mycophenolic-acid and Ischemia

Acute renal failure (ARF) is a common cause of mortality and morbidity in hospitalized patients. Ischemia is an important cause of ARF, and ARF caused by ischemic injury is referred to as ischemic acute tubular necrosis (ATN). There is growing evidence from models that ischemic ATN is associated with intrarenal inflammation. Consequently, intrarenal inflammation is an attractive target for the development of novel drug therapies for ARF. This review outlines ischemic ATN models, the pathophysiological roles of inflammatory cells such as T and B cells in ischemic ATN models, and effective T and B cell therapeutic reagents.

Topics: Animals; Anti-Inflammatory Agents; B-Lymphocytes; Cells, Cultured; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression Profiling; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Ischemia; Kidney; Kidney Tubular Necrosis, Acute; Mycophenolic Acid; Oligonucleotide Array Sequence Analysis; T-Lymphocytes

to evaluate the renal toxicity caused by tacrolimus and mycophenolate mofetil (MMF) in a single kidney ischemia and reperfusion model.. experimental study using Wistar rats, submitted to right nephrectomy and left renal ischemia for 20 minutes, separated into groups in the postoperative period (PO): 1) Control (nonoperated); 2) Sham (operated, without PO drug); 3) TAC0.1, TAC1 and TAC10, tacrolimus administered PO at doses of 0.1mg/kg, 1mg/kg and 10mg/kg via gavage, respectively; 4) MMF, administered mycophenolate mofetil 20mg/kg; 5) MMF/TAC1 and MMF/TAC0.5, with an association of mycophenolate mofetil 20mg/kg and tacrolimus 1mg/kg and 0.5mg/kg, respectively. They were killed on the 14th PO and the kidney was removed for tissue oxidative stress analysis, by the dosage of reduced glutathione (GSH), lipoperoxidation (LPO) and protein carbonylation (PCO), and histological analysis by glomerular stereology (Glomerular volume density, Numerical density glomerular and mean glomerular volume). Renal function was evaluated by the measurement of serum creatinine and urea.. both drugs caused alterations in renal function, and the toxicity of tacrolimus was dose-dependent. Subacute toxicity did not show significant glomerular histological changes, and there was renal and compensatory glomerular hypertrophy in all groups except TAC10.. Both drugs cause changes in renal function. Glomerular morphometry and stereology showed negative interference of immunosuppressants during compensatory glomerular hypertrophy.

Topics: Animals; Hypertrophy; Immunosuppressive Agents; Ischemia; Kidney; Mycophenolic Acid; Rats; Rats, Wistar; Reperfusion; Tacrolimus

Tacrolimus and mycophenolate mofetil are immunosuppressive agents widely used on the postoperative period of the transplants.. To evaluate the influence of the association of them on the abdominal wall healing in rats.. Thirty-six Wistar rats were randomly assigned in three groups of 12. On the early postoperative period, four of the control group and three of the experimental groups died. The three groups were nominated as follow: control group (GC, n=8); group I (GI, n=11, standard operation, mycophenolate mofetil and tacrolimus); group II (GII, n=10, standard operation, mycophenolate mofetil and tacrolimus). The standard operation consisted of right total nephrectomy and 20 min ischemia of the left kidney followed by reperfusion. Both NaCl 0.9% and the immunosuppressive agents were administered starting on the first postoperative day and continuing daily until the day of death on the 14th day. On the day of their deaths, two strips of the anterior abdominal wall were collected and submitted to breaking strength measurement and histological examination.. There were no significant differences in wound infection rates (p=0,175), in the breaking strength measurement and in the histological examination among the three groups.. The combination of the immunosuppressive agents used in the study associated with renal ischemia and reperfusion does not interfere in the abdominal wall healing of rats.

