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Kidney Week

Abstract: FR-PO368

Specialised Proresolving Mediators Protect the Diabetic Kidney Against Podocyte Loss

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Kantharidis, Phillip, Monash University Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia
  • Bose, Madhura, Monash University Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia
  • Mohan, Muthukumar, Monash University Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia
  • Tikellis, Chris, Monash University Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia
  • Brennan, Eoin, UCD Diabetes Complications Research Centre, School of Medicine & Conway Institute University College, Dublin, Ireland
  • Godson, Catherine, UCD Diabetes Complications Research Centre, School of Medicine & Conway Institute University College, Dublin, Ireland
  • Cooper, Mark E., Monash University Faculty of Medicine Nursing and Health Sciences, Clayton, Victoria, Australia

Group or Team Name

  • Diabetes Dept.
Background

Kidney macrophages are a heterogeneous population of cells that contribute to the chronic unresolved inflammation that underlies diabetic kidney disease (DKD). The macrophage subpopulations initiating and promoting inflammation in DKD, particularly in the glomerulus, have not been characterized. There has also been growing interest in specialised pro-resolving mediators (SPMs) such as Lipoxin A4 (LXA4) as potential reno-protective agents. The focus of this study was to investigate the effect of LXA4 on kidney macrophages in a model of DKD.

Methods

Six-week-old male ApoE KO mice were rendered diabetic by five daily IP injections of streptozotocin (55mg/kg). Controls received citrate buffer alone. After 10wks of diabetes, mice were randomly selected to receive twice weekly administration of either vehicle (0.02% ethanol) or LXA4 (5μg/kg) via IP (n=30/gp) for a further 6 weeks. At endpoint, mice were culled, and kidneys collected for gene expression analysis, single cell RNA sequencing (scRNA-Seq) of glomerular cells, immunohistochemistry and histology.

Results

Diabetic mice had elevated blood glucose, glycated haemoglobin and albuminuria, as well as increased expression of fibrotic (fibronectin, Col 4a3), inflammatory markers (IL1β, TNFα, MCP1, VCAM-1, ICAM-1) compared to control. Interestingly, LXA4 resulted in reduced albuminuria, Collagen IV, inflammatory and fibrotic markers (IL1β, MCP1, ICAM1 and VCAM1) independent of any changes in metabolic parameters. scRNA-Seq of the glomerular cell populations demonstrated an increase in macrophages in kidneys of diabetic mice. These changes were associated with renal injury, including the increased expression of apoptotic markers and depletion of podocytes (reduced by 42% in diabetic versus control). LXA4 reduced macrophage numbers and prevented podocyte loss in the diabetic kidney.

Conclusion

SPMs protect against DKD by reducing fibrotic and inflammatory signalling, as well as reducing monocyte recruitment and increased macrophage numbers in the diabetic kidney. These effects are accompanied with improved kidney function. These data further support the use of SPMs as typified by LXA4 as a novel treatment for DKD by targeting macrophages in the kidney.

Funding

  • Government Support – Non-U.S.