beraprost and Albuminuria

Diabetic nephropathy is one of the primary diseases of refractory renal failure and heads the list of patients undergoing dialysis. Therefore, it is very important to get treatment in incipient nephropathy.. Twenty-seven patients in incipient diabetic nephropathy of type 2 diabetes mellitus who showed signs of microalbuminuria were randomly, but not blindly, assigned to two groups, either the beraprost sodium (PGI(2)) group or the control group, and effects of the preparation on urinary albumin excretion or other parameters were examined for 24 months.. Urinary albumin excretion was significantly decreased after 18 months in beraprost sodium group; however, there was no change in the control group. Difference was observed between the two groups after month 12; however, it was not significant (p = 0.0673 at month 24). Three factors that affect urinary albumin excretion, e.g. blood pressure, blood sugar and protein intake, were almost constant during the study period. The level of creatinine clearance was significantly decreased in beraprost sodium group after 24 months as compared with the control group.. In this study, we found that the long-term 24-month administration of PGI(2) preparation, beraprost sodium, decreased albuminuria in patients of incipient diabetic nephropathy. The possible mechanisms are that the PGI(2) may have alleviated constriction effect of angiotensin II on efferent glomerular arteriole and attenuated glomerular hyperfiltration, and inhibited growth of mesangial cells by platelet-derived growth factor as well.

Topics: Aged; Albuminuria; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dietary Proteins; Epoprostenol; Female; Hemoglobin A; Humans; Lipids; Male; Middle Aged; Time Factors

Epithelial-mesenchymal transition (EMT) may contribute to podocyte dysfunction in diabetic nephropathy (DN). Aiming to identify novel therapeutic options, we investigated the protective effects of Panax notoginseng (PN) on podocyte EMT in diabetic rats and explored its mechanisms.. Diabetes was induced in rats with streptozotocin (STZ) by intraperitoneal injection at 55 mg/kg. Diabetic rats were randomly divided into three groups, namely, diabetic rats, diabetic rats treated with beraprost sodium (BPS) at 0.6 mg/kg/d or PN at 0.4 g/kg/d p.o., for 12 weeks. Urinary albumin/creatinine ratio (ACR), biochemical parameters, renal histopathology, and podocyte morphological changes were evaluated. Protein expression of EMT markers (desmin, α-SMA, and nephrin) as well as components of the Wnt/β-catenin pathway (wnt1, β-catenin, and snail) was detected by immunohistochemistry and Western blot, respectively.. In diabetic rats, severe hyperglycemia and albuminuria were detected. Moreover, mesangial expansion and podocyte foot process effacement were found markedly increased in diabetic kidneys. Increased protein expression of wnt1, β-catenin, snail, desmin, and α-SMA, as well as decreased protein expression of nephrin was detected in diabetic kidneys. All these abnormalities found in DN rats were partially restored by PN treatment.. PN ameliorated albuminuria and podocyte EMT in diabetic rats partly through inhibiting Wnt/β-catenin signaling pathway. These findings provide experimental arguments for a novel therapeutic option in DN.

Topics: Albuminuria; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epithelial-Mesenchymal Transition; Epoprostenol; Hyperglycemia; Male; Panax notoginseng; Plant Preparations; Podocytes; Rats; Rats, Sprague-Dawley; Streptozocin; Wnt Signaling Pathway

In a previous study, we reported that beraprost sodium (BPS), a stable prostaglandin I(2) (PGI(2)) analog, increases skin blood flow in the feet of both control subjects and patients with type 2 diabetes, and that the flow increase induced by BPS is lower in diabetic patients than in controls. The present study was undertaken to clarify factors associated with smaller increases in skin blood flow in the feet of patients with type 2 diabetes after the administration of BPS, and to investigate the relationship between microalbuminuria and the changes in skin blood flow induced by the PGI(2) analog. We studied 61 patients with type 2 diabetes: 10 received placebo (control) and 51 (31 with normoalbuminuria and 20 with microalbuminuria) received BPS. Using laser Doppler flowmetry, we measured the skin blood flow at the pulp of the right big toe before and 90 minutes after administration of 40 microg BPS, and calculated the change in blood flow, i.e., delta flux (peak flux at 90 minutes - basal flux at 0 minutes). Plasma concentrations of soluble thrombomodulin (TM) were determined using an enzyme immunoassay (EIA) sandwich method. BPS significantly increased skin blood flow in the treatment group compared with the placebo group (P <.01). The delta flux was positively correlated with the value of the ankle brachial index (ABI) (r =.41, P <.0038) and was negatively correlated with plasma TM levels (r = -.53, P <.0001). By multiple regression analysis both the ABI value and the plasma TM level retained a significant influence on delta flux. Furthermore, both the delta flux and the ABI value in patients with microalbuminuria were lower than in patients with normoalbuminuria (P <.05). The results suggest that BPS increases the skin blood flow of the toe of patients with type 2 diabetes and that the increased flow is independently influenced by the value of the ABI and the plasma TM levels; in addition, microalbuminuria is associated with the impairment of vasodilation in the feet in response to BPS.

