Inhibition of α2-adrenoceptor is renoprotective in 5/6 nephrectomy-induced chronic kidney injury rats.

In the present study, we investigated the renoprotective effects of long-term treatment with yohimbine, an α2-adrenoceptor inhibitor, in a 5/6 nephrectomy-induced chronic kidney disease (CKD) rat model. Male Sprague-Dawley rats were randomly allocated into the following groups: sham-operated, 5/6-nephrectomized (5/6 Nx), 5/6 Nx + low or high dose of yohimbine (0.3 or 3.0 mg/L in drinking water, respectively), and 5/6 Nx + hydralazine (250 mg/L in drinking water). The 5/6 Nx group presented with renal dysfunction, hypertension, noradrenaline overproduction, and histopathological injuries. Blood pressure decreased in both the yohimbine- and hydralazine-treated groups. Treatment with high dose of yohimbine, but not hydralazine, apparently attenuated urinary protein excretion and noradrenaline concentration of renal venous plasma. Renal fibrosis and upregulated fibrosis-related gene expression were suppressed by high dose of yohimbine. Furthermore, yohimbine, but not hydralazine, treatment ameliorated the urinary concentration ability. These findings suggest that long-term yohimbine treatment can be a useful therapeutic option to prevent the progression of CKD.

Protective Effect of Salvia Przewalskii Extract on Puromycin-Induced Podocyte Injury.

BACKGROUND: To determine the effect of Salvia przewalskii extract (SPE) from total phenolic acids on puromycin aminonucleoside (PAN)-induced rat podocyte injury. METHODS: The rats were divided into groups that were treated with either PAN only or PAN followed by tacrolimus or SPE. We evaluated the effects of SPE on podocyte injury 5, 10, 15 and 21 days following treatment. RESULTS: (1) Proteinuria was observed starting on day 5 in all groups. The peak levels of proteinuria differed among the groups with tacrolimus and high-dose SPE, which significantly decreased proteinuria relative to the PAN and low- and medium-dose SPE groups. The proteinuria in each group decreased by day 15 and returned to a normal level by day 21. (2) H&E and PAS staining revealed no abnormality in glomerular morphology. With electron microscopy, we observed foot process effacement in the rats of all groups starting on day 5, but rats in the tacrolimus and high-dose SPE groups exhibited a lower degree. (3) IHC staining of nephrin and podocin revealed unaffected expression and better linear distributions in the high-dose SPE and tacrolimus groups. Western blot analysis confirmed that SPE could improve the expression of proteins. (4) The mRNA levels of nephrin and podocin in the tacrolimus and high-dose SPE groups were significantly higher than that in the others. CONCLUSION: In our study, we first demonstrated the ability of SPE to reduce proteinuria, preserve the morphology and structure of podocytes and retain the levels of slit diaphragm proteins on PAN-induced rat podocytes injury.

Enhanced oral bioavailability of EGCG using pH-sensitive polymeric nanoparticles: characterization and in vivo investigation on nephrotic syndrome rats.

OBJECTIVE: Chronic kidney disease (CKD) is characterized by progressive loss of renal functions. At present, there are only limited therapeutic strategies to slow down the progress of CKD and there is an urgent need to develop new therapeutic strategies to treat CKD patients. Numerous research evidence supports the potential role of EGCG in the renal protection of CKD. However, the clinical use is still limited due to the poor oral bioavailability. The aim of this study was to develop pH-sensitive polymeric nanoparticles of EGCG to improve this deficiency. MATERIALS AND METHODS: EGCG-loaded nanoparticles (EGCG NPs) were prepared by an improved emulsion evaporation method. The formulation prepared was in spherical with uniform sizes, high encapsulation efficiencies and drug loading. The therapeutic efficacy of EGCG NPs on chronic kidney disease was investigated on model of rat Nephrotic syndrome by measuring urinary protein excretion and kidney pathology score. RESULTS: The mean particle size was found to be 91.3±0.8 nm and the encapsulation efficiency% and drug loading% of the formulation were 80.8%±1.6% and 6.3%±1.4%, respectively. The powder X-ray diffraction and differential scanning calorimetry of EGCG NPs showed that EGCG existed in amorphous form in NPs. The release of EGCG from NPs exhibited the lower burst release at pH 1.2 (<10%) and with the increase of pH value, the release of EGCG also gradually increased. During the observation period (24 hours), the total release amount was almost 68%. EGCG NPs could significantly modify the pharmacokinetic profile and increase the bioavailability of EGCG by more than 2.4-fold in comparison with the EGCG powder group. At the end of the fourth and sixth week, proteinuria excretion of nephrotic syndrome rats treated with EGCG NPs was significantly lower than those treated with EGCG powder, and kidney pathology scores in EGCG NPs treated rats were also significantly lower than EGCG powder treated rats. CONCLUSION: The results of pharmacodynamics showed that compared with EGCG powder treatment group, EGCG NPs treatment group had better efficacy and reduce kidney damage.

Renoprotective effect of epoetin beta pegol by the prevention of M2 macrophage recruitment in Thy-1 rats.

