SUBCLINICAL ACUTE KIDNEY INJURY (sAKI) MODIFIES BIOMARKER PROFILES IN SUBCLINICAL CHRONIC KIDNEY DISEASE (sCKD)

L SUCCAR1,  J WONG1, K TAYLOR1, A AU1, J ERLICH1, E ZOLTAN1
1University of New South Wales, Department of Nephrology, Prince of Wales Clinical School., Randwick, Sydney, Australia

Aim: To investigate biomarker profiles when ischaemic sAKI is superimposed on sCKD.
Background: sCKD (structural kidney damage without a rise in sCr) modifies diagnosis of nephrotoxin-induced AKI. Renal ischaemia in the presence of pre-existing sCKD may better reflect AKI in Australian adults.
Methods: sCKD was induced in Sprague Dawley rats by dietary supplementation with 0.25% adenine from day 0 to 28 or normal diet in controls. On day 56, sAKI was induced by brief duration renal ischaemic injury insufficient to induce sCr change in normal animals, viz bilateral clamping of the renal arteries for 30 minutes. sCr, urinary biomarkers (kidney injury molecule-1 (KIM-1), monocyte chemotactic protein 1 (MCP-1), clusterin, and interleukin-18 (IL-18)) and histological damage were measured after 1, 2, 3, 7 and 14 days.
Results: During induction of sCKD, urinary biomarker levels increased from day 3 to 21 and returned to baseline by day 56, despite absence of sCr rise. Rats displayed widespread medullary and up to 50% cortical damage. After sAKI in control rats, sCr did not increase and only KIM-1 rose from day 1 to 3 with focal medullary structural damage that recovered by day 7. In sCKD rats, all urinary biomarkers increased from day 1 to 7 post sAKI, and sCr increased continuously until day 14. Severe diffuse structural damage was also present from  day 1 after sAKI and persisted until 14 days.
Conclusions: Biomarker profiles are modified after sAKI is superimposed on sCKD. This impacts interpretation of AKI biomarker thresholds since sCKD in Australian adults is likely common and precursory to overt CKD.


Biography:
Dr Lena Succar is a Postdoctoral Research Fellow at the Prince of Wales Clinical School University of New South Wales, headed by Professor Zoltan Endre. Dr Succar’s research interest is centred on discovery of novel biomarker for early detection and profiling in CKD pathogenesis and progression, particular, in subclinical CKD (Which most likely reflects the adult population) and its modification after AKI.

VALIDATION OF NON-INVASIVE TRANSCUTANEOUS METHOD FOR GLOMERULAR FILTRATION RATE (GFR) IN OBESE MICE

T MULLINS1,2, W SHENG TAN1, L GALLO1,2
1School Of Biomedical Sciences, The University of Queensland, St Lucia, Australia, 2Mater Research Institute-UQ, Translational Research Institute, Woollongabba, Australia

Aim: To validate a non-invasive transcutaneous method for assessing glomerular filtration rate (GFR) in obese mice.
Background: The measurement of GFR in experimental rodents is pivotal to understanding the progression of kidney disease and the benefits of treatment strategies. Traditional methods can be invasive, inaccurate, and/or labour-intensive. This has led to development of a non-invasive clearance device (NIC-Kidney), which measures transcutaneous decay of injected FITC-sinistrin in conscious rodents. The technique has been tested and used in a range of mouse models. However, simultaneous comparisons to an established method have not been performed, and the technique is yet to be validated in obese mice.
Methods: Five-week-old male C57BL/6J mice were randomised to either a high fat diet (60% kcal from fat, n=13) or normal diet (n=12) for 10 weeks. Body composition was measured using NMR mini-spec. Mice were subjected to a single retro-orbital injection of FITC-sinistrin (10mg/100g) and transcutaneous decay using the NIC-Kidney Device was simultaneously compared to plasma clearance (two-phase exponential decay) in the same, conscious mice.
Results: Mice randomised to high fat vs normal diet developed obesity (BW: 32.2 vs 26.6 g, fat mass: 23 vs 14%, P<0.01). In lean mice, there was a linear relationship between transcutaneous and plasma clearance GFR values (linear regression: P<0.05, R2 = 0.35), which remained when GFR was adjusted for body weight (linear regression: P<0.01, R2 = 0.48). This relationship between GFR values, using the two methods, was not evident in obese mice.
Conclusions: The non-invasive transcutaneous method for assessing GFR is suitable for use in lean, but not obese, mice. This may be due to impairments in cutaneous blood flow in obesity, which requires study.


