VALIDATION OF HOUSEKEEPER GENES FOR NORMALISATION FOR RT-qPCR GENE EXPRESSION STUDIES IN ISCHAEMIC AND TOXICOLOGICAL CONDITIONS IN RAT MODELS

S HERATH1, K TAYLOR1, A AU2, L SUCCAR1, Z  ENDRE2, J  ERLICH1
1University Of New South Wales , Kensington , Australia, 2Prince of Wales hospital, Randwick, Australia

Aim: To identify the most stably expressed housekeeper genes (HKG’s) under ischaemic and nephrotoxic conditions in various rat kidney models.
Background: Appropriate selection of housekeeper genes is pivotal to obtain accurate results in real time PCR. A number of studies have identified that the transcription levels of most commonly used HKG’s vary considerably under different experimental conditions.
Methods: Control and adenine fed Sprague Dawley (SD) rats were equally divided into 6 intervention groups each consisting of 8 biological replicates. The intervention groups were, subclinical CKD (sCKD), acute kidney injury (AKI) only, AKI on a background of sCKD, chronic kidney disease (CKD) and a control group. sCKD was induced with adenine and AKI was induced with cisplatin or ischaemia. 10 commonly used candidate HKG’s from different functional classes were selected. The cycle threshold (Ct) value for each gene was determined and data obtained were analyzed utilizing NormFinder, Genorm, BestKeeper and comparative delta Ct statistical algorithms.
Results: Polyadenylate-binding nuclear protein 1 (PABPN1) and hydroxymethylbilane synthase (HMBS) were determined to be the most stable by all 4 algorithms. Bestkeeper/Genorm and Normfinder/comparative delta Ct approach respectively ranked succinate dehydrogenase (SDHA) and tyrosine-3-monooxygenase/tryptophan 5-monooxygenase-activation protein zeta (YWHAZ) as the third most stable HKG. A normalisation factor constructed by calculating the geometric mean of the three most stable HKG’s showed the least variability across the experimental groups. In comparison, the commonly used GAPDH and 18S were the least stable of all 10 HKG’s studied.
Conclusions: Construction of a normalisation factor by utilizing two or three most stable HKG’s which includes HMBS and PABPN1 produces the least variability to control for experimental errors and adjust for inter-sample variations in rat kidney studies.


Biography:
Fellow of the Royal Australasian College of Physicians and curently doing a PhD under the supervision of Professor Zoltan Endre and Dr Jonathan Erlich. Focus of current research is on ischaemia reperfusion injury especially in  the area of transplantation. Actively engaged in teaching at University of New South Wales and at Prince of Wales hospital, Randwick.

 

THE ENDOTHELIAL GLYCOCALYX IS DAMAGED WITH WORSENING KIDNEY DISEASE AND CORRELATES WITH MARKERS OF ENDOTHELIAL DYSFUNCTION

H LIEW1,2, M ROBERTS1,2, L MCMAHON1,2
1Department of Renal Medicine, Box Hill, Australia, 2Monash University, Melbourne, Australia

Background: Damage to the endothelial glycocalyx (EG) is an early indicator of vascular damage and a potential marker of endothelial dysfunction. EG damage is detected by biochemical markers and an increase in the perfused boundary region (PBR) in the sublingual capillaries using the novel Glycocheck device.
Aim: We aimed to assess EG damage in patients with kidney disease by measuring the PBR and biochemical markers of EG, and correlating it with markers of endothelial dysfunction (ED) and microalbuminuria.
Methods: Healthy controls, CKD patients (eGFR 15-60mL/min), dialysis patients, and kidney transplant recipients had blood taken for syndecan-1 (EG marker), vascular cell adhesion molecule, VCAM-1 (marker of ED), urine for albumin:creatinine ratio (uACR) and a PBR measurement performed.
Results: Median (interquartile range) ages were 35 (22-69), 71 (37-90),  67 (25-82) and 55 (34-77), p<0.001 years in the control (n=28), CKD (n=33), dialysis (n=33) and transplant (n=30) groups, respectively. Mean eGFR was 89±6, 31±11, 7±4, and 59±14 mL/min (p<0.001) and median uACR was 0.4 (0-2), 37 (0-730), 44 (5-642) and 5 (0-35) mg/mmol (p<0.001), respectively. Serum markers of EG damage and ED were highest in the dialysis group. Median syndecan-1 levels were 26 (10-146), 39 (18-160), 81 (40-530), and 38 (24-67) ng/L (p<0.001), respectively. Mean VCAM levels were 675±211, 1146±468, 1658±552, and 927±254 ng/mL (p<0.001), respectively. There was no difference detected in PBR (2.04±0.31, 2.05±0.28, 2.01±0.35, and 2.06±0.28µm, respectively, p=0.925). Syndecan-1 positively correlated with VCAM (r=0.434, p<0.001) and uACR (r=0.403, p<0.001).
Conclusion: Markers of the EG and ED are closely correlated, and are highest in dialysis patients, followed by CKD and transplant patients compared to controls. No difference in PBR was detected.


