting substrates from the overwhelmed glycolysis pathway, hyperglycemia-induced activation of the PKC pathway [115], oxidative stress [110], and increased actions of angiotensin [116] may contribute to the activation of the hexosamine pathway. Activation of protein kinase C Activation of intracellular signaling pathways is an important mechanism in the development of diabetic microvascular complications. The activation of the PKC pathway has been extensively studied (Fig. 3). PKC is a family of structurally and functionally related serine/threonine kinases. The a, b1, b2, d, e, and f isoforms are expressed in the vasculature [117,118]. Several mechanisms have been proposed to explain the activation of PKC pathway in diabetes patients, including de novo synthesis of DAG [19,119–121], an upstream activator of PKC; overexpression and activity of growth factors and vasoactive materials such as VEGF [122,123]; dyslipidemia [42,124]; oxidative stress [39,125]; and formation of AGEs [126]. Activation of PKC, especially the b isoform, in the vasculature causes multiple pathologic changes similar to those observed in patients with

Fig. 3. Activation of DAG-PKC pathway plays a key role in the pathogenesis of diabetic microvascular complications. Once activated, PKC, especially the b and d isoforms, will cause changes in gene expressions and vascular biology that contribute to the development of vascular lesions in patients with diabetes.

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diabetes, such as abnormal retinal blood flow [120,127], blood vessel leakage [128–130], and production and deposition of ECM proteins [15,131]. These effects are probably mediated through inhibition of nitric oxide production [132–134] and altered gene expression for vasoactive and growth factors such as ET-1 [135], VEGF [136], and TGF-b1 [15]; CTGF [137]; and cellular adhesion molecules such as platelet endothelial cell adhesion molecule and intercellular adhesion molecule [19]. In addition, PKC, especially the b and d isoforms, can be activated by VEGF [122], mediating its effect on vessel leakage [138] and retinal angiogenesis [123]. PKC activation by hyperglycemia might also down-regulate gap-junction of vascular cells to increase their permeability [139]. Much experimental evidence suggests that inhibiting the expression, translocation, or activity of PKC is effective in preventing the vascular pathologies induced by hyperglycemia. Because the biologic effects of PKC are isoform-specific and some of the isoforms (eg, PKC-e) may be cardiacprotective, it is important to apply isoform-selective inhibition in the prevention and treatment of diabetic microvascular complications. Of the PKC inhibitors, b-selective antagonist LY333531 [140] has shown the most promising effects in the prevention of diabetic vascular complications. Oral treatment with LY333531 can normalize retinal blood flow, leukocyte entrapment, vascular leakage, and pathologic angiogenesis in retinopathy [127,141–144]. LY333531 is also beneficial for diabetic nephropathy [15,16,127,145] and can restore neurovascular blood flow and nerve conduction velocity—all of which are altered in diabetic neuropathy [146–148]. In humans, LY333531 has not been associated with obvious side effects in healthy subjects and can restore acute hyperglycemia-induced impairment of vasodilation [149]. Ongoing phase II/III multicenter clinical trials evaluating the effects of LY333531 on diabetic retinopathy and neuropathy suggest that LY333531 can improve some clinical symptoms of diabetic neuropathy [144,150]. Altered expression and actions of hormones and growth factors Metabolic derangements in patients with diabetes alter the expression and action of many growth factors, which regulate vascular biology and tissue fibrosis that can contribute to the pathogenesis of diabetic microvascular complications. Increased concentration of VEGF has been reported in the ocular fluids [151] and retinal tissues [152,153] of diabetic patients and may be associated with the severity of proliferative diabetic retinopathy [151,153]. The detrimental effects of VEGF in the retina might be caused by retinal inflammation, leukocyte entrapment [154], vascular leakage, and neovascularization [7]. Although targeting the VEGF system in treatment for diabetic retinopathy is a promising approach, it should be applied with caution because other vital organs, such as myocardium, may require the presence of VEGF for