Biography:
Thomas Mullins completed a Bachelor of Science (First Class Honours) at The University of Queensland in 2017. His current research interests include diabetic nephropathy, anti-diabetic therapies that target the kidneys (SGLT2 inhibitors), and diabetes complications in pregnancy. Thomas is enrolled to commence a PhD project at The University of Queensland in the next academic quarter, supervised by Dr Helen Barrett, Dr Linda Gallo and Prof Karen Moritz. His PhD will focus on pregnancies complicated by type 2 diabetes mellitus, and associations of the microbiome with pregnancy and infant outcomes.

COMPARISON OF DIABETIC RENAL INJURY IN MALE AND FEMALE NOS3 DEFICIENT MICE.

L TIAN1, D NIKOLIC-PATERSON1,2, G TESCH1,2
1Monash Health, Clayton, Australia, 2Monash University Centre for Inflammatory Diseases, Clayton, Australia

Aim: To compare diabetic renal injury in male and female Nos3 deficient mice with equivalent diabetes.
Background: Streptozotocin (STZ)-induced diabetic nephropathy in male mice lacking endothelial nitric oxide synthase (Nos3-/-) is a widely used model for examining the development of diabetic nephropathy. In some mouse strains, females are partially protected from STZ-diabetes and are not used for studies of diabetic nephropathy. In this study, we sought to identify whether male and female Nos3-/- mice with equivalent diabetes develop similar renal injury, justifying the potential to use both sexes in studies of diabetic nephropathy.
Methods: Male and female Nos3-/- mice were made diabetic with multiple low-dose streptozotocin (STZ) injections. Groups of male and female mice with equivalent diabetes at week 2 after STZ were assessed for diabetic kidney injury (albuminuria, renal function impairment, glomerulosclerosis, tubular injury) at week 8.
Results: STZ-treated male and female Nos3-/- mice maintained similar blood glucose levels between weeks 2 and 8 and had equivalent HbA1c levels at week 8 (11.9±0.8% males vs 11.9±0.9% females). At week 8, urine albumin/creatinine levels were elevated 8-fold in both diabetic males and females. Plasma cystatin-C levels increased by 32% in diabetic males (441±64ng/mL) and 35% in diabetic females (463±38ng/mL). The glomerular area of collagen IV immunostaining increased by approximately 30% in both diabetic males and females. In addition, kidney expression of KIM-1 increased by 23±7 fold in males and 26±6 fold in females, indicating similar diabetic tubular injury.
Conclusion: Our study shows that male and female Nos3-/- mice develop equivalent diabetic kidney injury, demonstrating it is possible to include males and females together in studies of diabetic nephropathy.


Biography:
Lifang Tian is a visiting Chinese research fellow working in the Nephrology Department at Monash Health

β-CATENIN/FOXO AMELIORATES KIDNEY FIBROSIS

P RAO1, M PANG1,2, X QIAO1,2, H YU1, T CHEN1, H WANG1,2,  M HU1, Q CAO1,  Y WANG1,  G ZHANG3, Y WANG3, C P’NG4, B Nankivell4, V Lee1, S Alexander3, G Zheng1, D Harris1
1University of Sydney at Westmead Institute for Medical Research, Westmead, Australia, 2Shanxi Medical University, , China, 3Children’s Hospital at Westmead, Westmead, Australia, 4Westmead Hospital, Westmead, Australia

