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Background: The mechanisms whereby inhibitors of sodium‐glucose linked cotransporter‐2 (SGLT2) exert their nephroprotective effects in patients with diabetes are incompletely understood but have been hypothesized to include improved tissue oxygen tension within the renal cortex. The impact of SGLT2 inhibition is likely complex and region specific within the kidney. We hypothesize that SGLT2 inhibitors have differential effects on renal tissue oxygen delivery and consumption in specific regions of the diabetic kidney, including the superficial cortex, containing SGLT2‐rich components of proximal tubules, versus the deeper cortex and outer medulla, containing predominantly SGLT1 receptors. Methods: We measured glomerular filtration rate (GFR), microvascular kidney oxygen tension (PkO2), erythropoietin (EPO) mRNA, and reticulocyte count in diabetic rats (streptozotocin) treated with the SGLT2 inhibitor, dapagliflozin. Utilizing phosphorescence quenching by oxygen and an intravascular oxygen sensitive probe (Oxyphor PdG4); we explored the effects of SGLT2 inhibition on PkO2 in a region‐specific manner, in vivo, in diabetic and non‐diabetic rats. Superficial renal cortical or deeper cortical and outer medullary PkO2 were measured utilizing excitations with blue and red light wavelengths, respectively. Results: In diabetic rats treated with dapagliflozin, measurement within the superficial cortex (blue light) demonstrated no change in PkO2. By contrast, measurements in the deeper cortex and outer medulla (red light) demonstrated a significant reduction in PkO2 in dapagliflozin treated diabetic rats (p = 0.014). Consistent with these findings, GFR was decreased, hypoxia‐responsive EPO mRNA levels were elevated and reticulocyte counts were increased with SGLT2 inhibition in diabetic rats (p < 0.05 for all). Conclusions: These findings indicate that microvascular kidney oxygen tension is maintained in the superficial cortex but reduced in deeper cortical and outer medullary tissue, possibly due to the regional impact of SGLT‐2 inhibition on tissue metabolism. This reduction in deeper PkO2 had biological impact as demonstrated by increased renal EPO mRNA levels and circulating reticulocyte count. [ABSTRACT FROM AUTHOR]

This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). Empagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown. This was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2. Baseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: –1.40%; 95% confidence interval [CI]: –2.60 to –0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: –1.5 ml/m2; 95% CI: –2.6 to –0.5 ml/m2; p = 0.006), with a trend toward reduction in iICV (adjusted difference: –1.7 ml/m2; 95% CI: –3.8 to 0.3 ml/m2; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2. In individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes [EMPA-HEART]; NCT02998970) [Display omitted] [ABSTRACT FROM AUTHOR]

The current view of diabetic kidney disease, based on meticulously acquired ultrastructural morphometry and the utility of measuring plasma creatinine and urinary albumin, has been almost entirely focused on the glomerulus. While clearly of great importance, changes in the glomerulus are not the major determinant of renal prognosis in diabetes and may not be the primary event in the development of diabetic kidney disease either. Indeed, advances in biomarker discovery and a greater appreciation of tubulointerstitial histopathology and the role of tubular hypoxia in the pathogenesis of chronic kidney disease have given us pause to reconsider the current "glomerulocentric" paradigm and focus attention on the proximal tubule that by virtue of the high energy requirements and reliance on aerobic metabolism render it particularly susceptible to the derangements of the diabetic state. Such findings raise important issues for therapeutic advances specifically targeting the pathophysiological perturbations that develop in this part of the nephron. [ABSTRACT FROM AUTHOR]