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microvessel homeostasis. In contrast to the induction of VEGF in diabetic retinopathy or in nondiabetic patients with ischemic heart disease, the expression and action of VEGF is decreased in the myocardium in diabetic humans and rats suffering ischemic heart disease [36]. The importance of VEGF in cardiac function and blood vessel formation has been shown in mice null for VEGF in cardiomyocytes [37]. These mice have reduced coronary microvessels, reduced contractility, and impaired responses to b-adrenergic stimulation [37], similar to certain manifestations observed in patients with long-term diabetes [6]. Other growth factors may also play a role in microvascular disease in patients with diabetes. Platelet-derived growth factor–BB (PDGF-BB) is essential for the recruitment of mural cells (pericytes and vascular smooth muscle cells) to the blood vessels [155]. Mice genetically null for PDGF-B chain developed defective vasculature in multiple organs, including kidney and retinas [156–158], that resembles diabetic retinopathy and nephropathy. However, mRNA expression for PDGF-BB is increased instead of decreased in the retinal tissues of diabetic rats [135]. It is therefore hypothesized that this up-regulation of gene expression might be caused by an impaired PDGF-BB– mediated intracellular signaling pathway. Describing an active role for PDGF-BB in diabetic vasculopathy will require further investigation. Similarly, increased expression of the profibrotic factor TGF-b1 has been reported in kidney tissues from diabetic patients [159–161] and animals [162,163]. The induction of TGF-b1 expression probably is mediated through activation of PKC [15], increased oxidative stress [38], AGE-RAGE interaction [164], increased flux through polyol pathway [165], and hexosamine pathway [166]. In addition to its potent profibrotic effects, TGF-b1 is also known to induce cell cycle arrest that might lead to glomerular hypertrophy in diabetic nephropathy [167]. Ablation of TGF-b1 and its actions clearly prevents gene expression for ECM proteins, and the structural and functional changes found in diabetic kidneys [168–170]. The fibrotic effects of TGF-b1 may be mediated by the action of CTGF, the expression of which is also increased in kidneys from diabetic patients [171–174] and in mesangial cells cultured in high-glucose media [171,173]. Urinary secretion of CTGF is increased in patients with diabetic nephropathy and has been suggested to be a potential predicting marker for this complication [175]. The induction of CTGF expression in diabetic states may be the result of hyperglycemia [173], AGE-RAGE action [176–178], or activation of PKC [171,179], TGF-b1 [173,179], or VEGF [180]. Similar to TGF-b, CTGF stimulation has been reported to arrest the cell cycle of mesangial cells at G1 phase, and to induce mesangial expansion and mesangial hypertrophy [181]. In addition, CTGF is a potent profibrotic factor that induces gene expression for ECM components that characterize the glomerulosclerosis observed in diabetic nephropathy [173]. Although it is not clear whether the production of angiotensin II is increased in patients with diabetes, increased vascular sensitivity to this

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hormone has been seen [182]. Angiotensin II might have both blood pressure– dependent or –independent effects on vasculature. In addition to the induction of blood pressure [182], angiotensin II can act directly through its cell surface type 1 (AT1) receptor and regulate tissue remodeling, fibrosis, cell hypertrophy, and apoptosis [183], presumably through the induction of gene expression for profibrotic factors such as TGF-b1 [184], PAI-1 [185], and VEGF [186,187]. Suppression of angiotensin II production or action, either by angiotensin-converting enzyme inhibitors or AT1 receptor antagonists, has been beneficial in preventing diabetic retinopathy [187,188], nephropathy [189–195], and neuropathy [196]. Suppression of angiotensin II production or action also reduces the mortality and morbidity of diabetic complications, as shown in a growing number of clinical studies [197]. These effects are mediated through both antihypertension-dependent and -independent pathways because the protective effects are also observed in normotensive patients. Summary Understanding the pathogenesis of diabetic microvascular complications at molecular and cellular levels has advanced our ability to rationally design pharmacologic approaches to prevent and treat the complications of this chronic disease. Based on this information, specific interventions are being developed that may prevent the development of diabetic complications even when satisfactory euglycemic control is not achieved. References [1] The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–86. [2] The UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53. [3] Williamson JR, Kilo C. Capillary basement membranes in diabetes. Diabetes 1983; 32(Suppl 2):96–100. [4] Haneda M, Kikkawa R, Horide N, Togawa M, Koya D, Kajiwara N, et al. Glucose enhances type IV collagen production in cultured rat glomerular mesangial cells. Diabetologia 1991;34:198–200. [5] Cai J, Boulton M. The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye 2002;16:242–60. [6] Yarom R, Zirkin H, Stammler G, Rose AG. Human coronary microvessels in diabetes and ischaemia. Morphometric study of autopsy material. J Pathol 1992;166:265–70. [7] Ferris FL III, Davis MD, Aiello LM. Treatment of diabetic retinopathy. N Engl J Med 1999;341:667–78. [8] Engerman RL. Pathogenesis of diabetic retinopathy. Diabetes 1989;38:1203–6. [9] Robison WG Jr, McCaleb ML, Feld LG, Michaelis OE IV, Laver N, Mercandetti M, et al. Degenerated intramural pericytes (Ôghost cellsÕ) in the retinal capillaries of diabetic rats. Curr Eye Res 1991;10:339–50.

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