Biography:
Renal Research Fellow

TARGETING CD103+ DENDRITIC CELLS USING FLT3 INHIBITORS FOR TREATMENT OF KIDNEY DISEASE; RELEVANCE TO HUMAN KIDNEY DISEASE.

T CHEN1,2,3, Q CAO1,2, R WANG1,2, P RAO1,2, G ZHENG1,2, V LEE1,2,3, N ROGERS1,2,3, M PATEL1,3, CH P’NG1,3, H YU2, S ALEXANDER4, Y WANG1,2, D HARRIS1,2,3
1University of Sydney, Westmead, Australia, 2The Westmead Institute for Medical Research, Westmead, Australia, 3Westmead Hospital, Westmead, Australia, 4Children’s Hospital at Westmead, Westmead, Australia

Aim: 1- To examine CD141+ dendritic cells (DCs; human homologue of CD103+ DCs) in human kidney diseases.
2- To explore the role of CD103+ DCs and therapeutic potential of targeting CD103+ DCs by repurposing Flt3 inhibitors in experimental kidney diseases
Background: Whereas CD103+ DCs were previously considered to be a minor DC subset in kidney disease, we and others have proven that they have a major role. Flt3 is a receptor specifically expressed on tissue CD103+ DCs. Flt 3 inhibitors are currently used for cancer treatment.
Methods: A human study included 294 kidney biopsies from 01/07/2016 to 01/04/2017. For animal experiments, we used murine Adriamycin Nephropathy (AN), anti-GBM disease and ischaemia reperfusion injury (IRI).
Results: In humans, the number and proportion of CD141+ DCs were significantly increased in proliferative glomerulonephritis and acute tubular necrosis (ATN). CD141+ DCs were found mainly in tubulointerstitium, except in lupus nephritis where they were also present in glomeruli. CD141+ DC numbers correlated with increasing severity of ATN (P<0.001) as well as fibrosis in IgA nephropathy (P=0.025), but not diabetic nephropathy. In murine AN, anti-GBM disease and IRI, the number and proportion of kidney CD103+ DCs were significantly increased. In AN, CD103+ DCs played a pathogenic role through activation of CD8+ T cells. Treatment with a Flt3 inhibitor specifically depleted CD103+ DCs and significantly reduced renal injury. The effect of Flt3 inhibition is currently being studied in anti-GBM disease and IRI.
Conclusions: Kidney CD103+ DC numbers correlate with severity of human kidney disease. Targeting CD103+DCs with Flt3 inhibitors effectively reduces renal injury in experimental kidney disease, suggesting a novel therapeutic strategy with accelerated translational potential through drug repurposing.


Biography:
Dr Titi Chen is a nephrology fellow and NHMRC postgraduate scholar. She has a passion for research and is currently completing her PhD through the University of Sydney.

NADPH-OXIDASE NOX5 AGGRAVATES RENAL INJURY IN THE AKITA MOUSE MODEL OF DIABETIC NEPHROPATHY

J JHA1, R TOUYZ2, C KENNEDY3, M COOPER1, K JANDELEIT-DAHM1
1Department Of Diabetes, Melbourne, Australia, 2Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom, 3Department of Medicine, Ottawa Hospital Research Institute, Ottawa, Canada

