Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats

Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.

Analysis of Cyclosporine A Blood Concentration Monitoring in 154 Cases of Nephrotic Syndrome Patients and Its Effects on Efficacy and Safety / 中国药房

OBJECTIVE:To investigate the effects of blood concentration monitoring of cylosporin A(CsA) in patients with nephrotic syndrome(NS)on efficacy and safety. METHODS:The medical records of 154 NS patients receiving CsA and blood concentration monitoring in nephrology department of China-Japan Friendship Hospital during Jan. 2014-Aug. 2017 were analyzed retrospectively. The results of blood concentration monitoring in 63 adult inpatients with refractory NS receiving CsA for the first time within 6 months of initial treatment were analyzed statistically. The relationship of blood concentration monitoring with efficacy and safety was analyzed. RESULTS:The blood concentration of CsA in 154 patients were monitored for 512 times with an average of 3.32 times/person,and average blood concentration was(125.98±105.13)ng/mL. The patients with blood concentration of CsA＜100 ng/mL accounted for 44.14%. There was no statistical significance in average monitoring times or average blood concentration between male and female,average blood concentration of CsA among different age groups (P＞0.05). The blood concentration was monitored for 237 times in 63 adult inpatients with refractory NS receiving CsA for the first time within 6 months of initial treatment(induction period). Average blood concentration of effective group were significantly higher than ineffective group;the proportion of effective group with blood concentration＜100 ng/mL was significantly lower than that of ineffective group,with statistical significance (P＜0.05). Among 63 patients,17 patients suffered from ADR (the incidence of ADR was 26.98%). The average blood concentrations of ADR patients were significantly higher than those without ADR;the monitoring times of ADR patients with blood concentration＞150 ng/mL was significantly higher than those without ADR,with statistical significance(P＜0.05). There was no statistical significance in the incidence of ADR between effective group and ineffective group (P＞0.05). Among effective group,there was no statistically significance in average blood concentration between ADR patients and patients without ADR(P＞0.05);the monitoring times of ADR patients with blood concentration＞150 ng/mL was significantly higher than patients without ADR,with statistical significance(P＜0.05). With the increase of monitoring times,the incidence of ADR decreased gradually. There was no statistical significance in the incidence of ADR among patients who were monitored for different times (P＞0.05). CONCLUSIONS:The pharmacokinetics of CsA varies in different patients and many factors affect its blood concentration. The changes of blood concentration affect the efficacy and safety of CsA. It is difficult to determine the dosage of CsA based on experience in the treatment of NS with CsA. Great importance should be attached to blood concentration monitoring of CsA and the implementation of individualized dosage regimen based monitoring results so as to improve therapeutic efficacy and reduce the occurrence of ADR.

Preclinical evaluation of nephroprotective potential of a probiotic formulation LOBUN on Cyclosporine-A induced renal dysfunction in Wistar rats

ABSTRACT The aim of present study was to evaluate the nephroprotective effect of probiotic formulation LOBUN on Cyclosporine A (CsA) induced renal dysfunction in Wistar rats. CsA (20 mg/kg body weight s.c) was administered for 15 days to cause renal dysfunction in Wistar rats. The probiotic formulation LOBUN was administered with the dose of 500 mg/kg body weight (p.o) for twice (TGI) and thrice a day (TGII). The samples were analyzed for the parameters like blood urine nitrogen (BUN), serum creatinine, serum uric acid, total serum protein and urine proteins, urine potassium, urine sodium. The renal functional and histopathological studies revealed that the oral administration of probiotic formulation LOBUN has provided appreciable renoprotection and possibly alleviated the symptoms of Chronic Kidney Disease (CKD) at the dose of 500 mg/kg body weight administered thrice a day and also the results were supported by histopathological findings.