Summary: Cell-based therapy, designed to promote angiogenesis and improve organ function, has been under investigation for the treatment of ischemic heart disease for more than 10 years. Although believed to work primarily by repairing the microvasculature, this form of therapy has not been examined in the setting of chronic kidney disease caused by diabetes in which capillary rarefaction plays a pivotal pathogenetic role. Indeed, despite disease-associated dysfunction, the favorable safety profile of autologous, bone marrow–derived angiogenic cells and their efficacy in animal studies of chronic kidney disease would seem to provide a basis for clinical trials in advanced diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Aims Cardiac remodelling in diabetes includes pathological accumulation of extracellular matrix and myocyte hypertrophy that contribute to heart dysfunction. Attenuation of remodelling represents a potential therapeutic target. We tested this hypothesis using a new anti-fibrotic drug, FT011 (Fibrotech Therapeutics Pty Ltd), on diabetic Ren-2 rats, a model which replicates many of the structural and functional manifestations of diabetic cardiomyopathy in humans. Methods and results Homozygous Ren-2 rats were randomized to receive streptozotocin or vehicle then further randomized to FT011 (200 mg/kg/day) or vehicle treatment for 6 weeks. Prior to tissue collection, cardiac function was assessed via echocardiography and cardiac catheterization. Total collagen deposition and cardiomyocyte hypertrophy were assessed by picrosirius red and haematoxylin and eosin staining, respectively. Macrophage interstitial infiltration and type I and III collagen were quantitated by immunostaining. Without affecting blood pressure or hyperglycaemia, treatment of diabetic rats with FT011 significantly attenuated interstitial fibrosis (total collagen, 5.09 ±1.28 vs, 2.42 ±0.43%/area; type I collagen, 4.09 ±1.16 vs. 1.42 ±0.38%/area; type III collagen, 1.52 ±0.33 vs. 0.71 ±0.14 %/area; P < 0.05), cardiomyocyte hypertrophy (882 ±38 vs. 659 ±28 µm2; P < 0.05), and interstitial macrophage influx (66 ±5.3 vs, 44 ±7.9 number/section; P < 0.05). Cardiac myopathic dilatation was normalized, as evidenced by reduced left ventricular inner diameter at diastole (0.642 ±0.016 vs. 0.577 ±0.024 cm), increased ejection fraction (75 ±1.1 vs. 83 ±1.2%) and preload recruitable stroke work relationship (44 ±6.7 vs. 77 ±6.3 slope-mmHg; P < 0.05), and reduced end-diastolic pressure–volume relationship (0.059 ±0.011 vs. 0.02 ±0.003 slope-mmHg/μL; P < 0.05). Conclusions A direct anti-fibrotic agent, FT011, attenuates cardiac remodelling and dysfunction in experimental diabetic cardiomyopathy. This represents a novel therapy for the treatment of diabetic cardiomyopathy associated with cardiac fibrosis and hypertrophy. [ABSTRACT FROM PUBLISHER]

Summary: The long-term complications of diabetes are characterized by pathologic changes in both the microvasculature and conduit vessels. Although the fenestrated glomerular endothelium classically has been viewed as providing little in the way of an impediment to macromolecular flow, increasing evidence illustrates that this is not the case. Rather, hyperglycemia-mediated endothelial injury may predispose to albuminuria in diabetes both through direct effects and through bidirectional communication with neighboring podocytes. Although neo-angiogenesis of the glomerular capillaries may be a feature of early diabetes, particularly in the experimental setting, loss of capillaries in the glomerulus and in the interstitium are key events that each correlate closely with declining glomerular filtration rate in patients with diabetic nephropathy. The hypoxic milieu that follows the microvascular rarefaction provides a potent stimulus for fibrogenesis, leading to the glomerulosclerosis and tubulointerstitial fibrosis that characterize advanced diabetic kidney disease. Given the pivotal role the endothelium plays in both the development and the progression of diabetic nephropathy we need effective strategies that prevent its loss or accelerate its regeneration. Such advances likely will lead not only to improved tissue oxygenation and reduced fibrosis, but also to improved long-term renal function. [ABSTRACT FROM AUTHOR]

