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

No abstract

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.

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with premature mortality, generally thought to be exaggerated in patients with microalbuminuria. This prospective 8-year follow-up study aimed to determine outcome, mortality and cause of death in NIDDM patients with abnormal urinary albumin excretion compared to those with normal albumin excretion. We recruited 153 NIDDM patients with abnormal urinary albumin excretion and 153 control subjects with albumin excretion within the normal non-diabetic range, matched for age, sex and duration of diabetes, from three University hospital diabetic clinics in Newcastle upon Tyne. The outcome measures were status at follow-up, mortality and cause of death. Subjects with abnormal albumin excretion had a significantly higher 8-year mortality than matched control subjects (Odds Ratio 1.47, p = 0.02; 108 vs 66 per 1000 person years follow-up, p < 0.001). This difference was seen at all levels of abnormal albumin excretion, from just outside the normal range (10.6-29.9 microgram/min: 104 vs 61 per 1000 person years follow-up, p < 0.001) to more conventional definitions of microalbuminuria (> or = 30 micrograms/min: 111 vs 71 per 1000 person years follow-up, p < 0.01). Those with abnormal albumin excretion had an excess of vascular deaths compared to matched control subjects (Odds Ratio 1.70, p = 0.009), again at different levels of albumin excretion (10.6-29.9 micrograms/min p < 0.01, 30-150 micrograms/min p < 0.05). On multivariate analysis, age, initial ischaemic heart disease and initial albumin excretion rates were independent predictors of death from all causes.(ABSTRACT TRUNCATED AT 250 WORDS)

This study demonstrates that the function of the solitary kidney is not adversely affected by prolonged compensatory hyperfiltration, although there appears to be an increased prevalence of microalbuminuria and hypertension. Regular follow-up of kidney donors is recommended in order to manage their complications effectively and to detect hypertension and or renal impairment early in those who may develop it.

The association between diurnal blood pressure variation and diabetic nephropathy was assessed in four groups of Type 1 (insulin-dependent) diabetic patients who underwent 24-h ambulatory blood pressure monitoring using an oscillometric technique. Patients with nephropathy, who had never been treated for hypertension (group D3, n = 13), were individually matched for age, sex and diabetes duration to a group of microalbuminuric patients (D2, n = 26), to normoalbuminuric patients (D1, n = 26) and to healthy control subjects (C, n = 26). Group D3 was also compared to patients with advanced nephropathy receiving treatment for hypertension, mainly a combination of angiotensin converting enzyme inhibitors, metoprolol and diuretics (D4, n = 11). In group D3 24-h diastolic blood pressure (85 +/- 8 mm Hg) was comparable to the results obtained in D4 (85 +/- 8 mm Hg) but significantly higher than in D2 (78 +/- 7 mm Hg), D1 (73 +/- 7 mm Hg) and C (73 +/- 7 mm Hg, p < 0.05, Tukey's test). The night/day ratio of diastolic blood pressure was higher in D3 (86 +/- 5%) and D2 (85 +/- 7%) than in C (80 +/- 7%, p < 0.02). This ratio was also elevated in group D4 (94 +/- 8%) compared to D3 (p < 0.05) corresponding to a marked smoothing of the diurnal blood pressure curve. The 24-h heart rate (beats per min) was significantly elevated in D3 (84 +/- 8) and D2 (80 +/- 10) compared with C (73 +/- 11, p < 0.05 Tukey's test), suggesting the presence of parasympathetic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)