Background: Renal reactive oxygen species (ROS) play an important role in mediating kidney injury in diabetes. Increasing evidence suggests that the pro-oxidant enzyme, Nox5 plays a significant role in human diabetic nephropathy (DN). Nox5 is present in humans and rabbits but not in mice or rats. Thus, there is a paucity of information about Nox5 in conventional animal models of DN. We examined the role of Nox5 in the insulin deficient diabetic Akita mice model using human inducible transgenic mice that express Nox5 selectively in endothelial cells (VEcad+Nox5+) or in mesangial cells (SM22+Nox5+).
Methods: At week 10 mice were culled and kidneys were removed for the assessment of structural damage as well as gene and protein expression of markers of inflammation, fibrosis and oxidative stress. Protein expression of Nox5 and its localization in glomerular cells (endothelial and mesangial cells) were examined in transgenic mice by immunostaining.
Results: Expression of Nox5 was confirmed in glomerular endothelial and mesangial cells of transgenic mice. Diabetes induced increase in glomerulosclerosis, gene and protein expression of fibronectin and MCP-1 as well as nitrotyrosine were further increase in both diabetic Nox5 transgenic mice.
Conclusions: These findings suggest that Nox5 expression in endothelial or mesangial cells in an streptozotocin independent model of type 1 diabetes is associated with increased ROS production and accelerates renal injury in diabetes.


Biography:
Prof Jandeleit-Dahm is a physician scientist  and nephrologist. Her main research focus is the role of reactive oxygen species in the kidney and in cardiovascular complications of diabetes.

CYCLOPHILIN INHIBITION ATTENUATES RENAL FIBROSIS IN THE OBSTRUCTED KIDNEY

KG LEONG1,2, E OZOLS1,2, J KANELLIS1,2, J LILES3,D NIKOLIC-PATERSON1,2, F MA1,2
1Department of Nephrology, Monash Medical Centre, Clayton, Australia, 2Centre for Inflammatory Disease, Monash University, Clayton, Australia, 3Gilead Sciences, Foster City, USA

Aims: Determine whether therapeutic inhibition of cyclophilin (Cyp) function can suppress renal fibrosis in unilateral ureteric obstruction (UUO) and if cyclophilin A (CypA) has a specific role in this response.
Background: Cyclophilins are enzymes that regulate protein folding. Within this enzyme family, CypA promotes leukocyte recruitment and inflammation while CypD facilitates mitochondrial-dependent cell death. However, the role of cyclophilins in renal fibrosis is poorly understood.
Methods: C57BL/6J mice underwent UUO surgery and were killed on day 7; groups (n=10) were treated with 30mg/kg/BID of a pan-cyclophilin inhibitor (CYPi, which does not block calcineurin function) or vehicle by oral gavage from 1hr before surgery and continued to day 7. In addition, groups (n=10) of CypA-/- and wild type mice were killed on day 7 post-UUO. Controls had no UUO surgery.
Results: Compared to vehicle, CYPi treatment significantly reduced renal fibrosis in the obstructed kidney based on ↓37% collagen IV and ↓22% α-SMA staining area (P<0.01 vs vehicle) and reduced mRNA levels of α-SMA, collagen I, III and IV and TGF-b1 (all P<0.01 vs vehicle). CYPi treatment also reduced TUNEL+ apoptotic tubular cells by 60%, and reduced macrophage infiltration (P<0.001 vs vehicle). By contrast, CypA-/- mice showed no difference in renal fibrosis or in the infiltration of macrophages or T cells compared to wild type UUO mice.
Conclusions: Cyclophilins contribute to the development of renal fibrosis, inflammation and tubular apoptosis in obstructed kidney, although this does not involve CypA. Therapeutic targetting of cyclophilins, independent of calcineurin function, has potential for the treatment of renal fibrosis.


Biography:
Nephrologist undergoing my lab-based PhD studies at Department of Nephrology, Monash Health.

RARE VARIANTS IN BLK CONTRIBUTE TO THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

S JIANG1,2,3, V ATHANASOPOULOS1,2, J ELLYARD1,2, A CHUAH4, J CAPPELLO1,2, S PRABHU1, J CARDENAS5, J GU5, J ROCO1,2, I PAPA1,2, M YABAS1, G WALTERS1,2,3, G BURGIO1, K  MCKEON1,2, A ENDERS1,2, P CANETE1,2, S  ALEXANDER2,6, A KITCHING2,7, N SHEN8, J BABON9, M FIELD2, T ANDREWS2, V PASCUAL5, M COOK1,2, C VINUESA1,2
1Department of Immunology and Infectious Disease, ANU, Australia, 2Centre for Personalised Immunology, ANU, Australia, 3Department of Renal Medicine, The Canberra Hospital, Canberra, Australia, 4Genome Informatics Laboratory, ANU, Australia, 5Baylor Medical Institute, , Baylor, USA, 6Westmead Children’s Hospital, Sydney, Australia, 7Centre for Inflammatory Diseases, Department of Medicine, Monash University , Melbourne, Australia, 8China Australia Centre for Personalised Immunology, Renji Hospital, JiaoTong University, Shanghai , China, 9Walter and Eliza Hall Institute,, Melbourne, Australia