Background: Renal hypoxia plays a role in the development of diabetic nephropathy, and may be mediated by overactivity of the renin-angiotensin-aldosterone system (RAAS). In this study the localization of cellular hypoxia in an experimental model of diabetic nephropathy was assessed, and the effect of the angiotensin-converting enzyme inhibitor perindopril on hypoxia evaluated. Methods: Female Sprague–Dawley rats heterozygous for the Ren-2 gene were randomized to three groups ( n = 8 per group) – controls, diabetes or diabetes + perindopril. Diabetes was induced by injection of streptozotocin at 6 weeks of age. Perindopril was administered at a dose of 2 mg/kg daily from 6 weeks. Subjects were culled after 16 weeks. Areas of tissue hypoxia were localized using immunohistochemistry to detect pimonidazole uptake. Results: Diabetic rat kidneys were characterized by increases in tubulointerstitial collagen deposition compared with controls. Tubular hypoxia was significantly greater in diabetic rats, indicated by a 2.5-fold increase in the proportional area of pimonidazole immunostaining ( P < 0.001). Immunohistochemical staining for pimonidazole co-localized with osteopontin, and was associated with higher numbers of ED-1-positive cells (macrophages) within the tubulointerstitium. Treatment with perindopril ameliorated structural changes of diabetic nephropathy and reduced the amount of pimonidazole and ED-1 immunostaining to levels similar to that of controls. Conclusion: In diabetic Ren-2 rats the development of diabetic nephropathy was associated with tubular hypoxia. Co-localization of osteopontin with hypoxic cells suggests that tubular hypoxia may be involved in the pathogenesis of diabetic nephropathy. The degree of hypoxia and fibrosis was attenuated by treatment with perindopril. [ABSTRACT FROM AUTHOR]

Diastolic dysfunction is an increasingly recognized complication of diabetes that develops in relatively young patients as a result of diabetic cardiomyopathy (DCM). With recent advances in echocardiographic technology now permitting the reliable assessment of diastolic function in the rat, we examined cardiac function and structure in diabetic rodents and assessed the effects of intervening with trartilast, an antifibrotic compound that has been shown to attenuate the actions of transforming growth factor-β (TGF-β) in cardiac fibroblasts. We also sought to examine the mechanism whereby tranilast inhibits the actions of TGF-β. Six-week-old heterozygous (mRen-2)27 rats were randomized to receive either streptozotocin or citrate buffer and then further randomized to receive either tranilast (400 mg· kg-1·day-1 by twice daily gavage) or vehicle for another 8 wk. Cell signaling was examined in neonatal cardiac fibroblasts. After 8 wk, diabetic rats showed evidence of impaired diastolic function with reduced early-to-late atrial wave ratio and prolonged deceleration time in association with fibrosis, apoptosis, and hypertrophy (all P < 0.05). Treatment with tranilast prevented the development of diastolic dysfunction and the histopathological features of DCM. While tranilast did not affect Smad phosphorylation, it significantly attenuated TGF-β-induced p44/42 mitogen-activated protein kinase phosphorylation. [ABSTRACT FROM AUTHOR]

While neoangiogenesis in diabetes is of greatest clinical significance in the retina, the pathological formation of new blood vessels also develops in other vascular beds in diabetes, including the mesentery of the streptozotocin-induced diabetic rat. However, the contribution of bone marrow-derived cells to this process of vasculogenesis is unknown.In this study, male Sprague-Dawley rats were randomised to receive either streptozotocin or vehicle, and their mesenteric vasculature was examined after three weeks. Origins from bone marrow and endothelial cell differentiation were identified by immunolabelling for the stem cell factor receptor, c-kit and von Willebrand factor (vWF), respectively. Expression for the angiogenic chemokine, stromal derived factor-1 (SDF-1) was assessed by quantitative real-time polymerase chain reaction (PCR).At three weeks, rats with diabetes had a dramatic (190-fold) increase in lectin-labelled blood vessel profiles in the mesenteric bed (p<0.0001) in association with a five-fold increase in SDF-1 mRNA (p<0.01). Immunohistochemical studies identified abundant large, ovoid, lumen-forming, c-kit+ cells in the mesentery of diabetic, but not control, rats. Many of these c-kit+ cells also showed positive immunolabelling for vWF, consistent with endothelial differentiation.In conclusion, cells of bone marrow origin contribute to new vessel formation in the diabetic mesentery. This phenomenon may also apply to the neovascularisation that develops at clinically important sites such as in the retina. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: The pathological accumulation of extracellular matrix is a characteristic feature of diabetic cardiomyopathy that is directly related to a loss of function. Tranilast (n-[3,4-anthranilic acid), used for the treatment of fibrotic skin diseases, has also been shown to inhibit transforming growth factor-β (TGF-β)-induced matrix production in kidney epithelial cells. Methods: To investigate the effects of tranilast in the diabetic heart, we examined its effects in cultured cardiac fibroblasts and then assessed its effects in (mRen-2)27 diabetic rats with established disease (8 weeks after streptozotocin). Results: In vitro studies demonstrated a 58% reduction in TGF-β1-induced 3[H]-hydroxyproline incorporation with tranilast 30 μM (p<0.01). At 16 weeks, diabetes in the Ren-2 rat was associated with increased cardiac fibrosis and evidence of TGF-β1 activation, as measured by the abundance of phosphorylated Smad2. Despite persistent hyperglycaemia and hypertension, tranilast attenuated cardiac fibrosis by 37% (p<0.05) in association with reduction in phospho-Smad2 (p<0.01). Conclusion: These findings indicate that tranilast has antifibrotic actions in the Ren-2 model of experimental diabetic cardiac disease by mechanisms that might attributable to reduced TGF-β activity. [Copyright &y& Elsevier]

