J WANG1, Q CAO1, Y WANG1, D HARRIS1, G ROBERTSON2, D BURG2, M HALASZ2, V LEE1
1Westmead Institute Of Medical Research, Westmead, Australia, 2Cellmid Limited, Sydney, Australia
Aim: To determine the efficacy of anti-Midkine (MK) antibodies in ameliorating kidney damage and dysfunction in the Adriamycin (ADR) nephropathy model.
Background: MK is known for its role in development and cancer where it promotes cell survival, proliferation and migration. Additionally, MK is implicated in inflammation and autoimmunity where it modulates chemotaxis, chemokine expression and immunological tolerance. Clinical studies have found progressive increases in systemic and urinary MK levels related to disease severity in chronic kidney disease (CKD)1-CKD5 patients. MK levels are also elevated in diverse experimental kidney disease models post injury or pathogenesis, and are associated with renal inflammation, fibrosis and progressive injury. More importantly, MK-deficient mice exhibit markedly reduced glomerulosclerosis, tubulointerstitial inflammation and damage than MK +/+ mice in ischaemic, diabetic and nephrectomy models, suggesting that MK’s pathological role in exacerbating renal injury and dysfunction operates primarily via its immunomodulatory functions.
Methods: ADR was administered once to male Balb/c mice via tail vein injections. Anti-MK antibodies were administered in prophylaxis mode by intraperitoneal injections to ADR-treated mice prior to ADR treatment, as well as periodically following treatment. All mice were sacrificed after 27 days for subsequent tissue processing and biochemical analysis for assessment of renal histology and function.
Results: ADR-treated mice administered with anti-MK antibodies exhibited significantly reduced overall kidney tissue damage in contrast with those administered with vehicle. Reduced proteinuria, serum creatinine and improved serum albumin levels were also observed in anti-MK antibody administered mice.
Conclusions: Our results indicate that MK plays a crucial role in modulating kidney injury and dysfunction in a murine model of FSGS, and therapeutic antibodies against MK may contribute to the treatment of chronic proteinuric renal disease.
Jeffrey Wang is a second year PhD student under the renal department at the Westmead Institute of Medical Research. He is currently under the supervision of Assoc. Prof Vincent Lee from the Westmead Hospital, and Assoc. Prof Graham Robertson from Cellmid Limited. Jeffrey completed his bachelor degree with honours in science from the University of New South Wales in 2015, majoring in cellular biology and biochemistry. He began his PhD candidature at the Westmead Institute in 2016, and his current research focuses on exploring therapeutic options behind the molecule Midkine and inflammation and fibrosis in chronic kidney disease.