Aim: To examine the role of β-catenin/Foxo in kidney fibrosis.
Background: The conflicting effects of TGF-β (profibrotic versus anti-inflammatory) have caused a major challenge in the treatment of kidney fibrosis. β-catenin/TCF is central to all TGF-β’s profibrotic signaling pathways and activates profibrotic genes. β-catenin also binds to Foxo in competition with TCF and promotes cell survival under oxidative stress. We propose that promoting β-catenin/Foxo will protect against β-catenin/TCF mediated profibrotic changes and kidney fibrosis.
Methods: Kidney biopsies of patients with chronic kidney disease (CKD) or a kidney transplant were assessed by Proximity Ligation Assay (PLA) for β-catenin/Foxo and β-catenin/TCF interactions in relation to kidney fibrosis. Mouse tubular epithelial C1.1 cells were treated with TGF-β1 (3ng/ml) with or without ICG-001 (5µM), which inhibits β-catenin/TCF. Foxo1 and TCF1 were knocked out by CRISPR/Cas9-mediated gene knockout. We also evaluated kidney fibrosis in murine unilateral ureteric obstruction (UUO). β-catenin/Foxo and β-catenin/TCF interactions were examined by co-immunoprecipitation assays (co-IP) and PLA. Profibrotic gene expressions were examined by western blot and immunofluorescence.
Results: PLA of CKD and kidney transplant patient biopsies showed that β-catenin/Foxo correlated negatively (r=-0.7405, P<0.001) and β-catenin/TCF positively (r=0.8061, P<0.001) with kidney fibrosis. Combined treatment with TGF-β1 and ICG-001 protected against TGF-β1-induced profibrotic gene expression while the protection was not seen in Foxo1 KO C1.1 cells. PLA and co-IP showed direct evidence for the promotion of β-catenin/Foxo with TGF-β1 and ICG-001 in C1.1 cells. UUO mice treated with TGF-β1 and ICG-001 had significantly reduced kidney fibrosis, via promotion of β-catenin/Foxo interaction as shown by PLA.
Conclusions: These results indicate that β-catenin/Foxo plays a protective role against TGF-β’s profibrotic activity and thereby prevents kidney fibrosis.


Biography:
Padmashree Rao is the student of the University of Sydney at Westmead Institute for Medical Research. Her research has been focused on kidney fibrosis. TGF-beta, a cytokine causing kidney fibrosis, also exhibits anti-inflammatory and wound healing effects. Her project aims to prove that targeting beta-catenin/Foxo will prevent beta-catenin/TCF-mediated fibrosis and may be used as a novel target for the treatment of kidney fibrosis.

PAR-2 DOES NOT CONTRIBUTE TO TUBULAR DAMAGE OR RENAL FIBROSIS IN THE OBSTRUCTED KIDNEY.

Y HAN1,2,  F MA1,2, E OZOLS1,2,  P CHEW1,2, D VESEY3, G GOBE3,  C MORAIS4, R LOHMAN4, J SUEN4,  D FAIRLIE4, D NIKOLIC-PATERSON1,2
1Dept of Nephrology, Monash Medical Centre, Clayton, Australia, 2Centre for Inflammatory Diseases, Monash University, Clayton, Australia, 3Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, The University of Queensland, Brisbane, Australia, 4Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia

Aim: To determine whether Protease Activated-Receptor-2 (PAR-2) contributes to tubular cell activation and renal fibrosis in the obstructed kidney.
Background: Activation of PAR2 has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR-2 in cultured tubular epithelial cells induces cell proliferation and secretion of fibronectin, CCL2 and TGF-β1; suggesting that PAR-2 signalling may promote tubulointerstitial inflammation and fibrosis. We tested this hypothesis in the unilateral ureteric obstruction (UUO) model in which activation of tubular epithelial cells drives tubulointerstitial inflammation and fibrosis.
Methods: UUO surgery was performed in groups (n=10) of Par2-/- and WT (littermate control) C57BL6/J mice which were killed 7 days later.
Results: WT mice exhibited a 5-fold increase in PAR-2 mRNA levels in the UUO kidney. In situ hybridisation localised PAR-2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in PAR-2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Renal fibrosis was not different between Par2-/- and WT UUO in terms of collagen IV deposition and accumulation of α-SMA+ myofibroblasts, while increased mRNA levels for col I, col IV, α-SMA, CTGF and TGF-β1 were also not different. Similarly, no difference in up-regulation of macrophage markers (CD68 and CD206) or inflammation markers (TNF-α, NOS-2, MCP-1, IL-36α) was evident. Tubular damage was equivalent between Par2-/- and WT mice based on the percentage of damaged tubules on PAS stained sections, increased levels of KIM-1 mRNA and decreased levels of α-Klotho mRNA.
Conclusions: PAR-2 expression is substantially up-regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of renal inflammation or fibrosis.


Biography:
Dr Nikolic-Paterson is form the Department of nephrology at Monash Medical Centre and his research interests focus on the mechanism of renal inflammation and fibrosis.

DEFICIENCY OF MINERALOCORTICOID SIGNALING IN MACROPHAGES PROVIDES PROTECTION AGAINST KIDNEY AND CARDIAC INJURY IN HYPERTENSIVE DIABETIC MICE.