Topics: Abdominal Wall; Animals; Immunosuppressive Agents; Ischemia; Kidney; Mycophenolic Acid; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Tacrolimus

Ischaemia/reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), which is characterized by sterile inflammation and oxidative stress. Immune cell activation can provoke overproduction of inflammatory mediators and reactive oxygen species (ROS), leading to perturbation of the microcirculation and tissue oxygenation associated with local and remote tissue injury. This study investigated whether the clinically employed immunosuppressant mycophenolate mofetil (MMF) was able to reduce I/R-induced renal oxygenation defects and oxidative stress by preventing sterile inflammation. Rats were divided into three groups (n=6/group): (1) a sham-operated control group; (2) a group subjected to renal I/R alone (I/R); and (3) a group subjected to I/R and MMF treatment (20 mg/kg prior to I/R) (I/R+MMF). Ischaemia was induced by a vascular occluder placed on the abdominal aorta for 30 minutes, followed by 120 minutes of reperfusion. Renal I/R deteriorated renal oxygenation (P<.001) and oxygen delivery (P<.01), reduced creatinine clearance (P<.01) and tubular sodium reabsorption (P<.001), and increased iNOS, renal tissue injury markers (P<.001), and IL-6 (P<.001). Oral MMF administration prior to insult restored renal cortical oxygenation (P<.05) and iNOS, renal injury markers, and inflammation parameters (P<.001) to near-baseline levels without affecting renal function. MMF exerted a prophylactic effect on renal microvascular oxygenation and abrogated tissue inflammation and renal injury following lower body I/R-induced AKI. These findings may have clinical implications during major vascular or renal transplant surgery.

Topics: Acute Kidney Injury; Animals; Aorta, Abdominal; Disease Models, Animal; Hemodynamics; Immunosuppressive Agents; Ischemia; Kidney; Male; Microcirculation; Microvessels; Mycophenolic Acid; Oxygen Consumption; Rats, Wistar; Renal Circulation; Reperfusion Injury

To evaluate renal histological changes and renal function in single kidney rats submitted to renal ischemia-reperfusion and to immunosuppression with tacrolimus and mycophenolate-mofetil.. Experimental study with 80 Wistar rats distributed into control, Sham and six other groups treated with immunosuppressive drugs. Animals undergoing surgery, right nephrectomy and left renal clamping, killed on the 14th day and analyzed for renal histology, urea and creatinine.. The group receiving tacrolimus at higher doses (T3) showed renal histological lesions indicative of early nephrotoxicity, and significant increase in urea and creatinine. The group M (mycophenolate-mofetil alone) and the group M2 (mycophenolate-mofetil combined with half the usual dose of tacrolimus) presented a slight rise in serum urea. The groups using mycophenolate-mofetil alone or combined with tacrolimus showed creatinine levels similar to that of the group T3.. Histologically, the association of injury by ischemia-reperfusion with the use of tacrolimus or mycophenolate-mofetil alone demonstrated a higher rate of renal changes typical of early nephrotoxicity. In laboratory, the combination of injury by ischemia-reperfusion with tacrolimus at higher doses proved to be nephrotoxic.

Topics: Animals; Calcineurin Inhibitors; Creatinine; Immunosuppression Therapy; Immunosuppressive Agents; Ischemia; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Nephrons; Random Allocation; Rats, Wistar; Reperfusion Injury; Tacrolimus; Time Factors; Urea

Two patients with systemic lupus erythematosus presented with vision loss, and were diagnosed with retinal vasculopathy. Patient 1 had occlusive vasculitis with macular oedema and retinal ischaemia in the right eye. Corticosteroid therapy was increased and intravenous rituximab added. Intravitreal therapy and panretinal photocoagulation were performed. Patient 2 presented with a left central retinal vein occlusion without vasculitis but was on anticoagulation therapy due to having an antiphospholipid syndrome. Both patients maintained a stable visual acuity.. Occlusive lupus retinal vasculitis has severe visual and systemic consequences (central nervous system vasculitis). It is crucial to differentiate it from standard vascular occlusion syndromes.

