Chronic Cyclosporine Nephrotoxicity Research Articles

A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice.

Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg for four weeks. Animals were treated with DA-1229 at a dose of 300 mg/kg per day in food for four weeks. Although DPP-4 activity did not increase in the kidneys of mice with induced cyclosporine nephrotoxicity, DA-1229 treatment significantly suppressed DPP-4 activity in both plasma and renal tissues. DPP-4 inhibition by DA-1229 led to significantly decreased albuminuria and urinary excretion of 8-isoprosatane. DPP-4 inhibition also substantially suppressed pro-inflammatory effects, profibrotic molecules, and macrophage infiltration, and led to the improvement in renal structural changes. Our results suggest that DPP-4 inhibition by DA-1229 provides renoprotective effects in an animal model of cyclosporine nephrotoxicity via antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. DPP-4 inhibition may be a useful new therapeutic approach for the management of progressive renal disease in cyclosporine nephrotoxicity.

Nephroprotective Potential of Mesenchymal Stromal Cells and Their Extracellular Vesicles in a Murine Model of Chronic Cyclosporine Nephrotoxicity.

BackgroundCell therapies and derived products have a high potential in aiding tissue and organ repairing and have therefore been considered as potential therapies for treating renal diseases. However, few studies have evaluated the impact of these therapies according to the stage of chronic kidney disease. The aim of this study was to evaluate the renoprotective effect of murine bone marrow mesenchymal stromal cells (BM-MSCs), their extracellular vesicles (EVs) and EVs-depleted conditioned medium (dCM) in an aggressive mouse model of chronic cyclosporine (CsA) nephrotoxicity in a preventive and curative manner.MethodsAfter 4 weeks of CsA-treatment (75 mg/kg daily) mice developed severe nephrotoxicity associated with a poor survival rate of 25%, and characterized by tubular vacuolization, casts, and cysts in renal histology. BM-MSC, EVs and dCM groups were administered as prophylaxis or as treatment of CsA nephrotoxicity. The effect of the cell therapies was analyzed by assessing renal function, histological damage, apoptotic cell death, and gene expression of fibrotic mediators.ResultsCombined administration of CsA and BM-MSCs ameliorated the mice survival rates (6–15%), but significantly renal function, and histological parameters, translating into a reduction of apoptosis and fibrotic markers. On the other hand, EVs and dCM administration were only associated with a partial recovery of renal function or histological damage. Better results were obtained when used as treatment rather than as prophylactic regimen i.e., cell therapy was more effective once the damage was established.ConclusionIn this study, we showed that BM-MSCs induce an improvement in renal outcomes in an animal model of CsA nephrotoxicity, particularly if the inflammatory microenvironment is already established. EVs and dCM treatment induce a partial recovery, indicating that further experiments are required to adjust timing and dose for better long-term outcomes.

Effects of Atorvastatin and Carvedilol on Chronic Cyclosporine Nephrotoxicity in Rats

Background: To evaluate possible renoprotective effects of carvedilol and atorvastatin in CsA induced kidney injury in a rat model. Methods: Twenty-two rats were divided into five groups. Control, CsA, CsA+karvedilol, CsA+Atorvastatin, CsA +karvedilol+atorvastatin groups. Drugs were given for 21 days. Results: Serum BUN and creatinine were significantly higher in the CsA group compared to control and were significantly lower in the CsA+carvedilol+atorvastatin group compared to CsA group. Tissue MDA levels were found to be lower in group 3, 4 and 5 than in CsA group. Tissue SOD in CsA +carvedilol and CsA+atorvastatin groups were found higher than the control and CsA groups. Tissue NO levels were found to be higher only in CsA+carvedilol+atorvastatin group compared to CsA group. Apical budding, hyaline casts and apoptosis in the tubular system was significantly higher in the CsA group than in the treatment groups. Osteopontin showed strong positivity especially in the CsA group. Osteopontin density was lower in the treatment group. Conclusions: This is the first study to evaluate MDA, SOD and NO at tissue level for carvedilol in cyclosporine nephrotoxicity. Carvedilol and atorvastatin may contribute to the reduction of renal injury in chronic CsA nehropathy. These agents have provided a protective effect on renal functions especially in combined treatment.