G TESCH1,2, E OZOLS1, M YOUNG3, D NIKOLIC-PATERSON1,2
1Monash Health, Clayton, Australia, 2Monash University Centre for Inflammatory Diseases, Clayton, Australia, 3Hudson Institute of Medical Research, Clayton, Australia

Aim: To evaluate whether macrophage mineralocorticoid receptor signaling contributes to the development of kidney and cardiac disease in hypertensive diabetic mice.
Background: Mineralocorticoid receptor antagonists (MRAs) reduce hypertension, inflammation and tissue injury in human and experimental diabetes. Furthermore, inflammation and injury in diabetic kidneys and hearts is dependent on infiltrating macrophages. Therefore, we hypothesized that the tissue protective effects of MRAs in diabetes is partially due to inhibition of MR signaling in macrophages.
Methods: Transgenic mice with intact myeloid MR (MRflox/flox = WT) or myeloid MR deficiency (MRflox/flox LysMCre = MyMRKO) were developed on the hypertensive endothelial nitric oxide synthase deficient (Nos3-/-) mouse strain. Groups of these mice (n=13) were made diabetic with low dose streptozotocin (STZ) and were assessed after 15 weeks for the development of hypertension (systolic blood pressure), nephropathy (renal function impairment, albuminuria, renal injury) and cardiomyopathy (cardiac dysfunction–echocardiography).
Results: MR intact Nos3-/- mice with diabetes developed hypertension, albuminuria, renal function impairment (elevated cystatin-C), tubular injury (increased KIM-1 gene expression), and reduced cardiac function  (LV fractional shortening: diabetic 21% versus non-diabetic 31%), but no neutrophil infiltrate. In comparison, myeloid MR deficient Nos3-/- mice with similar diabetes had equivalent levels of hypertension, albuminuria and tubular injury, but showed improved renal function (plasma cystatin-C 48%↓, p<0.01) and improved cardiac function (LV fractional shortening  28%, p<0.01).
Conclusion: MR signaling in macrophages promotes injury in the diabetic kidneys and hearts of Nos3-/- mice without affecting hypertension. Therefore, MRAs can suppress diabetic nephropathy and diabetic cardiomyopathy by reducing macrophage-mediated injury independent of their ability to lower blood pressure.


Biography:
The research career of Greg Tesch has focused on the role of inflammation in diabetic nephropathy and other chronic kidney diseases.

TISSUE-RESIDENT MUCOSAL-ASSOCIATED INVARIANT T (MAIT) CELLS IN HUMAN RENAL FIBROSIS AND CHRONIC KIDNEY DISEASE (CKD)

HG HEALY1,2,3, B LAW1,2,4,  X WANG1,2, K KILDEY1,2,  K GIULIANI1,2,  K BEAGLEY4, R WILKINSON1,2,3,4, A KASSIANOS1,2,3,4
1Pathology Queensland, Brisbane, Australia, 2Royal Brisbane and Women’s Hospital, Brisbane, Australia, 3University of Queensland, Brisbane, Australia, 4Queensland University of Technology, Brisbane, Australia

Aim: To functionally characterise mucosal-associated invariant T (MAIT) cells present in human chronic kidney disease (CKD).
Background: MAIT cells are a specialised lymphocyte population associated with chronic inflammatory disorders in peripheral tissues. To date, MAIT cell research has focused primarily on mucosal tissue, with limited studies on non-mucosal organs such as kidneys. In this study, we evaluated MAIT cells in human native kidneys with tubulointerstitial fibrosis, the pathological hallmark of CKD.
Methods: MAIT cells were identified, enumerated and phenotyped from human kidney tissue by multi-colour flow cytometry. Localisation of MAIT cells was performed by immunofluorescence microscopy. MAIT cells and human primary proximal tubular epithelial cells (PTEC) were co-cultured under hypoxic (1% O₂) conditions to examine mechanistic tubulointerstitial interactions.
Results: We detected significantly elevated numbers of MAIT cells (TCR-Vα7.2+ CD161++) in diseased biopsies with interstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue. The increased numbers of MAIT cells also correlated significantly with loss of kidney function (eGFR). MAIT cells in fibrotic biopsies expressed cytokine receptors (IL-7Rα, IL-18Rα), activation receptor (NKG2D), extravasation marker (CD44) and tissue-resident markers (CD69, CD103 and CD49a). Immunofluorescent staining of fibrotic kidney tissue localised the accumulation of MAIT cells within the tubulointerstitial compartment, adjacent to PTEC. Notably, under in vitro pro-fibrotic/hypoxic conditions, PTEC induced the up-regulated expression of tissue-resident markers on MAIT cells.
Conclusion: We provide the first characterisation of MAIT cells in human kidney tissue. Collectively, our data suggest that human MAIT cells are retained as tissue-resident lymphocytes and are positioned to contribute to the fibrotic process via complex interactions with PTEC. Further dissection of kidney MAIT cells is now required for the development of novel CKD therapeutics.