Topics: Acenocoumarol; Antibodies, Monoclonal, Murine-Derived; Anticoagulants; Antiphospholipid Syndrome; Cataract; Diagnosis, Differential; Female; Fluorescein Angiography; Humans; Immunosuppressive Agents; Ischemia; Lupus Erythematosus, Systemic; Macular Edema; Middle Aged; Mycophenolic Acid; Prednisone; Retinal Vasculitis; Retinal Vein Occlusion; Rituximab; Tomography, Optical Coherence

We investigated a novel allotransplantation model using an aortocava patch in ewes.. We carried out 10 uterine orthotopic allotransplantations in ewes with end-to-side anastomosis of the aortocava donor patch on the left external iliac vessel recipient. The immunosuppressive protocol was a combination of cyclosporine (10 mg/kg/day) and mycophenolic acid (3 g/day). An estimation of the immunosuppressive therapy exposure was performed by measuring the area under the curve (AUC) of immunosuppressive plasma concentrations. The graft was assessed by vaginoscopy, magnetic resonance imaging (MRI) and second look laparotomy at 6, 8 and 10 weeks, respectively. The median (range) times for cold and warm ischemia were 95 min (75-130) and 91 min (55-165), respectively. All the vascular anastomoses were patent at the end of the surgery. The median AUC of cyclosporine and mycophenolic acid were 1.24 mg h/l (0.34-3.85) and 18.40 mg h/l (3.76-42.35), respectively. Of the 10 ewes receiving a transplant, 6 could be assessed. Cervical biopsies showed signs of necrosis in all six ewes. The MRI results correlated with the macroscopic observations of the 'second look' laparotomy. The aortocava vascular pedicles were thrombosed, adding to the peripheral neovascularization. Graft histology showed endometrial tissue in two out of six ewes.. Mobility of the transplant within the pelvis, the length of the vascular pedicle and rejection can explain the high rate of transplant necrosis. The particular digestive anatomy and physiology of ruminants makes it difficult to administer an optimal immunosuppressive treatment. MRI appears to be a good non-invasive examination for graft estimation.

Topics: Animals; Aorta; Area Under Curve; Cyclosporine; Endometrium; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Ischemia; Magnetic Resonance Imaging; Mycophenolic Acid; Sheep; Time Factors; Transplantation, Homologous; Uterus; Vagina

Diabetes mellitus and its complications are a public health problem of epidemic proportions. Both diabetes and chronic kidney disease (CKD) increase the risk of acute kidney injury (AKI). Months after a single episode of acute ischaemia to the diabetic kidney, we have found an accelerated progression of nephropathy, with impaired function, severe renal inflammation, microvascular dysfunction, fibrosis and apoptotic cell death. We termed this entity the post-ischaemic inflammatory syndrome. We now test the hypothesis that blocking inflammation ameliorates the post-ischaemic inflammatory syndrome.. Obese-diabetic ZS rats (F(1) hybrids of spontaneously hypertensive heart failure and Zucker fatty diabetic rats) were treated with mycophenolate mofetil (MMF), subjected to renal ischaemia or sham surgery, and monitored via the powerful technique of intravital microscopy.. Amelioration of post-ischaemia inflammation with MMF therapy improved long-term renal function, microvascular dysfunction, fibrosis and apoptosis.. These data support the hypothesis that the post-ischaemic inflammatory syndrome accelerates diabetic CKD, is a critical determinant of injury, and can be successfully treated.

Topics: Animals; Apoptosis; Blood Flow Velocity; Capillary Permeability; Diabetic Nephropathies; Erythrocyte Aggregation; Fibrosis; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Ischemia; Kidney; Male; Mycophenolic Acid; Nephritis; Rats; Scavenger Receptors, Class E; Syndrome