Topics: Adult; Albuminuria; Ankle; Blood Flow Velocity; Brachial Artery; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Epoprostenol; Female; Foot; Glycated Hemoglobin; Humans; Kinetics; Lipids; Male; Middle Aged; Regression Analysis; Skin; Skin Temperature; Thrombomodulin

To determine the relationship of skin microangiopathy and other diabetic microvascular complications, we measured changes in skin blood flow after the administration of the prostacyclin (PGI2) analogue, beraprost sodium (BPS), in 82 patients with non-insulin-dependent diabetes mellitus and 20 healthy subjects. The diabetic patients had various degrees of retinopathy and nephropathy. Using laser Doppler flowmetry we measured skin blood flow at the dorsum of the right big toe at various times after the administration of 40 micrograms BPS and calculated the blood flow change (delta flux = peak flux--basal flux). We also determined the ankle pressure index (API), an ankle/brachial systolic pressure ratio. The basal blood flow was higher in healthy subjects than in diabetic patients (P < 0.001). BPS significantly increased blood flow in both diabetic patients and healthy subjects (P < 0.001). In all 102 subjects delta flux was positively correlated with the API (R = 0.40, P < 0.001). Despite no differences in API among the diabetic retinopathy and nephropathy subgroups, the delta flux in diabetic patients with progressive retinopathy and macroalbuminuria was significantly lower than in healthy subjects or in diabetic patients with less severe retinopathy and nephropathy (P < 0.05). The results suggested that BPS increases skin blood flow and the flow increase induced by BPS is related partly to the levels of API. The effect of BPS on skin blood flow decreased with an increases in the severity of retinopathy and nephropathy. Diabetic skin microangiopathy appears to coexist with other microvascular diabetic complications and may be proportional to their severity.

Topics: Adult; Albuminuria; Ankle; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Epoprostenol; Female; Humans; Laser-Doppler Flowmetry; Male; Middle Aged; Pressure; Reference Values; Regional Blood Flow; Skin; Skin Temperature; Ultrasonography; Vasodilation; Vasodilator Agents

A study of albuminuria, creatinine clearance (CCr) and blood pressure of streptozotocin (STZ)-induced diabetic rats with or without treatment by a prostacyclin (PGI2) analog, beraprost sodium (BPS), is described. Glomerular prostanoid synthesis was measured by gas chromatography (GC) mass spectrometry. Renal specimens stained with hematoxylin and eosin and periodic acid-Schiff were examined by light microscopy. Mean values of albuminuria in BPS-treated diabetic rats were significantly decreased compared with those in nontreated diabetic rats. The ratio of kidney to body weight in the BPS-treated diabetic rats was significantly lower than that in the nontreated diabetic rats. Levels of CCr and blood pressure were decreased in diabetic rats after the treatment with BPS. GC mass spectrometry showed that BPS did not influence the glomerular synthesis of PGI2 and TXB2. No histologic injury in the renal tissues was observed in the diabetic rats with or without BPS treatment. We concluded that BPS (PGI2 analog) might decrease the levels of urinary albumin excretion and CCr due to its vasodilating effects in the early phase of STZ-induced diabetes in rats.

Topics: Albuminuria; Animals; Blood Pressure; Body Weight; Creatinine; Diabetes Mellitus, Experimental; Epoprostenol; Gas Chromatography-Mass Spectrometry; Kidney Glomerulus; Male; Organ Size; Prostaglandins; Rats; Rats, Sprague-Dawley

Although prostaglandins have been shown to inhibit the evolution of the nephritis in NZB/W mice, the mechanisms of this effect are unknown. To characterize such inhibition, we injected the prostacyclin (PGI2) analogue, beraprost, into NZB/W mice, using 0.5 mg, 1.0 mg or 5.0 mg beraprost/kg body weight of test animals three times in 1 week when the mice were 2 months old. Evaluation included measurement of urine albumin excretion, serological parameters and splenic T cell subset, as well as examination of renal histology by light and fluorescence microscopy. Mice given beraprost showed a marked decrease in urine albumin excretion and in glomerular hypercellularity compared with untreated controls. Maximal beneficial effects occurred when the dose was 5.0 mg/kg of beraprost. These effects correlated with a reduction of immune complex deposition in glomeruli. In addition, beraprost reduced serum levels of immunoglobulins and anti-double-stranded DNA antibodies, and decreased the number of helper (L3T4+) T cells in splenocytes. These results indicate that beraprost attenuates the nephritis of NZB/W mice, and that the source of this effect is the reduced production of autoantibodies and deposition of immune complexes in glomeruli.

Topics: Albuminuria; Animals; Epoprostenol; Female; Flow Cytometry; Immune Complex Diseases; Immunodiffusion; Kidney; Mice; Mice, Inbred NZB; Nephritis