The protective effect of neutralizing high-mobility group box1 against chronic cyclosporine nephrotoxicity in mice

Background: High-mobility group box1 (HMGB1) is known to be involved in innate immune response through interaction with receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), besides its proper role within the nucleus. Immunological pathways, including TLR signaling, are also involved in chronic cyclosporine (CsA) nephrotoxicity. This study was designed to determine whether neutralizing HMGB1 prevents chronic CsA nephrotoxicity.Methods: Chronic CsA nephrotoxicity was induced by CsA subcutaneous injection daily for 4weeks under salt-depletion in mice. Anti-HMGB1 neutralizing antibody for HMGB1 blockade (600mcg/mouse) was administered weekly to mice in the anti-HMGB1 treatment group. The effects of HMGB1 neutralization were evaluated in terms of renal function as well as histological and immunopathological examination.Results: Anti-HMGB1 administration prevented the increases in serum creatinine and 24h albuminuria and the decrease in creatinine clearance associated with CsA treatment. Increased tubulointerstitial fibrosis and transforming growth factor (TGF)-β immunohistochemical staining associated with CsA treatment were also prevented by anti-HMGB1 administration. Anti-HMGB1 administration prevented the activation of the TLR4 signaling pathway, which resulted in the reduction of nuclear factor kappa B (NF-κB) expression. In cultured tubular cells, anti-HMGB1 pretreatment also prevented the increases in fibronectin and collagen IV levels associated with CsA treatment.Conclusions: Neutralizing HMGB1 with an anti-HMGB1 antibody ameliorated chronic CsA nephrotoxicity via inhibition of the TLR4 signaling pathway. Our study suggests that HMGB1 blockade can be beneficial for increasing allograft survival in renal transplant recipients by protecting against calcineurin inhibitor-induced nephrotoxicity.

Roles of osteopontin and nuclear transcription factor in chronic cyclosporine nephrotoxicity

Roles of osteopontin and nuclear transcription factor in chronic cyclosporine nephrotoxicity

Human Adipose Tissue Derived Mesenchymal Stem Cells Aggravate Chronic Cyclosporin Nephrotoxicity by the Induction of Oxidative Stress

The aim of this study was to investigate whether hATMSCs protect against cyclosporine (CsA)-induced renal injury. CsA (7.5 mg/kg) and hATMSCs (3×106/5 mL) were administered alone and together to rats for 4 weeks. The effect of hATMSCs on CsA-induced renal injury was evaluated by assessing renal function, interstitial fibrosis, infiltration of inflammatory cells, and apoptotic cell death. Four weeks of CsA-treatment produced typical chronic CsA-nephropathy. Combined treatment with CsA and hATMSCs did not prevent these effects and showed a trend toward further renal deterioration. To evaluate why hATMSCs aggravated CsA-induced renal injury, we measured oxidative stress, a major mechanism of CsA-induced renal injury. Both urine and serum 8-hydroxydeoxyguanosine(8-OHdG) levels were higher in the CsA+hATMSCs group than in the CsA group (P<0.05). An in vitro study showed similar results. Although the rate of apoptosis did not differ significantly between HK-2 cells cultured in hATMSCs-conditioned medium and those cultured in DMEM, addition of CsA resulted in greater apoptosis in HK-2 cells cultured in hATMSCs-conditioned medium. Addition of CsA increased oxidative stress in the hATMSCs-conditioned medium. The results of our study suggest that treatment with hATMSCs may aggravate CsA-induced renal injury because hATMSCs cause oxidative stress in the presence of CsA.