The present study determined the effect of immune suppression with mycophenolate mofetil (MMF) on sodium-sensitive hypertension following recovery from ischemia reperfusion (I/R)-induced acute renal failure. Male Sprague-Dawley rats fed 0.4% NaCl chow were subjected to 40 min bilateral I/R or control sham surgery. After 35 days of recovery, when plasma creatinine levels had returned to normal, the rats were switched to 4.0% NaCl chow for 28 days and administered vehicle or MMF (20 mg.kg(-1).day(-1) ip). High-salt mean arterial pressure was significantly higher in I/R rats (144 +/- 16 mmHg) compared with vehicle-treated sham rats (122 +/- 2 mmHg). Treatment of I/R rats with MMF during the period of high salt intake prevented the salt-induced increase in arterial pressure (114 +/- 3 mmHg). Conscious creatinine clearance was lower in I/R rats (0.27 +/- 0.07 ml.min(-1).100 g body wt(-1)) compared with vehicle-treated sham rats (0.58 +/- 0.04 ml.min(-1).100 g body wt(-1)); MMF treatment prevented the decrease in creatinine clearance in I/R rats (0.64 +/- 0.07 ml.min(-1).100 g body wt(-1)). I/R injury also significantly increased glomerular tissue damage and increased the presence of ED-1 positive (macrophages) and S100A4 positive cells (fibroblasts) in the renal interstitium. The I/R rats treated with MMF exhibited a significant reduction in infiltrating macrophages and fibroblasts and decreased histological damage. The present data indicate that infiltrating immune cells mediate or participate in the development of sodium-sensitive hypertension and renal damage in rats apparently recovered from renal I/R injury.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Cell Movement; Creatinine; Disease Models, Animal; Fibroblasts; Hypertension; Immunosuppressive Agents; Ischemia; Kidney; Macrophages; Male; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sodium Chloride, Dietary; Time Factors

Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agent in transplantation. Kidney grafts undergo more or less prolonged cold ischemia after harvesting which results in variable degrees of ischemia reperfusion injury. To determine whether the inhibition of early events of cellular infiltration may influence the severity of damage induced by ischemic acute renal failure, 45 Sprague Dawley rats were given MMF at a dose of 20mg/kg/day (MMF-rats) by gavage 2 days before (pre-MMF group, n=15) or after (post-MMF group, n=15) clamping the left renal artery for 40 minutes followed by rigt-sided nephrectomy. (control group, n=15) received vehicle. Serum Creatinine (Screat) was measured daily in all groups. On the 2nd post-ischemic day Screat was significantly lower (p=0.001) in pre-MMF group compared with post-MMF group and control group (4 +/- 2mg/dl post-MMF group vs 1.7 +/- 1.2 mg/dl pre-MMF group, control group 5+/-2, p< 0.05). Kidney biopsies shown that the histologic damage was 54 +/- 28% in post-MMF group vs 34+/- 22% in pre-MMF group and 61 +/- 25% in control group (pre-MMF vs post-MMF, p NS). On the 5th day post-ischemic, MMF-rats showed more severe tubulointerstitial necrosis (pre-MMF group: 17 +/- 20 %, post-MMF group: 33 +/- 27%) than controls (4 +/- 5%). The severity of ATN was significantly higher in post-MMF group compared with controls (p=0.01). Tubulointersticial T-lymphocyte (T CD 5) and monocyte (ED 1) infiltration evaluated on the 2nd post-ischemic day was less intense in group I (T CD5: 3 +/- 3, ED 1: 10 +/- 9, cel/mm2) compared to post-MMF group (T CD 5: 10 +/- 4, ED 1: 55 +/- 40) and to control group (T CD 5: 10+/- 4, ED 1: 64 +/- 46). However, on the 5th post-ischemia day, ED 1 infiltration was significantly higher in post-MMF group (24 +/- 18%) compared to pre-MMF group (5 +/- 5, p NS) and also in pre-MMF group vs control group (31 +/- 33, p< 0.05). Our results suggest that MMF given before a renal ischemic insult may reduce the severity of histologic damage resulting from ischemia reperfusion injury.

Topics: Acute Kidney Injury; Animals; Immunosuppressive Agents; Ischemia; Kidney; Male; Mycophenolic Acid; Rats; Rats, Sprague-Dawley

In order to evaluate whether immunosuppressive agents such as mycophenolate mofetil (MMF) and azathioprine would differently influence the outcome of the renal transplants, we prospectively analyzed the incidence of acute rejection episodes, cytomegalovirus infection within the first 6 months following renal transplantation and 5 yr graft survival rate after minimizing influences of donor factors by grafting the same cadaveric donor kidney. There was no significant difference in sex, HLA mismatch, cold ischemic time, and patients' weight between the two groups. Contrary to the previous studies which demonstrated that MMF could lower the incidence of acute rejection episodes and improved graft survival rate, the two groups showed no significant difference in the incidence of acute rejection episodes and 5-yr graft survival rate as well. This discrepancy in these results might explain that donor factors could be important to cadaveric renal transplantation. Thus, we suggest that the influences of donor factors should be considered in further clinical studies of cadaveric renal transplantation.

