P0967ENHANCING podocyte regeneration with bromoindirubin-3´-oxime (BIO) as a potential terapeutic target in diabetic kidney disease
Abstract
Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease. RAS and SGLT2 inhibitors are well established in reducing the progression of DN in early stages but true tissue regeneration is not achieved. BIO, a glucose synthase kinase 3 inhibitor (GSK3β), improves outcomes in non-diabetic kidney injury by enhancing podocyte regeneration from local podocyte progenitors. We hypothesized that treating podocytes in hyperglycemic conditions with BIO could revert the oxidative stress damage typically seen in DN.
To study the effect of BIO on podocytes, we isolated glomeruli from wildtype mice by perfusing them with magnetic beads and stimulated the purified glomeruli for 24 hours with or without 10µM BIO in presence or absence of 30mM glucose. The response to the stimuli was assessed by characterizing the overall gene expression via RT-qPCR. Additionally, differentiated murine podocytes (K5P5) and murine glomerular endothelial cells (GEnCs) were stimulated under the same conditions with the same subsequent readouts to differentiate the response of podocytes from that of the endothelial compartment.
To understand, if BIO could represent a potential new therapeutic option under the aspect of pharmacological safety, we uninephrectomized male BKS-Lepr-/- mice, fed them with a salt-free chow to induce DN. To mimic the human condition more closely we treated the mice with and without BIO, but in presence of the human standard of care therapy (SOC; metformin, ramipril,…
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