Chronic heart failure is an increasingly common cause of premature death and poor quality of life. Community-based epidemiological studies have provided much-needed information on the demography of chronic heart failure, providing insight into its influence on public health. In most patients, chronic heart failure is accompanied by a range of concomitant disorders that both contribute to the cause of the disease and have a key role in its progression and response to treatment. Information on the most common comorbidities in chronic heart failure--ischaemic heart disease, hypertension, and diabetes mellitus--is presented for prespecified subgroups in the reports of many large-scale, multicentre trials; despite their limitations, these subanalyses provide guidance in therapeutic decision-making. Similarly, because chronic heart failure is commonly an endpoint in intervention trials of both hypertension and diabetes, such studies afford important information on the prevention of chronic heart failure in these common diseases. [ABSTRACT FROM AUTHOR]

Background. Mutations in the gene coding for the podocyte slit‐pore membrane protein, nephrin, are responsible for the Finnish‐type congenital nephrotic syndrome. The present study sought to examine whether nephrin expression may also be altered in experimental diabetes, and how such changes related to the development of proteinuria. In addition, the study also sought to examine nephrin expression in animals treated with different anti‐proteinuric therapies. [ABSTRACT FROM PUBLISHER]

Focuses on a study that examined the effect of angiotensin receptor blockade and dietary sodium restriction on the plasma concentration and urinary excretion of transforming growth factor- β in hypertensive patients with type 2 diabetes and elevated albumin excretion rate. Research design and methods; Results; Conclusions.

Background. Osteopontin is a macrophage chemotactic protein that has been pathogenetically linked to tissue injury in non‐diabetic kidney disease. [ABSTRACT FROM PUBLISHER]

Despite the use of laser photocoagulation and knowledge of the beneficial effects of good glycaemic control, visual loss due to diabetic retinopathy remains the commonest cause of blindness in the working population. This visual loss is principally the result of proliferative diabetic retinopathy and macular oedema. The processes by which diabetes mellitus results in retinopathy are incompletely understood, but recent evidence has suggested a pathogenetic role for the renin-angiotensin system (RAS) and vascular endothelial growth factor (VEGF) in the eye in response to chronic hyperglycaemia. This review will explore evidence of a local RAS in the eye, the involvement of VEGF in diabetic retinopathy and the interaction between the RAS and VEGF in the pathogenesis of retinal neovascularization.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Evaluates the role for endothelin (ET) antagonists in diabetic renal disease. Specificities and potencies in inhibiting ET receptor mediated effects; Importance of blood pressure reduction in retarding the progression of diabetic nephropathy; Effects of selective and non-selective ET antagonists and angiotensin converting enzymes inhibitors on growth factor expression in experimental diabetes.