Topics: ABO Blood-Group System; Adult; Azathioprine; Body Weight; Cadaver; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunophenotyping; Immunosuppressive Agents; Ischemia; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Time Factors; Tissue Donors; Treatment Outcome

Cellophane wrapping of the kidneys (Page kidney) induces perinephrits and hypertension, assumed to be due to renal ischemia resulting from parenchymal compression by the fibrous hull surrounding the kidneys. We investigated if interstitial nephritis, rather than plasma angiotensin activity, played a role in the development of hypertension in the Page kidney model.. We followed for 7 weeks rats with bilateral cellophane wrapping of the kidneys that received 20 mg/kg/day of the immunosuppressive antiproliferative drug mycophenolate mofetil (MMF) (two-kidney wrap/MMF) (N = 10) or vehicle (two-kidney wrap) (N = 10), and sham-operated rats (N = 10).. The two-kidney wrap group had progressive increment in blood pressure, inflammatory damage occupying 25% to 50% of the renal tubulointerstitial region and increased number of angiotensin II-positive cells, angiotensin II content, and oxidative stress in the kidney. MMF treatment prevented the development of hypertension and renal inflammation without modifying the perinephritic hull or the increment it induced in the intrarenal pressure. The plasma levels of angiotensin II were similar in the two-kidney wrap group, the two-kidney wrap/MMF group and the sham-operated animals and unchanged from baseline, despite the blood pressure increase in the two-kidney wrap group.. Our results indicate that renal wrap hypertension is unrelated to plasma angiotensin II levels and related to the inflammatory damage caused by the external compression of the kidney.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Cellophane; Disease Models, Animal; Glutathione; Hypertension, Renal; Immunosuppressive Agents; Ischemia; Kidney; Kidney Function Tests; Male; Malondialdehyde; Mycophenolic Acid; Nephritis, Interstitial; Pressure; Rats; Rats, Sprague-Dawley

Immunosuppressive agents may have an impact on ischemia/reperfusion (I/R) injury. The immunosuppressant mycophenolate mofetil (MMF) presents properties that can attenuate such injury. This study investigated the effects of MMF on renal I/R injury. Male Wistar rats received MMF (20 mg/kg per d) or vehicle by gavage beginning 2 d before ischemia and maintained during the entire study. Ischemic injury was induced by bilateral renal arteries occlusion for 60 min. Control rats received MMF and underwent sham operation. At days 1, 2, and 14, post-ischemia renal function was assessed and kidneys were removed for histologic and immunohistochemical studies. MMF given to nonischemic rats did not alter renal function. There was no functional protection at 24 h post-ischemia with MMF. At 2 d, post-ischemia rats pretreated with MMF presented higher inulin clearance compared with untreated rats (0.42 +/- 0.04 versus 0.15 +/- 0.02 ml/min per 100 g; P < 0.001) and attenuated renal blood flow decrease (5.23 +/- 0.28 versus 3.24 +/- 0.37 ml/min; P < 0.01). The immunostaining for intercellular adhesion molecule-1 (ICAM-1) was less intense in rats pretreated with MMF. These rats also presented an earlier decreased infiltrating macrophages/lymphocytes and cell proliferation at day 1 post-ischemia. The functional and immunohistochemical analyses performed at day 14 post-ischemia returned to values similar to controls in both groups of rats. To determine whether mycophenolic acid (MPA) could induce cytoprotection, the effects of MPA on normoxic and hypoxic/reoxygenated (H/R) isolated tubule suspensions were also investigated. MPA was not deleterious to normoxic tubules and it was not protective against H/R tubules. In conclusion, pretreatment with MMF attenuates I/R injury in rats and does not limit the recovery from ischemia. The protective effect of MMF by reducing inflammation precedes the hemodynamic changes and tubular injury.