Drug Interaction Between Cyclosporine and Mtor Inhibitors in Experimental Model of Chronic Cyclosporine Nephrotoxicity and Pancreatic Islet Dysfunction

Drug Interaction Between Cyclosporine and Mtor Inhibitors in Experimental Model of Chronic Cyclosporine Nephrotoxicity and Pancreatic Islet Dysfunction

Drug Interaction Between Cyclosporine and mTOR Inhibitors in Experimental Model of Chronic Cyclosporine Nephrotoxicity and Pancreatic Islet Dysfunction

It is known that sirolimus (SRL) aggravates cyclosporine A (CsA)-induced nephrotoxicity and pancreatic injury, but the influence of everolimus (EVR) on CsA-induced organ injury is undetermined. Rats were treated with CsA (15 mg/kg) and EVR or SRL (0.3 mg/kg) subcutaneously for 4 weeks. The influences of EVR or SRL on CsA-induced nephrotoxicity and pancreatic islet dysfunction were compared, and drug interactions between CsA and EVR or SRL were evaluated at blood and tissue levels. Treatment with EVR or SRL alone did not cause severe pancreatic dysfunction and renal injury, but when combined with CsA they aggravated CsA-induced pancreatic and renal injury. Drug interactions between CsA and EVR or SRL differed at the tissue level. Combined treatment with CsA and SRL significantly increased the CsA or SRL levels in kidney and pancreas compared with CsA or SRL alone. However, combined treatment with CsA and EVR did not increase CsA or EVR levels in kidney and pancreas. Both EVR and SRL aggravate CsA-induced organ injury, but the pharmacologic interaction between EVR and CsA at the tissue level is less than that between CsA and SRL. This finding provides better understanding of the difference between EVR and SRL when combined with CsA treatment.

Tranilast Prevents the Progression of Chronic Cyclosporine Nephrotoxicity Through Regulation of Transforming Growth Factor β/Smad Pathways

Purpose Our aim was to investigate the role of tranilast in transforming growth factor (TGF) β/Smad pathways using a rat model of chronic cyclosporine (CsA) nephrotoxicity. Methods Thirty Sprague-Dawley (SD) rats were equally randomized in to 5 groups for gavage treatments daily for 4 weeks: normal control (N), olive oil; CsA (25 mg/kg), (M) CsA plus low-dose tranilast group (T1; CsA 25 mg/kg and tranilast 100 mg/kg); CsA plus medium-dose tranilast group (T2; CsA 25 mg/kg and tranilast 200 mg/kg); and CsA plus high-dose tranilast group (T4; CsA 25 mg/kg and tranilast 400 mg/kg). Kidneys were harvested at the end of the fourth week. TGF-β1 as well as Smad3 and Smad7 were detected by reverse-transcription polymerase chain reaction and immunohistochemistry. Results The administration of tranilast decreased the expression of TGF-β1 and Smad3 by CsA-treated rats, whereas it increased both mRNA and protein levels of Smad7. Semiquantitative analysis of mRNA production revealed these treatments to markedly reduce the amount of TGF-β1: T1: 0.8452 ± 0.0825 vs 0.8529 ± 0.0606 ( P < .05); T2: 0.8414 ± 0.0696 vs 0.8529 ± 0.0606 ( P < .05); T4: 0.8336 ± 0.0592 vs 0.8529 ± 0.0606 ( P < .05). For Smad3: T1: 0.8581 ± 0.0328 vs 0.8613 ± 0.0542 ( P < .05); T2: 0.8528 ± 0.0599 vs 0.8613 ± 0.0542 ( P < .05); T4: 0.8436 ± 0.0185 vs 0.8613 ± 0.0542 ( P < .05). The significantly elevated dose-dependent amounts of Smad7 were: T1: 0.9026 ± 0.0522 vs 0.8678 ± 0.0246, ( P < .05); T2: 0.9087 ± 0.0506 vs 0.8678 ± 0.0246 ( P < .05); T4: 0.9151 ± 0.0793 vs 0.8678 ± 0.0246 ( P < .05). Conclusion Regulation of TGF-β/Smad pathways is one of the mechanisims by which tranilast mitigates the progression of chronic CsA nephrotoxicity in rats.