It has been suggested that the cytokine vascular endothelial growth factor (VEGF) has an important role in the pathogenesis of diabetic retinopathy, but its role in nephropathy has not been clearly demonstrated. Assessment of VEGF, 125I-VEGF binding, and vascular endothelial growth factor receptor-2 (VEGFR-2) in the kidney was performed after 3 and 32 weeks of streptozotocin-induced diabetes. Gene expression of both VEGF and VEGFR-2 was assessed by Northern blot analysis and the localization of the ligand and receptor was examined by in situ hybridization. VEGF and VEGFR-2 protein were also evaluated by immunohistochemistry. Binding of the radioligand 125I-VEGF was evaluated by in vitro and in vivo autoradiography. Diabetes was associated with increased renal VEGF gene expression. VEGF mRNA and protein were localized to the visceral epithelial cells of the glomerulus and to distal tubules and collecting ducts in both diabetic and nondiabetic rats. Renal VEGFR-2 mRNA was increased after 3 weeks of diabetes but not in long-term diabetes. In situ hybridization and immunohistochemical studies revealed that glomerular endothelial cells were the major site of VEGFR-2 expression. In addition, VEGFR-2 gene expression was detected in cortical and renomedullary interstitial cells and on endothelial cells of peritubular capillaries. There was an increase in 125I-VEGF binding sites after 3 but not 32 weeks of diabetes. The major VEGF binding sites were in the glomeruli. 125I-VEGF binding was also observed in medullary rays and in the renal papillae. These studies indicate an early and persistent increase in renal VEGF gene expression in association with experimental diabetes. In addition, an early and transient increase in renal VEGF receptors was also observed in diabetic rats. These findings are consistent with a role for VEGF in mediating some of the changes observed in the diabetic kidney. [ABSTRACT FROM AUTHOR]

Transforming growth factor-beta (TGF-beta) and the renin-angiotensin system (RAS) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology may also be an important determinant of progressive renal dysfunction in diabetic nephropathy. In the present study, we investigated tubulointerstitial injury, TGF-beta1 expression, and the effect of blocking the RAS by inhibition of ACE. We randomized 36 male SD rats to control and diabetic groups. Diabetes was induced in 24 rats by administration of streptozotocin; 12 diabetic rats were further randomized to receive the ACE inhibitor ramipril (3 mg/l drinking water). At 6 months, experimental diabetes was associated with tubulointerstitial damage, a 70% increase in expression of TGF-beta1 (P < 0.05 vs. control), and a 120% increase in alpha1 (IV) collagen gene expression (P < 0.01 vs. control). In situ hybridization demonstrated a diffuse increase in both TGF-beta1 and alpha1 (IV) collagen mRNA in renal tubules. In addition, intense expression of both transcripts was noted in regions of focal tubular dilatation. Administration of the ACE inhibitor ramipril prevented tubulointerstitial injury and the overexpression of TGF-beta1 and alpha1 (IV) collagen mRNA. Changes in gene expression were accompanied by parallel changes in immunostaining for TGF-beta1 and type IV collagen. The observed beneficial effects of ramipril on the tubulointerstitium in experimental diabetes suggest that this mechanism may contribute to the therapeutic effect of ACE inhibitors in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor inhibition attenuates early kidney enlargement in experimental diabetes.Background.Renal enlargement is an early feature of both human and experimental diabetes. Although the precise mechanisms underlying its development are incompletely understood, locally active growth factors have been suggested to have a key role. Having previously documented increased expression of the proproliferative and antiapoptotic growth factor, epidermal growth factor (EGF), in early diabetes-related kidney growth, the present study sought to evaluate its pathogenetic role by blocking its action with a specific inhibitor.Methods.Sprague-Dawley rats were randomized to receive streptozotocin (diabetic) or buffer (control) and then further randomized to receive either vehicle or the inhibitor of the EGF receptor tyrosine kinase, PKI 166 (100 mg/kg/day) for 2 days and 3 weeks following streptozotocin administration.Results.Experimental diabetes was associated with an increase in kidney weight and tubular epithelial cell proliferation as identified by increased expression of proliferating cell nuclear antigen (PCNA) and 5-bromo-2′-deoxyuridine (BrdU) incorporation. PKI 166 resulted in a 30% reduction in kidney weight in diabetic rats (P<0.01) and reduced tubular epithelial cell proliferation (P<0.01). In addition, EGF receptor inhibition also led to a 40% increase in tubular epithelial cell apoptosis at 3 weeks (P<0.01). Diabetes-associated glomerular enlargement was similarly attenuated by PKI 166, although glomerular hyperfiltration was unaffected.Conclusion.These findings suggest that the EGF-EGF receptor (EGFR) axis has a significant role in the development of early diabetes-related kidney growth. The impact of EGFR inhibition on the later development of renal dysfunction, however, remains to be determined. [ABSTRACT FROM AUTHOR]

The article discusses a research regarding the effect of basal insulin glargine allocation on the initial and recurrent episodes of heart failure hospitalization (HFH). Particular focus is given on the Outcome Reduction With Initial Glargine Intervention (ORIGIN) Trial involving people with impaired glucose tolerance, diabetes mellitus and impaired fasting glucose. Results show that insulin glargine allocation has a neutral effect on both first and reccurent HFH.