Topics: Acute Kidney Injury; Animals; Ectodysplasins; Immunohistochemistry; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Ischemia; Kidney; Kidney Tubules, Proximal; L-Lactate Dehydrogenase; Lymphocytes; Male; Membrane Proteins; Mycophenolic Acid; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Renal Circulation; Reperfusion Injury

Topics: Acute Kidney Injury; Animals; Disease Progression; Immunosuppressive Agents; Ischemia; Kidney Transplantation; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Renal Circulation

Mycophenolate mofetil (MMF) is a new immunosuppressive agent which has been used successfully after kidney and heart transplantation. Experience with MMF after liver transplantation is still limited. In particular, there is no information about influence on ischemia-reperfusion injury (IRI). Therefore, the aim of this investigation was to assess the effects of mycophenolic acid (MPA), the pharmacologically active metabolite of MMF, in the cold-preserved or normal rat liver. Livers of male Sprague-Dawley rats were subjected to cold ischemia in University of Wisconsin (UW) solution (24 h, 4 degrees C) and reperfused for 2 h in the absence or presence of MPA (100 microg/ml, n=5-6 each). Another group received MPA pretreatment for 20 min prior to ischemia ( n=7). In further experiments, livers were perfused with a bile salt-free Krebs-Henseleit buffer in a continuous fashion (controls, n=5). MPA was infused from 20-40 min after starting perfusion in therapeutic concentrations (5 microg/ml, 10 microg/ml, 40 microg/ml, and 100 microg/ml; n=3-6 each). There was no significant influence of MPA on portal pressure nor on postischemic efflux rates of LDH. MPA pretreatment resulted in a significant improvement of bile flow during reperfusion (0.32+/-0.05 microl/min x g liver) compared with controls (0.17+/-0.04 microl/min x g liver, mean+/-SEM). In contrast, postischemic bile flow was not influenced by continuous administration of MPA during the reperfusion period only (0.18+/-0.07 microl/min x g liver). In continuously perfused livers, MPA increased bile salt-independent bile flow (1.00+/-0.06 microl/min x g liver) in a dose-dependent manner, reaching half-maximal effects around 5 microg/ml (1.66+/-0.15 microl/min x g liver) and maximal effects at 40 microg/ml (2.61+/-0.28 microl/min x g liver). In conclusion, neither preischemic nor postischemic administration of MPA influences IRI to hepatocytes significantly after hypothermic liver preservation in UW solution. In contrast to other immunosuppressive agents, MPA exhibits strong choleretic effects, which are related to a stimulation of bile salt-independent bile formation.

Topics: Animals; Bile; Cold Temperature; Immunosuppressive Agents; Ischemia; L-Lactate Dehydrogenase; Liver; Male; Mycophenolic Acid; Organ Preservation; Perfusion; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Recent animal data suggest that inducible nitric oxide synthase (iNOS) derived nitric oxide (NO) plays an important role in the pathogenesis of renal ischaemia-reperfusion injury (IRI) and that inhibition of iNOS ameliorates IRI. Mycophenolate mofetil (MMF), a lymphocyte selective anti-proliferative agent, has been shown to inhibit NO production in vitro. The aim of this study is to evaluate the effect of MMF on NO production and iNOS gene expression in vivo during renal IRI.. Renal IRI was induced by clamping the left renal pedicle of male BALB/c mice for 30 min, followed by 15 min of reperfusion. The mice received placebo or MMF at 40, 80 or 120 mg/kg/day by oral gavage for 5 days before the operation. Sham-operated mice served as the operation control. The amount of NO produced and the level of iNOS gene expression in the kidney tissue during IRI was assessed by spin trapping electron paramagnetic resonance (EPR) spectroscopy and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) respectively.. In the sham-operated kidneys, only low levels of NO and iNOS mRNA were detected. In mice with renal IRI, the amount of NO detected was significantly increased, which was reduced in a dose dependent fashion by pre-treatment with MMF. Pre-treatment with MMF also substantially reduced iNOS gene expression in the kidney tissue.. We conclude that pre-treatment with MMF inhibits the production of NO and the induction of iNOS gene expression in the kidney during IRI. These results suggest that MMF might have the potential to ameliorate renal IRI.