Paricalcitol attenuates cyclosporine-induced kidney injury in rats

Despite its benefits, the clinical use of cyclosporine A (CsA) is limited by its nephrotoxic properties. Because paricalcitol (19-nor-1,25-hydroxyvitamin D(2)) has renoprotective effects, we tested whether it can blunt renal dysfunction and fibrosis in a rat model of CsA-induced nephropathy. Treatment with CsA decreased creatinine clearance, increased monocyte/macrophage infiltration, and increased the expression of inflammatory cytokines within the kidney. Paricalcitol reduced the decline in kidney function and pro-fibrotic changes and also blunted the increased transforming growth factor (TGF)-beta1 expression and Smad signaling. Using an in vitro model, we treated HK-2 cells with CsA and found that paricalcitol attenuated the CsA-induced increases in phosphorylated extracellular signal-regulated and c-Jun N-terminal kinases, and also prevented the activation of nuclear factor-kappaB. Paricalcitol effectively prevented TGF-beta1-induced epithelial-to-mesenchymal transitions and extracellular matrix accumulation as evidenced by attenuated collagen deposition and fibrosis in CsA-treated rats. In addition, paricalcitol decreased the number of TUNEL-positive nuclei and reduced the expression of pro-apoptotic markers in CsA-treated HK-2 cells. Thus, paricalcitol appears to attenuate CsA-induced nephropathy by suppression of inflammatory, pro-fibrotic, and apoptotic factors through inhibition of the nuclear factor-kappaB, Smad, and mitogen-activated protein kinase signaling pathways.

Serum indoxyl sulfate as an early marker for detecting chronic cyclosporine nephrotoxicity

Cyclosporine A (CsA) is an effective agent for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS), but its use can also be complicated by renal toxicity. Because no biochemical markers from urine or blood samples have yet been established for detecting CsA-induced renal injury to date, repeated renal biopsies are therefore required for all patients with long-term CsA treatment. The purpose of the present study was therefore to detect early change of CsA nephropathy (CsAN) using blood samples. Several biochemical markers were analyzed in an attempt to examine the renal function in 24 patients with FR-SDNS who had been treated with CsA. Those included serum cystatin C and indoxyl sulfate, as well as creatinine and beta2-microglobulin. Renal biopsy findings indicated chronic CsAN in 13 of the 24 patients. Among those markers, only serum indoxyl sulfate was significantly elevated in patients with CsAN. It may be possible for measurement of serum indoxyl sulfate level to replace repeated renal biopsies in evaluation of chronic CsAN in pediatric patients with FR-SDNS.

Polymerized type I collagen reduces chronic cyclosporine nephrotoxicity

Polymerized type I collagen (P-collagen) has been successfully used to reduce human hypertrophic scars due to its anti-fibrotic and anti-inflammatory properties. We therefore carried out a study to determine if P-collagen reduces functional and structural injury in chronic cyclosporine [cyclosporine A (CsA)] nephropathy. Four groups of six male Wistar rats fed with a low sodium diet were treated with vehicle, P-collagen (0.8 mg/day, i.p.), CsA (15 mg/kg) or CsA + P-collagen for 15 days. Mean arterial pressure, renal blood flow and glomerular filtration rate were measured in all groups. Structural injury such as arteriolopathy, tubulo-interstitial fibrosis (TI-fibrosis) and positive apoptotic cells were quantified. The mRNA expression levels of transforming growth factor-beta (TGF-beta), kidney injury molecule (Kim-1), alpha-smooth muscle actin (alpha-SMA), glutathione peroxidase, catalase and Cu/Zn superoxide dismutase (SOD) as well as MnSOD were assessed. Antioxidant enzyme activity, renal lipoperoxidation and urinary excretion of oxygen peroxide (UH(2)O(2)V) were determined. Cyclosporine produced renal dysfunction and induced the development of arteriolopathy, TI-fibrosis and tubular apoptosis. These alterations were associated with increases in TGF-beta, Kim-1 and alpha-SMA mRNA levels as well as with a significant increase of oxidative stress and a reduction of SOD activity. P-Collagen partially ameliorated CsA-induced renal dysfunction and structural injury and prevented both tubular apoptosis and increased oxidative stress. This renoprotective effect was found to be associated with a reduction of TGF-beta, Kim-1 and alpha-SMA mRNA levels. This study has therefore demonstrated that P-collagen appears to have anti-fibrotic and anti-apoptotic properties and highlights the possibility that the compound might be useful in a strategy to reduce chronic CsA nephrotoxicity.