Aim: To assess the contribution of rare genetic variants in BLK to SLE
Background: SLE is a relapsing autoimmune disease of which excessive Type 1 Interferon (T1IFN) production is central to SLE pathogenesis. Genetics represent one of the most potent risk factors for SLE, yet no GWAS-associated variant has a proven contribution to pathophysiology. Although BLK is reproducibly associated with SLE by GWAS, its mechanism remains unelucidated.
Methods: SLE patients and controls underwent whole exome sequencing. BLK, BLK variants and interacting partners were purchased or generated with site directed mutagenesis. IRF5 interaction and phosphorylation was tested by western blot. IFNb activity was measured using a dual luciferase assay in HEK293T and CRISPR-Cas9 engineered Ramos cells. Patient lymphocyte RNA profiling was performed by microarray with QuSAGE algorithm analysis.
Results: Seven unique rare BLK SNPs were found in 22.9% (n=20/87) of SLE patients compared with 6.2% (n=6/97, p<0.0001) of healthy controls or 2.8% (n=3/102, p<0.002) of an immunodeficiency cohort. Computational modelling predicted these SNPs disrupted residues critical to BLK function. Overexpression confirmed significant impairment of kinase ability of BLK SNPs. Similar to the related Src-kinase LYN, wildtype BLK was capable of interacting with and repressing IRF5-mediated IFNb production, although BLK SNPs impaired repression of IFNb expression. CRISPR-Cas9 engineered BLK mutation into Ramos cells resulted in enhanced IFNb expression in response to R848 stimulation. Microarray confirmed increased T1 IFN responsive gene expression in SLE patients with BLK SNPs.
Conclusions: Rare variants in BLK are observed at high frequency in SLE patients. These variants are deleterious, altering protein function enhancing T1IFN expression directly linking genetic variation in BLK to SLE pathogenesis.

FOLLISTATIN MODULATES ISCHAEMIA-REPERFUSION-INDUCED RENAL FIBROSIS IN MICE

D FANG1,2, B LU1, S HAYWARD3 D DE KRETSER3,4, P COWAN1,2, K DWYER2

1Immunology Research Centre, St. Vincent’s Hospital Melbourne, Victoria; 2Department of Medicine, the University of Melbourne, Victoria; 3Hudson Institute of Medical Research, Victoria; 4Monash University, Clayton, Victoria

Aim: To examine the therapeutic potential of follistatin in renal fibrosis.

Background: Activin and its binding protein, follistatin, play critical roles in the regulation of inflammation and fibrosis. Activins are upregulated in ischaemia-reperfusion injury (IRI). Injection of a viral vector carrying the follistatin gene (rAAV-FS) results in sustained elevation of circulating follistatin in mice and attenuates ischaemia-reperfusion-induced acute kidney injury.

Methods: 2 groups of mice underwent renal IRI surgery. Group 1 had rAAV-FS or empty-vector (control) injected 4 weeks before IRI (to ensure elevated follistatin levels at the time of injury). Group 2 had the vectors injected immediately before IRI (i.e. normal follistatin levels at the time of injury, but increasing thereafter). Mice were sacrificed 4 weeks post-reperfusion. Serum activin, follistatin and creatinine, Masson’s stained kidney sections and pro-fibrotic markers were assessed.

Results: Four weeks post-IRI, control mice had increased expression of pro-fibrotic markers (TGFβ-1, p<0.01; connective tissue growth factor (CTGF), p<0.05; collagen I, p<0.01; collagen IV, p<0.01), renal fibrosis (p<0.01), and serum creatinine (p<0.01). Compared to control mice, rAAV-FS treated IRI mice had 6-fold increase in circulating follistatin levels (p<0.0001) with associated reductions in activin A and B (p<0.001). rAAV-FS treated IRI mice in group 1 had significant reduction in expression of pro-fibrotic markers (TGFβ-1, p<0.05; CTGF, p<0.05; collagen I, p<0.01; collagen IV, p=0.05), renal fibrosis (p<0.01), and serum creatinine (p<0.05). However, rAAV-FS treated IRI mice in group 2 did not have statistically significant reduction in pro-fibrotic markers, renal fibrosis (p=0.06) and serum creatinine.