Biography:
A/Prof Helen Healy is the Head of the Conjoint Kidney Research Laboratory and Director of Kidney Health Service, RBWH. A/Prof Healy has pioneered research into PTEC-immune cell interactions in the human system. She has a particular research focus on using our understanding of the mechanisms of CKD to develop effective treatments for this common chronic disease.

ROLE OF JNK SIGNALLING IN PODOCYTE DAMAGE AND PROTEINURIA IN EXPERIMENTAL GLOMERLULAR DISEASE.

F MA1,2, J LIU1,2, E OZOLS1,2,  PCHEW1,2, J HO1,2, Y HAN1,2, K BLEASE3, B BENNETT3, G TESCH1,2, D NIKOLIC-PATERSON1,2
1Dept of Nephrology, Monash Medical Centre, Clayton, Australia, 2Monash University Centre for Inflammatory Diseases, Clayton, Australia, 3Celgene, San Diego, USA

Aim: To determine whether JNK signalling in podocytes contributes to podocyte damage and proteinuria in glomerular disease.
Background: Activation of the c-Jun amino terminal kinase (JNK) is evident in podocytes and infiltrating macrophages in human and experimental glomerulonephritis. In vitro studies indicate that JNK signalling facilitates podocyte damage in response to inflammatory cytokines and toxins (e.g. puromycin aminonucleoside, PAN): however, the role of JNK in podocyte damage in glomerular disease remains unclear.
Methods: Podocyte damage (area of synaptopodin staining), proteinuria and macrophage infiltration was assessed in two disease models. WKY rats received a JNK inhibitor (CC-930), or vehicle, on days 7-28 of anti-GBM disease. Mice with Jnk gene deletion in podocytes (Jnk1f/fJnk2-/-PodCre known as JnkPod) were examined in the anti-GBM disease model with wild type and Jnk2-/- control groups. Finally, SD rats received a JNK inhibitor (CC-401), or vehicle, on days 0-8 of PAN-induced podocyte damage.
Results: Systemic JNK inhibition prevented podocyte damage, proteinuria and glomerular lesions in rat anti-GBM disease (all P<0.001 vs vehicle). This was associated with reduced macrophage infiltration and activation. JnkPod mice develop normally and exhibit normal kidney structure and function. However, JnkPod mice were not protected from podocyte damage, albuminuria, glomerular damage, renal function impairment or macrophage infiltration on day 7 of anti-GBM disease. PAN induced JNK activation in podocytes on day 4 which preceded the peak of proteinuria on day 8. However, systemic JNK inhibition failed to protect rats against PAN-induced podocyte damage or proteinuria.
Conclusions: Contrary to in vitro studies, JNK signalling in podocytes does not induce podocyte damage in vivo. Systemic JNK blockade reduces podocyte damage in anti-GBM disease via indirect effects, most probably on macrophages.


Biography:
Dr Nikolic-Paterson is from the Department of Nephrology at Monash Medical Centre and his research interests focus on the mechanisms of renal inflammation and fibrosis.

LOW DOSE INTERLEUKIN-2 THERAPY MODULATES AUTOIMMUNITY AND RENAL INJURY IN EXPERIMENTAL ANTI-MYELOPEROXIDASE GLOMERULONEPHRITIS

J DICK1, P GAN1, M ALIKHAN1, R KITCHING1, S HOLDSWORTH1
1Monash University , Clayton , Australia