Tranilast Attenuates Chronic Cyclosporine Nephrotoxicity in Rats

Our aim was to explore the effects of the anti-allergic and antifibrotic agent tranilast on chronic cyclosporine (CsA) nephrotoxicity in rats. Methods Eighteen Sprague-Dawley rats were randomized to be given the following daily treatments by gavage for 4 weeks: (1) controls, olive oil; (2) CsA group, CsA 25 mg/kg; (3) CsA plus tranilast group, CsA 25 mg/kg and tranilast 400 mg/kg. We examined the body weights and the effects of tranilast on histopathology, macrophage (Mϕ) infiltration, and expression of osteopontin (OPN). Results The administration of tranilast improved body weight gain by CsA-treated rats (232 ± 24 vs 203 ± 6 g; P < .05). This treatment reduced the expression of OPN protein and infiltration of macrophages (9.14 ± 2.7 vs 22.44 ± 5.68 ED-1 positive cells per high power field, P < .05). Furthermore compared with the CsA alone group, it ameliorated tubulointerstitial fibrosis scores (1.18 ± 0.08 vs 2.57 ± 0.21, P < .05). Conclusion Tranilast attenuated tubulointerstitial fibrosis through decreased expression of OPN protein and macrophage infiltration, showing renal protective effects in rats with chronic CsA nephrotoxicity.

Late Conversion to Everolimus Complicated With Necrotizing Glomerulonephritis in a Renal Allograft Recipient: Case Report

Conversion from calcineurin inhibitors (CNI) to proliferation signal inhibitors (PSI), such as sirolimus or everolimus (EV), may improve the course of chronic allograft nephropathy. Herein we have presented a case of a kidney recipient with chronic cyclosporine (CsA) nephrotoxicity who was converted from CsA to EV at 5.5 years posttransplantation. There were no significant changes in immunofluorescence (IFL) or in electron microscopy (EM) in the preconversion biopsy. Two months after conversion, proteinuria and creatinine increased. The biopsy showed focal, segmental necrosis of the glomerular tuft with the formation of segmental cellular crescents and increased endocapillary cellularity. IFL showed granular deposits of IgG, IgM, and C3 mostly along the capillary walls; it was negative for C4d. EM revealed electron-dense deposits within the glomerular basement membrane (GBM) and in the subendothelial region with significant reduction in the capillary lumina due to GBM reduplication and widening of lamina rara interna with the formation of fibrillary structures therein: focal, segmental glomerulosclerosis. EV was withdrawn and we administered tacrolimus and steroid pulses with improvement. Five months after the withdrawal of EV, a third graft biopsy showed remission of the necrotizing glomerulonephritis. However, the patient demanded dialysis at 17 months after conversion to EV. We concluded that necrotizing glomerulonephritis with immune complex deposition in a renal allograft was possibly induced by late conversion from CNI to EV. Reconversion to CNI may be recommended in cases of PSI-associated posttransplantation glomerulonephritis but the long-term prognosis is uncertain.

