We estimated glomerular cell number in 50 normotensive type 1 diabetic patients with raised albumin excretion rate (AER) and investigated any change after 3 years in a subgroup of 16 placebo-treated patients. Biopsies from 10 normal kidney donors were used as controls. Mesangial and endothelial cell number was increased in the 50 diabetic patients at the start of the study compared with control subjects. There was no difference in podocyte number. Glomerular volume was increased in diabetic patients, but surface area of glomerular basement membrane (GBM) underlying the podocytes did not differ between groups. AER correlated positively with mesangial cell number in microalbuminuric patients (r ‫؍‬ 0.44, P ‫؍‬ 0.012) and negatively with podocyte number in proteinuric patients (r ‫؍‬ ؊0.48, P ‫؍‬ 0.040). In the 16 placebo-treated patients, glomerular volume increased after 3 years owing to matrix accumulation and increased GBM surface area. Although overall cell number did not differ significantly from baseline, the decrease in podocyte number during follow-up correlated with AER at follow-up (r ‫؍‬ ؊0.72, P ‫؍‬ 0.002). In conclusion, crosssectional analysis of podocyte number in type 1 diabetic patients with raised AER but normal blood pressure shows no significant reduction compared with nondiabetic control subjects. Longitudinal data provide evidence for an association between podocyte loss and AER, but whether cellular changes are a response to, a cause of, or concomitant with the progression of nephropathy remains uncertain. Diabetes 51:3083-3089, 2002

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Inhibiting the actions of VEGF is a new therapeutic paradigm in cancer management with antiangiogenic therapy also under intensive investigation in a range of nonmalignant diseases characterized by pathological angiogenesis. However, the effects of VEGF inhibition on organs that constitutively express it in adulthood, such as the kidney, are mostly unknown. Accordingly, we examined the effect of VEGF inhibition on renal structure and function under physiological conditions and in the setting of the common renal stressors: hypertension and activation of the reninangiotensin system. When compared with normotensive SpragueDawley (SD) rats, glomerular VEGF mRNA was increased 2-fold in transgenic (mRen-2)27 rats that overexpress renin with spontaneously hypertensive rat (SHR) kidneys showing VEGF expression levels that were intermediate between them. Administration of either an orally active inhibitor of the type 2 VEGF receptor (VEGFR-2) tyrosine kinase or a VEGF neutralizing antibody to TGR(mRen-2)27 rats resulted in loss of glomerular endothelial cells and transformation to a malignant hypertensive phenotype with severe glomerulosclerosis. VEGFR-2 kinase inhibition treatment was well tolerated in SDs and SHRs; although even in these animals there was detectable endothelial cell loss and rise in albuminuria. Mild mesangial expansion was also noted in hypertensive SHR, but not in SD rats. These studies illustrate: (i) VEGF has a role in the maintenance of glomerular endothelial integrity under physiological circumstances, (ii) glomerular VEGF is increased in response to hypertension and activation of the renin-angiotensin system, and (iii) VEGF signaling plays a protective role in the setting of these renal stressors.albuminuria ͉ endothelium ͉ hypertension ͉ Ren-2 ͉ renin-angiotensin system

OBJECTIVE-Podocyte-specific, doxycycline (DOX)-inducible overexpression of soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1) in adult mice was used to investigate the role of the VEGF-A/VEGF receptor (VEGFR) system in diabetic glomerulopathy.RESEARCH DESIGN AND METHODS-We studied nondiabetic and diabetic transgenic mice and wild-type controls treated with vehicle (VEH) or DOX for 10 weeks. Glycemia was measured by a glucose-oxidase method and blood pressure by a noninvasive technique. sFlt-1, VEGF-A, VEGFR2, and nephrin protein expression in renal cortex were determined by Western immunoblotting; urine sFlt-1, urine free VEGF-A, and albuminuria by enzyme-linked immunosorbent assay; glomerular ultrastructure by electron microscopy; and VEGFR1 and VEGFR2 cellular localization with Immunogold techniques.RESULTS-Nondiabetic DOX-treated transgenic mice showed a twofold increase in cortex sFlt-1 expression and a fourfold increase in sFlt-1 urine excretion (P Ͻ 0.001). Urine free VEGF-A was decreased by 50%, and cortex VEGF-A expression was upregulated by 30% (P Ͻ 0.04). VEGFR2 expression was unchanged, whereas its activation was reduced in DOX-treated transgenic mice (P Ͻ 0.02). Albuminuria and glomerular morphology were similar among groups. DOX-treated transgenic diabetic mice showed a 60% increase in 24-h urine sFlt-1 excretion and an ϳ70% decrease in urine free VEGF-A compared with VEH-treated diabetic mice (P Ͻ 0.04) and had lower urine albumin excretion at 10 weeks than VEH-treated diabetic (D) mice: D-VEH vs. D-DOX, geometric mean (95% CI), 117.5 (69 -199) vs. 43 (26.8 -69) g/24 h (P ϭ 0.003). Diabetes-induced mesangial expansion, glomerular basement membrane thickening, podocyte foot-process fusion, and transforming growth factor-␤1 expression were ameliorated in DOX-treated diabetic animals (P Ͻ 0.05). Diabetes-induced VEGF-A and nephrin expression were not affected in DOX-treated mice.CONCLUSIONS-Podocyte-specific sFlt-1 overexpression ameliorates diabetic glomerular injury, implicating VEGF-A in the pathogenesis of this complication. Diabetes 57:2824-2833, 2008

Type 2 diabetes mellitus increases atherothrombotic risk. Platelets in individuals with diabetes show increased activity at baseline and in response to agonists, ultimately leading to increased aggregation. Increased expression of platelet surface adhesion molecules and receptors, enhanced production of thromboxane and thrombin and disturbances in platelet calcium homeostasis are well documented. As intra-arterial thrombi are initiated by platelets, strategies to limit acute thrombotic events have largely focused on antiplatelet agents. Aspirin remains the cornerstone of antiplatelet therapy but appears to have limited benefit in diabetes. Use of thienopyridines and platelet glycoprotein IIb/IIIa receptor inhibitors has been shown to benefit high-risk patient populations. This review summarises the different platelet abnormalities characterised in diabetes and the role of currently used antiplatelet agents.