Conclusions: Elevated follistatin around IRI seems crucial to protect against renal fibrosis development. These data suggest early post-IRI may be the key period that follistatin acts to modulate renal fibrosis.

DOMINANT HLA-MEDIATED PROTECTION FROM THE RISK OF AUTOIMMUNE RENAL DISEASE IS CONFERRED BY ANTIGEN-SPECIFIC REGULATORY CELLS

OOI JD1, PETERSEN J2, TAN YH2, HUYNH M1, WILLETT ZJ1, RAMARATHINAM SH2, EGGENHUIZEN PJ1, LOH KL2, WATSON KA3, GAN PY1, ALIKHAN MA1, DUDEK NL2, HANDEL A4, HUDSON BG5, FUGGER L6, POWER DA7, HOLT SG8, COATES PT9, GREGERSEN JW10, PURCELL AW2, HOLDSWORTH SR1,11, LA GRUTA NL2,3, REID HH2, ROSSJOHN J2, KITCHING AR1,11

1Monash University Centre for Inflammatory Diseases, Clayton, VIC, 2 Monash University Biomedicine Discovery Institute, Clayton, VIC, 3 Dept. of Microbiology and Immunology, Melbourne University, Melbourne, VIC, 4 University of Georgia, GA, USA, 5 Vanderbilt University, TN, USA, 6 University of Oxford, Oxford, UK, 7 Dept. of Nephrology, Austin Health, Heidelberg, VIC, 8 Dept. of Nephrology, Melbourne Health, Parkville, VIC, 9 Royal Adelaide Hospital, Adelaide, SA, 10 Dept. of Medicine, Viborg Regional Hospital, Viborg, Denmark, 11 Dept. of Nephrology, Monash Health, Clayton, VIC.

Aim: To use Goodpasture’s disease (GPD), a classical form of HLA-linked autoimmunity, to define the mechanism of HLA-mediated risk, and dominant protection from risk of disease.

Background: The mechanisms underpinning HLA-mediated susceptibility to, and protection from autoimmune diseases are unknown. GPD is HLA-linked and characterised by an immunodominant CD4+ self-epitope derived from the a3 chain of Type IV collagen (a3135-145).

Methods: HLA-DR transgenic mice, cells from HLA-typed healthy humans and from patients with GPD were used, with HLA-DR-a3135-145 tetramers, X-ray crystallography, and in vivo/in vitro models of autoimmunity.

Results: Autoreactive a3135-145-specific T cells clonally expanded in GPD patients. In a3135-145-immunised HLA-DR15 transgenic mice with GPD, a3135-145-specific T cells infiltrated the kidney. Structurally, HLA-DR15 and HLA-DR1 presented a3135-145 in different binding registers, resulting in differential T cell receptor (TCR) usage. HLA-DR15-a3135-145 tetramer+ CD4+ T cells in disease susceptible HLA-DR15 transgenic mice exhibited a conventional phenotype (Tconv), secreting pro-inflammatory cytokines. In contrast, HLA-DR1-a3135-145 tetramer+ cells in disease resistant HLA-DR1 and HLA-DR15/DR1 transgenic mice were largely CD4+Foxp3+ regulatory T cells (Tregs) expressing tolerogenic cytokines. In HLA-DR15/DR1 transgenic mice, HLA-DR1-a3135-145 specific Tregs conferred protection to a3135-145-specific autoimmunity and protected from GPD (a3135-145-immunised, Treg intact vs Treg depleted: segmental necrosis 0±0 vs 50±13% P<0.01, serum urea 9±1 vs 31±10 P<0.001). HLA-DR15+ and HLA-DR1+ healthy human donors displayed altered a3135-145-specific TCRs, with HLA-DR15-a3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-a3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes (a3135-145 tetramer+ Treg:Tconv ratios: DR15 0.04±0.00, DR1 9.61±1.79, P<0.001).

Conclusions: These studies define, for the first time in an autoimmune disease, a mechanism for the dominantly protective effect of HLA, where HLA polymorphisms determine the abundance of self-epitope specific Tregs, leading to protection or causation of autoimmunity.

