Osteopontin Plays a Critical Role in Interstitial Fibrosis but Not Glomerular Sclerosis in Diabetic Nephropathy

Background/Aims: Osteopontin (OPN) has been implicated in the pathology of several renal conditions. The aim of this study was to clarify the roles of OPN in diabetic nephropathy. Methods: Diabetes mellitus (DM) was induced in wild-type (WT) and OPN knockout (KO) mice by injecting streptozotocin. The mice were killed 20 weeks after induction of DM and their kidneys removed. Results: Renal mRNA expression of OPN was increased in WT-DM mice compared to WT-sham mice. Immunohistochemistry showed high levels of OPN expression in the proximal tubules of WT-DM mice. Kidney weight and urinary albumin excretion increased to similar levels in the WT-DM and KO-DM mice. Interstitial fibrosis was increased in WT-DM mice compared to KO-DM mice. However, there were no differences in the degree of mesangial expansion or glomerular hypertrophy between the two groups. F4/80-positive cells (macrophages) and FSP-1-positive cells (fibroblasts) showed significantly higher infiltration in WT-DM mice than in KO-DM mice. Renal mRNA expression of NADPH oxidase subunits and urinary 8-isoprostane excretion were also increased in WT-DM mice. Conclusions: These results indicated that OPN is a key molecule that induces interstitial fibrosis in the diabetic kidney, but does not induce glomerular sclerosis

HbA1c is an Independent Determinant of Renal Vascular Resistance Estimated by Doppler Sonography in Non-Diabetic Hypertensive Patients

Background Diabetic nephropathy is a progressive disease that leads to renal failure and end stage renal disease. A frequent and early manifestation of diabetic nephropathy is hyaline arteriolosclerosis. The noninvasive method for estimating the severity of arteriolosclerosis is measurement of the renal resistive index (RI). In this study, we determined whether or not normal blood glucose control, classified as an HbA1c < 5.8%, was a sufficiently low level to prevent arteriolosclerosis in patients with essential hypertension. Methods The study subjects were 93 patients with essential hypertension with HbA1c levels <5.8%. Patients with a history of medication for diabetes mellitus were excluded. Blood flow velocity of the renal interlobar arteries was assessed by a Doppler ultrasonography and the RI calculated. Results RI correlated positively with age, body mass index, pulse pressure, pulse rate and HbA1c, and negatively with diastolic blood pressure. A multivariate analysis identified age, pulse pressure and HbA1c as significant independent determinants of RI. Our data show that RI correlates with HbA1c independent of other variables, even in normoglycemic patients with HbA1c levels <5.8%. Conclusions The results of this cross-sectional study suggest that blood glucose levels should be kept as low as possible in order to prevent arteriolosclerosis in the kidney in hypertensive patients

Effects of amlodipine and candesartan on arterial stiffness estimated by cardio-ankle vascular index in patients with essential hypertension: A 24-week study

AbstractBackground: Aortic stiffness assessed by brachio-ankle pulse wave velocity (baPWV) can be used to predict cardiovascular events. However, baPWV is dependent on blood pressure. Antihypertensive drugs have been reported to reduce baPWV; but it is difficult to determine if this effect is associated with lowered blood pressure or reduced arterial stiffness.Objectives: The primary end point of this study was to assess whether antihypertensive drugs reduce arterial stiffness as estimated by cardio-ankle vascular index (CAVI). The secondary end point was to compare the effects of 2 widely used drugs, the calcium-channel blocker amlodipine and the angiotensin II receptor blocker candesartan, on arterial stiffness.Methods: Between October 2005 and September 2006, consecutive Japanese outpatients with essential hypertension (EHT) (defined as using antihypertensive drugs at screening, systolic blood pressure [SBP] > 140 mm Hg, or diastolic BP [DBP] >90 mm Hg) were assigned to treatment for 24 weeks with either amlodipine (5–10 mg/d) or candesartan (8–12 mg/d). Arterial stiffness was evaluated with CAVI before and after 24 weeks of treatment. Relative change in arterial stiffness from baseline was also compared. The evaluator was blinded to treatment.Results: Twenty patients (11 men, 9 women; mean [SD] age, 62 [10] years) were included in the study. There were no significant differences in clinical characteristics between the 2 groups. At baseline, mean (SD) CAVI was not significantly different in the amlodipine group compared with the candesartan group (8.93 [0.93] vs 8.46 [1.34], respectively). During the 24-week treatment period, mean SBP and DBP decreased significantly in both the amlodipine (14/10 mm Hg; P = 0.006 and P = 0.005) and the candesartan groups (13/11 mm Hg; P = 0.033 and P = 0.005). Amlodipine was associated with a significant change in CAVI from baseline (8.93 [0.93] vs 8.60 [1.50]; P = 0.017), whereas candesartan was not (8.46 [1.34] vs 8.81 [1.20]). The percentage change in CAVI was significantly different in the amlodipine group compared with the candesartan group (−7.14 [8.83] vs 5.85 [16.0], respectively; P = 0.038). After 24 weeks of treatment, the CAVI of the amlodipine group was still numerically larger than baseline CAVI of the candesartan group, although the difference was not statistically significant. Furthermore, there was no significant difference in absolute CAVI between the 2 groups after 24 weeks, but the relative change from baseline was significant in favor of amlodipine. Logistic regression analysis revealed that amlodipine improved CAVI independent of its antihypertensive effect.Conclusion: These data suggest that amlodipine and candesartan had different effects on aortic stiffness estimated by CAVI, despite similar effects on brachial blood pressure after 24 weeks of treatment in these Japanese patients with EHT