Toll-like Receptor Expression in Patients With Renal Allograft Dysfunction

Toll-like receptor (TLR) is known to be a mediator of innate immunity, but recent reports have shown that TLR provides a link to adaptive immunity involved in allograft rejection. To explore the expression patterns in various conditions of renal transplantation, we examined TLR subunit mRNA expressions in renal allograft biopsies of acute rejection (AR; n = 11), chronic rejection (CR; n = 15), chronic cyclosporine nephrotoxicity (CsAN; n = 22), and immunoglobulin A nephropathy (IgAN; n = 9) patients. Control tissues (n = 7) were obtained from normal renal cortical tissue of renal cell carcinoma patients. The diagnosis was made according to the Banff 97 classification. The expressions of TLR 2, 3, 4, and 9 mRNA were analyzed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) using SYBR green. Statistical analysis was performed using analysis of variance (ANOVA) and the Student t test. TLR 2 and 3 mRNA expressions were not significantly different in any group ( P > .05). In contrast, TLR 4 mRNA expression was significantly increased in all allograft groups compared with that of controls, and significantly higher in the CsAN than other transplant groups ( P < .05). TLR 9 mRNA expression was up-regulated in CsAN and IgAN compared with AR and CR ( P < .05). These results suggested that TLR4 mRNA expression was increased in renal allograft patients with chronic allograft dysfunction. Further studies are needed to correlate TLR subtypes with various causes of graft dysfunction among renal allograft patients.

Nigella sativa Oil for Prevention of Chronic Cyclosporine Nephrotoxicity: An Experimental Model

Nephrotoxicity is the main secondary effect of cyclosporine A (CsA) treatment. The antioxidant action of Nigella sativa oil (NSO) may explain the protective effect of these agents against various hepatotoxic and nephrotoxic models in vivo and in vitro. This study was designed to investigate the possible protective effects of NSO, in prevention of chronic CsA-induced nephrotoxicity in rats. Animals were randomly divided into four experimental groups: the control group received sunflower oil, the other groups were treated with CsA (25 mg/kg/day b.w. orally) or NSO (2 ml/kg orally) or CsA + NSO, respectively. Urine and serum creatinine levels, tissue superoxide dismutase, glutathione peroxidase and catalase enzyme activities, and nitric oxide and malondialdehyde levels were measured, and histological examination was performed. In our study, CsA caused a significant deterioration in the renal function, morphology and gave rise to severe oxidative stress in the kidney. NSO significantly improved the functional and histological parameters and attenuated the oxidative stress induced by CsA. In conclusion, our study demonstrated for the first time that NSO protects kidney tissue against oxygen free radicals, preventing renal dysfunction and morphological abnormalities associated with chronic CsA administration.

Renal Protective Effects of Leukotriene Receptor Blockers in an Experimental Model of Cyclosporine Nephrotoxicity

Background Chronic cyclosporine (CsA) nephrotoxicity is associated with renal fibrosis and hyaline arteriolopathy. Fibrogenic cytokines, such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF), play a pivotal role in CsA nephrotoxicity. Previous studies have demonstrated the possible role of leukotrienes (LT) in chronic CsA nephrotoxicity. The aim of this study was to examine the possible beneficial effects of LT blockers in attenuating the morphological and histochemical effects induced by CsA in a rat model of CsA nephrotoxicity. Materials and Methods Twenty-four male Wistar rats were divided into 3 groups (n = 8). The first group (G1) was treated with vehicle intraperitoneally (IP) for 60 days. The second group (G2) was treated with 15 mg/kg CsA IP for 60 days. The third group (G3) was treated with the same dose of CsA plus 4 mg/kg montelukast administered by oral gavage for 60 days. Results There was a statistically significant decrease in glomerular filtration rate (GFR) among G2 compared with G1 animals: 0.41 ± 0.03 vs 1.63 ± 0.12 mL/min ( P < .001), or G3 hosts: 0.41 ± 0.03 vs 0.95 ± 0.05 mL/min ( P < .005), respectively. The percentage of hyaline arteriolopathic changes was higher in G2 than G1 or G3: 81.66% ± 8.2% vs 11.83% ± 0.87% ( P < .01) or 37.0% ± 8.8% ( P < .01), respectively. Fibrosis score was higher in G2 compared with G1 or G3: 1.5 ± 0.04 vs 0.16 ± 0.02 ( P < .001) and 1.0 ± 0.05 ( P < .05), respectively. TGF-β and VEGF immunoexpression were significantly increased in G2 compared with G1 ( P < .05) or G3 ( P < .05). Conclusions Our study suggested that LT may play a critical role in the pathogenesis of chronic CsA nephrotoxicity; the administration of montelukast, a LT receptor blocker, may prevent CsA-induced nephrotoxicity.