BACKGROUND: Glomerulonephritis (GN) develops via accumulation of extracellular matrix through macrophage recruitment in glomeruli. It is unclear whether epoetin beta pegol (continuous erythropoietin receptor activator, CERA), a long-acting erythropoiesis-stimulating agent, exerts a renoprotective effect by preventing glomerulosclerosis. We examined the renoprotective effect of CERA in rats with Thy-1 glomerulonephritis (Thy-1-GN), an animal model for mesangial proliferative glomerulonephritis. METHODS: Thy-1-GN was induced in F344 rats by injection of anti-Thy1.1 antibody. CERA (25 µg/kg) was intravenously administered 4 h before anti-Thy1.1 antibody injection. After 6 days, blood and urine was collected for biochemical analysis and kidneys harvested for analysis of histopathology and mRNA expression. RESULTS: In Thy-1-GN rats, CERA suppressed increased urinary total protein, urea nitrogen, and N-acetyl-ß-(D)-glucosaminidase. CERA significantly prevented glomerulosclerosis and expression of α-smooth muscle actin, collagen-1, and fibronectin. Increased macrophage infiltration and up-regulated monocyte chemotactic protein-1 were significantly suppressed by CERA. Furthermore, CERA also suppressed up-regulation of arginase-1, a marker of M2 macrophages. Arginase-1 expression levels strongly correlated with levels of collagen-1 and fibronectin mRNA. CONCLUSIONS: These results suggest that CERA has potential to protect kidney function through the prevention of glomerulosclerosis, accompanied by prevention of M2 macrophage recruitment.

Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice.

The ability to selectively inactivate immune cells with immunosuppressants is a much sought-after modality for the treatment of systemic lupus erythematosus and autoimmunity in general. Here, we designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). Treatment with MPA-loaded nanogels increased the median survival time (MST) of lupus-prone NZB/W F1 mice by 3 months with prophylactic use (MST was 50 weeks versus 38 weeks without treatment), and by 2 months when administered after the development of severe renal damage (MST after proteinuria onset was 12.5 weeks versus 4 weeks without treatment). Equivalent and greater doses of MPA administered in buffer were not efficacious. Nanogels had enhanced biodistribution to organs and association with immune cells. CD4-targeted nanogels yielded similar therapeutic results compared with nontargeted formulations, with protection from glomerulonephritis and decreases in IFN-γ-positive CD4 T cells. DCs that internalized nanogels helped mediate immunosuppression, as they had reduced production of inflammatory cytokines such as IFN-γ and IL-12. Our results demonstrate efficacy of nanogel-based lupus therapy and implicate a mechanism by which immunosuppression is enhanced, in part, by the targeting of antigen-presenting cells.

Therapeutic effects of anticoagulant agents on preeclampsia in a murine model induced by phosphatidylserine/phosphatidylcholine microvesicles.

Preeclampsia (PE) is a placenta-mediated pregnancy complication that results in high maternal and neonatal mortality and morbidity worldwide. Currently, there is no satisfactory pharmacotherapeutic treatment to stop the PE progression. In this study, we investigated the therapeutic effects of anticoagulant agents, including annexin V, heparin, and a fusion protein of annexin V and hirudin (AND), in a murine PE model induced by intravenous injection of phosphatidylserine/phosphatidylcholine (PS/PC) microvesicles. Compared with the control pregnant animals, the pregnant mice injected with PS/PC presented PE-like symptoms, including elevated systolic blood pressure, proteinuria, and reduction of antithrombin III and blood platelets. However, the PE-like symptoms were significantly alleviated after the PS/PC-injected mice were treated with annexin V, AND, or heparin. Furthermore, fibrin deposition in the placentas in the anticoagulant treated mice was remarkably improved, compared with that in the mice injected with PS/PC alone. The data demonstrate that anticoagulants are effective to prevent the occurrence of PE in the murine model and also suggest that hypercoagulation in the placenta is a contributing factor in the pathogenesis of PE.

The possible roles of hyperlipidemia and mononuclear cells in glomeruli in puromycin aminonucleoside nephrosis in rats.

The possibility that hyperlipidemia and an increase of mononuclear cells in the glomeruli could participate in the pathogenesis of minimal change glomerulopathy was evaluated in puromycin aminonucleoside (PAN) nephrosis in rats. Significant increases in intraglomerular CD4-, IL-2-receptor (R)- and ED-1-positive cells were found in PAN rats. Urinary protein excretion and mononuclear cells in the glomeruli of 1% cholesterol diet-fed rats significantly increased, compared with standard diet feeding. Moreover, administration of a subnephrogenic dose of PAN in cholesterol diet-fed rats substantially increased urinary protein excretion and mononuclear cells in the glomeruli. Additionally, antihyperlipidemia agents and immunosuppressive agents prevented urinary protein excretion and increases of CD4-, IL-2R- and ED-1-positive cells in the glomeruli of PAN nephrotic rats. Monoclonal antibodies directed against these cells also prevented urinary protein excretion. These results suggest that CD4-, IL-2R- and ED-1-positive cells and hyperlipidemia are involved in the progression, but not the pathogenesis, of PAN.