Effect of inhibiting TGF-β1 on Smad2/3 and ILK signaling molecules in chronic cyclosporine A nephropathy in mouse / 中国免疫学杂志

Objective:To investigate the effect of specific inhibition of transforming growth factor-β1 (TGF-β1) with SB-431542 on the Smad2/3 and integrin-linked kinase (ILK) signaling molecules in tubule interstitial fibrosis(TIF)-induced cyclosporine A(CsA) in mouse.Methods:50 BALB/c mice were randomly divided into 5 groups (10 mice per group):the CsA model group (CMG),the interventional model group (IMG),the solvent control group (SCG),the low-salt control group (LCG),and the normal control group (NCG).The model mouse was established with low-sodium diet and intragastric administration of cyclosporine A,which was dissolved in olive oil at a dose of 60 mg/(kg·d).After 4 weeks,a specific inhibitor of TGF-β1 (SB-431542)was administered intraperitoneally with 10 mg/(kg·2 d) for 10 days (every other days).Mice were sacrificed at day 38.Serum creatinine (Scr) was measured,hydroxyp roline (Hyp)level and morphological changes of renal tissue were analyzed,expression levels of TGF-β1,P-Smad 2/3 and ILK were respectively detected by immunohistochemistry or Western blot,mRNA levels of TGF-β1,Smad 2/3 and ILK were respectively detected real-time polymerase chain reaction (RT-PCR).Results:Compared with three control groups (NCG,LCG and SCG),mice weight was decreased significantly,Scr level was increased significantly in two modeling groups (CMG and IMG) (P<0.01),and these changes in CMG were more obvious than those of IMG (P<0.05).Different levels of tubulointerstitial injury,interstitial infiltration of inflammatory cells and blue collagen staining in two modeling groups were observed,and particularly evident in CMG.TGF-β1,P-Smad2/3 and ILK immunostaining were mainly expressed in tubulointerstitium.The TGF-β1,P-Smad2/3 and ILK mRNA and immunostaining levels in two modeling groups were significantly increased as compared with three control groups (P<0.01),but their levels in IMG were significantly lower than those of CMG (P<0.05).The level of Hyp in renal tissue was positively correlated with Scr,TGF-β1,Smad2/3 and ILK (r=0.860,0.711,0.776,0.676,P<0.01).Conclusion:The activation of the TGF-β1/Smads signaling pathway plays an important role in the development of chronic CsA-induced TIF.The activation of ILK is closely correlated with the development of TIF,and may be used as a downstream factor of TGF-β1/Smads signaling pathway in regulating CsA-induced TIF.

IL-17 Induces MPTP opening through ERK2 and P53 signaling pathway in human platelets / 华中科技大学学报（医学）（英德文版）

The opening of mitochondrial permeability transition pore (MPTP) plays a critical role in platelet activation. However, the potential trigger of the MPTP opening in platelet activation remains unknown. Inflammation is the crucial trigger of platelet activation. In this study, we aimed to explore whether and how the important inflammatory cytokine IL-17 is associated with MPTP opening in platelets activation by using MPTP inhibitor cyclosporine-A (CsA). The mitochondrial membrane potential (ΔΨm) was detected to reflect MPTP opening levels. And the platelet aggregation, activation, and the primary signaling pathway were also tested. The results showed that the MPTP opening levels were increased and Δψm reduced in platelets administrated with IL-17. Moreover, the levels of aggregation, CD62P, PAC-1, P53 and the phosphorylation of ERK2 were enhanced along with the MPTP opening in platelets pre-stimulated with IL-17. However, CsA attenuated these effects triggered by IL-17. It was suggested that IL-17 could induce MPTP opening through ERK2 and P53 signaling pathway in platelet activation and aggregation.

Plasma cell granuloma in cyclosporin-induced gingival overgrowth: four cases report with interleukin-6 and phospholipase C-gammar1 immunohistochemistry

No abstract available.

Analysis of prevention and treatment of cyclosporine-A's hepatotoxicity in patients with renal transplantation / 解放军医学杂志

Objective To study the hepatotoxicity of cyclosporine-A, tacrolimus and other immunosuppressive drugs in patients with renal transplantation. Methods In 346 cases undergone renal transplantation, ALT, AST, BILT and BILD levels of venous blood 1-90 days after operation, and treatment methods and outcome were reviewed, in order to evaluate the effectiveness of the treatment of hepatotoxicity. Results In CsA group, the occurrence rate of liver dysfunction was 26.9%, in whom ALT, AST and BILD increased apparently (P0.05). In MMF and MRZ group, the incidence of liver dysfunction was almost the same. In 18 cases the drug was changed into FK506, ALT, AST, BILT and BILD all apparently decreased 1 week later (P