Effects of Spironolactone in an Experimental Model of Chronic Cyclosporine Nephrotoxicity

Background Cyclosporine (CsA)-associated nephrotoxicity is a long-term complication in transplant patients. Chronic CsA nephrotoxicity is associated with renal fibrosis and hyaline arteriolopathy. The aim of this study was to investigate the effect of spironolactone on functional and structural alterations as well as on platelet-derived growth factor B (PDGF-B) and transforming growth factor (TGF) β expression induced by CsA in a rat model of chronic CsA nephrotoxicity. Materials and Methods Twenty-four rats were divided into 3 groups. Group 1 (G1) received vehicle only (V); G2, CsA (15 mg/kg/d; CsA) by intraperitoneal (IP) injection; and G3, a similar CsA dosage + spironolactone (20 mg/kg/d; CsA + Ald.) by the oral route. At the end of 28 days, glomerular filtration rate (GFR) and blood CsA levels were measured as well as histopathological and immunohistochemical analyses performed on renal tissue. Results Mean CsA trough levels in G2 and G3 were both above 2000 ng/mL. In G2, GFR was lower than G1 and G3 (0.35 ± 0.05, 1.64 ± 0.24, and 1.20 ± 0.25 mL/min, respectively; P < .001). There was a significantly increased number of arteriolopathic changes in G2 and G3 vs G1 (16% ± 3.7%, 15% ± 6.8%, 3% ± 1.2%, respectively; P < .001). Interstitial fibrosis was significantly increased in G2 vs G1 and G3 (52%, 0%, 27%, respectively; P < .05). Marked by up-regulated PDGF-B and TGF β expressions were observed in G2 vs G1 or G3: 100%, 0%, 37.5%, respectively, for PDGF-B ( P < .001) and 87.5%, 0%, 12.5%, respectively, for TGF β ( P < .001). Conclusion Our results suggested that chronic CsA nephrotoxicity may be mitigated by aldosterone receptor blockade which seemed to be associated with down-regulation of PDGF-B and TGF β expression.

Prevention of chronic cyclosporine nephrotoxicity in Sprague Dawely rats: role of colchicine and omega-3-fatty acids

Prevention of chronic cyclosporine nephrotoxicity in Sprague Dawely rats: role of colchicine and omega-3-fatty acids

Activation of Intrarenal Complement System in Mouse Model for Chronic Cyclosporine Nephrotoxicity

PurposeLocal activation of the complement system plays a role in target organ damage. The aim of our study was to investigate the influence of cyclosporine (CsA)- induced renal injury on the complement system in the kidney.Materials and MethodsMice fed a low salt (0.01%) diet were treated with vehicle (VH, olive oil, 1mL/kg/day) or CsA (30mg/kg/day) for one or four weeks. Induction of chronic CsA nephrotoxicity was evaluated with renal function and histomorphology. Activation of the complement system was assessed through analysis of the expression of C3, C4d, and membrane attack complex (MAC), and the regulatory proteins, CD46 and CD55. CsA treatment induced renal dysfunction and typical morphology (tubulointerstitial inflammation and fibrosis) at four weeks.ResultsCsA-induced renal injury was associated with increased the expression of C3, C4d, and MAC (C9 and upregulation of complement regulatory proteins (CD 46 and CD55). Immunohistochemistry revealed that the activated complement components were mainly confined to the injured tubulointerstitium.ConclusionCsA-induced renal injury is associated with activation of the intrarenal complement system.