A PERIPHERALLY ACTING CANNABINOID RECEPTOR 1 ANTAGONIST SUPPRESSES RENAL INTERSTITIAL FIBROSIS

FY MA1,2, E OZOLS1,2, P CHEW1,2, P VITORINO3, D SPERANDIO,3 AS RAY,3 J LILES3, DJ NIKOLIC-PATERSON1,2.

1Department of Nephrology, Monash Medical Centre, Clayton, Victoria; 2Centre for Inflammatory Diseases, Monash University, Clayton, Victoria; 3Gilead Sciences, Foster City, CA, USA.

Aim: To determine whether cannabinoids promote renal fibrosis via the CNR1.

Background: Cannabinoids act in the nervous system and the periphery through type 1 and 2 cannabinoid receptors (CNR1 and CNR2). These receptors play opposing roles in models of diabetic nephropathy with CNR1 antagonists and CNR2 agonists being protective. We sought to determine whether CNR1 directly promotes renal fibrosis using a selective, peripherally acting CNR1 antagonist (CNR1i).

Methods: Wistar rats underwent unilateral ureteric obstruction (UUO) surgery. Groups (n=10) were treated with 60mg/kg/BID CNR1i by oral gavage or vehicle from the time of surgery until being killed 7 days later.

Results: Vehicle treated UUO kidneys displayed a marked increase in the area of interstitial collagen IV and a-SMA staining which was reduced by 37% and 27%, respectively, by CNR1i (both P<0.001). PCR analysis showed that CNR1i treatment reduced mRNA levels of pro-fibrotic molecules (Col I, Col IV, a-SMA, TGF-b1; all P<0.01 vs vehicle). This was associated with a reduction in CCL2 mRNA expression and macrophage infiltration. Western blotting found that CNR1i treatment significantly inhibited ERK and JNK activation in the UUO kidney, whereas Akt activation was unaffected.

Conclusions: Peripheral blockade of CNR1 significantly attenuated renal interstitial fibrosis in the obstructed kidney.

CYCLOPHILIN INHIBITION PREVENTS SEVERE RENAL ISCHAEMIA/REPERFUSION INJURY

KG LEONG1,2, E OZOLS1,2, J KANELLIS1,2, J LILES3, DJ NIKOLIC-PATERSON1,2, FY MA1,2.

1Department of Nephrology, Monash Medical Centre, Clayton, Victoria; 2Centre for Inflammatory Diseases, Monash University, Clayton, Victoria; 3Gilead Sciences, Foster City, CA, USA.

Aim: To determine whether cyclophilin (Cyp) inhibition can prevent renal ischaemia/reperfusion (I/R) injury.

Background: Cyclophilins are a family of enzymes which regulate protein folding. Of these enzymes CypD is an essential component of the mitochondrial permeability membrane pore (mPTP). During acute cellular injury, such as that occurring in I/R injury, the mPTP facilitates mitochondrial release of cytochrome c and calcium ions causing cell damage and cell death. We investigated whether a novel cyclophilin inhibitor (CYPi), which does not block calcineurin function, could prevent anticipated renal I/R injury.

Methods: Mice were anaesthetised with ketamine/xylazine and bilateral renal ischaemia (17min at 37 degrees) induced using non-traumatic vascular clamps and animals killed 24hr after reperfusion. Controls were sham operated. Renal I/R injury studies were performed in C57BL/6J mice (n=10/group) which were treated with 30mg/kg/BID CYPi or vehicle by oral gavage starting 1 hour prior to surgery.

Results: Renal I/R injury caused acute renal failure at day 1 in WT mice (179.0±19.1umol/L vs 12.2±1.4umol/L serum creatinine (sCr) in sham control; P<0.001). CYPi caused substantial protection from renal failure (sCr 36.4±6.7umol/L; P<0.001 vs vehicle). Scoring of PAS stained sections found that the percentage of tubules exhibiting damage in the outer medulla was reduced from 73.0±3.7% in vehicle to 46.7±14.8% in CYPi treated; P<0.001). Apoptotic tubular cells in the vehicle I/R group (11.4±3.2 TUNEL+ cells/mm2) was reduced with CYPi treatment (4.3±0.9 TUNEL+ cells/mm2; P<0.001). In addition, CYPi treatment reduced macrophage infiltration and TNF-α mRNA levels (both P<0.01 vs vehicle).

Conclusions: Cyclophilin inhibition prevented anticipated I/R-induced acute renal failure by suppressing tubular apoptosis and necrosis.

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