Abstract: Effect of HMGCoA Reductase Inhibitors on Cardiac Remodelling and Mortality in Rats. Following Hyperglycemia and Myocardial Infarction. Aims: The presence of diabetes mellitus (DM) in patients with myocardial infarction (MI) increases mortality, due in part to the presence of known cardiovascular risk factors. However little is known about the impact of DM on cardiac remodelling and on clinical outcomes. We aimed to investigate whether hyperglycaemia may adversely and additionally affect LV remodelling post-MI, and whether the addition of a statin, known to reduce mortality both post MI and in humans with DM, has an effect on these outcomes. Methods: Eight week old Sprague-Dawley rats were allocated to 5 groups - control (non-DM)/sham, control-MI, DM-sham, DM-MI and DM-MI with statin gavage (DM-MI/ATV). Echocardiogram and invasive pressure volume analysis were performed prior to sacrifice for estimation of cardiac function. Tissue was analysed for total cardiac collagen, collagen I and III. Results: Hyperglycaemia in the remodelling period significantly increased mortality (70% survival in the C-MI group vs 27% in the DM-MI group), worsened cardiac function and increased fibrosis. All of these variables were attenuated by the addition of a statin. Conclusion: Hyperglycaemia increased mortality in MI and exacerbated LV remodeling, and this was attenuated with statin use. This study confirms the importance of early and intensive treatment of hyperglycaemia in patients with MI and suggests that in humans with both DM and MI the addition of a statin may be beneficial. [Copyright &y& Elsevier]

Abstract: Tranilast is an anti-inflammatory drug in use for asthma and atopic dermatitis. In studies over the last decade it has been revealed that tranilast can reduce fibrosis occurring in the kidney during diabetes, thereby delaying and/or preventing kidney dysfunction. We report a structure–activity study aimed at optimizing the antifibrotic activity of tranilast. A series of cinnamoyl anthranilates were prepared and assessed for their ability to prevent TGF-β-stimulated production of collagen in cultured renal mesangial cells. We reveal derivatives with improved potency and reduced cellular toxicity relative to tranilast. 3-Methoxy-4-propargyloxycinnamoyl anthranilate reduces albuminuria in a rat model of progressive diabetes, and thus has potential as an innovative treatment for diabetic nephropathy. [Copyright &y& Elsevier]

Role of hyperlipidemia in progressive renal disease: Focus on diabetic nephropathy. Background It has been suggested that lipids promote renal injury and that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors confer renoprotection in certain renal diseases, including diabetic nephropathy. Methods Sprague-Dawley rats were randomized to sham, subtotal nephrectomy (STNx) or STNx + atorvastatin groups. After 12 weeks, proteinuria, renal function, glomerular injury, renal transforming growth factor-βbgr (TGF-βbgr) gene expression and macrophage (ED1-positive cells) accumulation were assessed. In addition, the effects of HMG CoA reductase in human diabetic nephropathy were reviewed. Results Atorvastatin therapy was associated with a modest reduction in proteinuria and glomerulosclerosis without influencing lipid levels or renal function in STNx rats. These effects were associated with decreased renal TGF-βbgr1 gene expression and less glomerular and tubulointerstitial macrophage accumulation. The renoprotective effects of HMG CoA reductase inhibitors in both insulin- and non–insulin-dependent diabetic subjects with either incipient or overt nephropathy appear to be highly variable. Conclusions HMG CoA reductase inhibition appears to confer renoprotection via effects on prosclerotic cytokines such as TGF-βbgr and macrophage accumulation, independent of their lipid-lowering properties. The role of lipid-lowering agents in early or overt diabetic nephropathy remains to be fully ascertained. [ABSTRACT FROM AUTHOR]