REDOX MODULATING SMALL MOLECULE IMPROVES DIABETIC KIDNEY DISEASE IN THE DB/DB MODEL OF TYPE 2 DIABETES
Amelia Fotheringham1,2, Hakeem Masagos1,2, Rani Whiddett1, Domenica McCarthy1, Preeti Chandrashekar1, Irina Buckle1, Brian Tse3, Kamil Sokolowski3, Mitchell Sullivan1,4, Josephine Forbes1,2 1Mater Research- The University of Queensland, Woolloongabba, QLD, Australia2Faculty of Medicine, University of Queensland, St Lucia, QLD, Australia3Preclinical Imaging Facility, Translational Research Institute, Woolloongabba, QLD, Australia4School of Chemistry and Molecular Biology, University of Queensland, St Lucia, QLD, Australia
Abstract
Aim: To examine the efficacy of an orally bioavailable redox modulator to attenuate DKD in a preclinical model of T2D and obesity.
Background: Mitochondrial dysfunction is a contributing pathway in diabetic kidney disease (DKD), yet therapeutics targeting mitochondrial pathways are lacking. MitoA is a redox modulator with a favourable clinical safety profile which we investigated for DKD.
Methods: Male BKS.Cg-Dock7m+/+ Leprdb/J (db/db) mice received (i) H2O (Veh), (ii) the redox modulator (MitoA, 10mg/kg) or (iii) Ramipril (Ram, 3mg/kg) from 11-21 weeks of age (oral, daily, n=7-9/group). Non-diabetic littermates (Con) were treated with vehicle. Renal function (mGFR, uACR, serum cystatin C) and glucose homeostasis were assessed at week 10 and 20. Renal oxygenation and blood flow were determined by ultrasound imaging before euthanasia. Flow cytometry was performed to characterise freshly isolated kidney cell subsets, expression of mitochondrial ribosomal protein (Mrpl11), and superoxide generation (mitoSOX). Mechanistic investigations were carried out in HK2 cells.
Results: MitoA and Ram attenuated increases in uACR in diabetes (p<0.01, p<0.0001 vs Veh (delta-uACR)), reducing endpoint uACR (p<0.05 vs Veh). MitoA reduced glomerular injury (p<0.01 vs Veh), increased renal vascularity (p<0.001 vs Con) and decreased renal Tgf-β1 expression (p<0.05 vs Veh). Diabetes increased renal proximal tubule cell (PTC) numbers, this was attenuated with MitoA (p=0.05 vs Veh). Relative proportions of renal cells remained unchanged. MitoA tended to increase Mrpl11 (MFI) in PTCs and total isolated kidney cells (p=0.054, p=0.07 respectively, (vs Veh)). Renal transmission electron microscopy suggested mitochondrial hypertrophy and disorganised cristae in diabetes was lessened by MitoA.
Conclusions: MitoA attenuates progression of albuminuria and early markers of DKD in the db/db model of T2D. Research is ongoing to understand the mechanism.
Biography
Dr Amelia Fotheringham is a EMCR in the lab of Professor Josephine Forbes at Mater Research- The University of Queensland. Her research focuses on diabetic kidney disease, and pathways implicated in the pathogenesis of diabetic kidney disease such as mitochondrial dysfunction and Advanced Glycation End Products. Dr Fotheringham has also been involved in projects looking for novel genetic determinants of renal function using the collaborative cross gene mine, and dietary determinants of renal function with ageing using nutritional geometry. Dr Fotheringham has been privileged to present her work regularly at meetings both internationally and locally, and lucky enough to collaborate with research groups across Australia.