Topics: Animals; Gene Expression; Ischemia; Male; Mice; Mice, Inbred BALB C; Mycophenolic Acid; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Renal Circulation; Reperfusion Injury

Chronic renal allograft nephropathy is associated with both immune and ischemic injury which may act synergistically to promote an inflammatory response. The immunosuppressant mycophenolic acid and the polyphenolic agents curcumin and quercetin possess properties that might ameliorate such injury. We studied the effects of these agents in models of ischemic renal injury and skin allograft rejection.. Ischemic acute tubular necrosis was produced in rats by renal pedicle occlusion with contralateral nephrectomy. Animals were treated with mycophenolic acid, quercetin and curcumin, or a combination of agents. Animals were killed on days 2 and 7 after operation and tissue samples were collected. Renal tubular apoptosis and cellular proliferation were assessed by immunohistochemistry. Expression of the cytokines RANTES and AIF were evaluated by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR).. Treatment with the polyphenolic compounds alone or in combination with mycophenolic acid was associated with less tubular damage, attenuation of renal inflammation, and prolongation of skin graft survival. A combination of agents decreased serum creatinine on day 2 from 4.5 to 0.9 mg./dl. (p< or =0.01) and at day 7 from 3.8 to 0.6 mg./dl. (p< or =0.01). Treatment with the polyphenolic compounds inhibited apoptosis at day 2. By RT-PCR, RANTES and AIF were detected at high levels on days 2 and 7. Treatment with these agents alone or in combination strongly attenuated this increased expression.. The combination of mycophenolic acid with curcumin and quercetin reduces renal injury and facilitates repair. These agents may have a role in therapeutic regimens that are both immunosuppressive and renoprotective.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokine CCL5; Curcumin; Gene Expression Regulation; Graft Rejection; Immunohistochemistry; Immunosuppressive Agents; Ischemia; Kidney; Male; Mycophenolic Acid; Nephritis; Quercetin; Rats; Rats, Sprague-Dawley; Skin Transplantation

Topics: Animals; Curcumin; Drug Synergism; Flavonoids; Graft Rejection; Immunosuppressive Agents; Ischemia; Kidney; Male; Mycophenolic Acid; Quercetin; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Skin Transplantation

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Ischemia; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prednisolone; Radiography; Splanchnic Circulation; Tacrolimus

Intracellular ATP depletion is a hallmark event in ischemic injury. It has been extensively characterized in models of chemical anoxia in vitro. In contrast, the fate of GTP during ischemia remains unknown. We used LLC-PK proximal tubular cells to measure GTP and ATP changes during anoxia. In 45 min, antimycin A decreased ATP and GTP to 8% and 2% of controls, respectively. Ischemia in vivo resulted in comparable reductions in GTP and ATP. After 2 h of recovery, GTP levels in LLC-PK cells increased to 65% while ATP increased to 29%. We also investigated steady-state models of selective ATP or GTP depletion. Combinations of antimycin A and mycophenolic acid selectively reduced GTP to 51% or 25% of control. Similarly, alanosine selectively reduced ATP to 61% or 26% of control. Selective GTP depletion resulted in significant apoptosis. Selective ATP depletion caused mostly necrosis. These models of ATP or GTP depletion can prove useful in dissecting the relative contribution of the two nucleotides to the ischemic phenotype.

Topics: Adenosine Triphosphate; Alanine; Animals; Antibiotics, Antineoplastic; Antimycin A; Apoptosis; Cell Hypoxia; Cells, Cultured; Deoxyglucose; Enzyme Inhibitors; Guanosine; Guanosine Triphosphate; Ischemia; Kidney Cortex; Kidney Tubules, Proximal; LLC-PK1 Cells; Male; Models, Biological; Mycophenolic Acid; Necrosis; Oxidative Phosphorylation; Rats; Rats, Sprague-Dawley; Swine

Topics: Colitis; Colon; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Ischemia; Kidney Transplantation; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Tacrolimus