Aim: To determine the potential of low dose IL-2 therapy in experimental ANCA-associated vasculitis (AAV).
Background: Low dose IL-2 expands regulatory T cells (Tregs) and is a potential therapy for autoimmune disease.
Methods: Anti-MPO autoimmunity was induced in C57BL/6 mice by immunisation with MPO. T cell mediated anti-MPO glomerulonephritis was triggered on day 16 in immunised mice by anti-GBM globulin, and MPO-ANCA induced glomerulonephritis by passive transfer of MPO-ANCA/LPS. Mice were treated with IL-2, 25,000units/day for 7 days. Immune responses were measured by flow cytometry, ELISPOT and ELISA.
Results: IL-2 increased splenic Tregs (26.2±0.8vs17±0.3 %CD4+, P<0.0001) and up-regulated expression of the suppressive markers CTLA4 and PD-1. Mice treated with IL-2 before MPO immunisation developed attenuated Th1 and Th17 autoimmunity, measured by splenocyte ELISPOT (IFN-γ 68±12vs123±16 spots, P=0.009; IL-17A 31±7vs70±12 spots P=0.003). This was associated with reduced segmental glomerular necrosis (24±4vs48±6%, P=0.0054) and reduced albuminuria. IL-2 pre-treatment did not alter humoral immunity.Treatment with IL-2 before passive transfer of MPO-ANCA/LPS increased numbers of intra-renal Tregs (2316±402vs1246±170 CD4+Foxp3+cells/kidney, P=0.02) and reduced intra-renal F4/80hiCCR2hi inflammatory macrophages (P<0.01).To evaluate therapy in established autoimmunity, mice were treated with IL-2 12 days after MPO immunisation. Although splenic Tregs were expanded, T effector response was also enhanced with more IFN-γ and IL17A producing cells (both P<0.01). Conversely, IL-2 therapy attenuated ANCA production (0.49±0.04 vs 0.29±0.03 OD480, P=0.0019), this was associated with suppressed T follicular helper cell generation. The net effect of IL-2 therapy was exacerbation of glomerular necrosis (87±3vs26±4%, P<0.0001) and increased albuminuria.
Conclusions: IL-2 has diverse and context specific effects on cellular and humoral autoimmunity. The potentiation of T effector responses in established autoimmunity may limit its utility in AAV.


Biography:
Dr Jonathan Dick studied medicine at the University of Oxford and University College London before training in internal medicine and nephrology in London. He recently completed a PhD at Monash University supervised by Professors Steve Holdsworth and Richard Kitching on novel roles for complement in pre-clinical models of ANCA-vasculitis.

COMBINED INHIBITION OF CCR2 AND ACE PROVIDES ADDED PROTECTION AGAINST PROGRESSION OF DIABETIC NEPHROPATHY IN NOS3 DEFICIENT MICE.

G TESCH1,2,  N PULLEN3, D NIKOLIC-PATERSON1,2
1Monash Health, Australia, 2Monash University Centre for Inflammatory Diseases, Clayton, Australia, 3Pfizer Worldwide Research & Development, Cambridge, USA

Aim: To evaluate intervention with a CCR2 antagonist (CCR2A) in a model of progressive diabetic glomerulosclerosis and determine whether a CCR2A provides added benefit over conventional treatment with an angiotensin converting enzyme inhibitor (ACEi).
Background: Blockade of chemokine CC motif receptor 2 (CCR2) inhibits kidney macrophage accumulation and suppresses early glomerular damage in diabetic animals. CCR2As are in clinical trials for diabetic nephropathy prompting investigation into whether they provide added benefit over ACEi.
Methods: Diabetes was induced in hypertensive endothelial nitric oxide synthase (Nos3) deficient mice by streptozotocin (STZ). Groups of diabetic Nos3-/- mice received a CCR2A (PF-04634817) as an early intervention (2-15 weeks after STZ). The late intervention (weeks 8-15 after STZ) involved PF-04634817 alone, ACEi (captopril) alone, or combined ACEi + CCR2A.
Results: Early intervention with CCR2A inhibited kidney inflammation and glomerulosclerosis, albuminuria, podocyte loss and renal function impairment, but not hypertension. Late intervention with CCR2A also inhibited kidney inflammation, glomerulosclerosis, renal dysfunction but did not affect albuminuria. ACEi alone suppressed hypertension and albuminuria, partially reduced podocyte loss and glomerulosclerosis, but did not affect renal dysfunction. Compared to ACEi alone, combined intervention with ACEi + CCR2A provided better protection against kidney damage (inflammation, glomerulosclerosis, renal function impairment), but not albuminuria.
Conclusion: Combining CCR2A and ACEi provides broader and superior renal protection than ACEi alone in a model of established diabetic glomerulosclerosis with hypertension.


Biography:
Greg Tesch is head of diabetes research in the Nephrology Department at Monash Health. His work is primarily focused on understanding the inflammatory mechanisms which promote diabetic nephropathy and developing novel anti-inflammatory treatments for diabetic nephropathy and other chronic kidney diseases.

1192021

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