Endocrine Abstracts

Diabetic nephropathy (DN) and cardiomyopathy (DC) are two major complications of diabetes that account for over two thirds of deaths among diabetic patients. Our previous studies have shown that thyroid hormone (TH) signalling – in addition to its critical role in physiological growth and organ development – plays similar roles in pathological conditions that encompass cellular dedifferentiation, cyto-architectural reorganization and compensatory growth. Though the role of TH signalling in cell differentiation and growth is well-known, it remains unclear whether its alterations contribute to the pathobiology of diabetic cells and/or in the adaptive repair of diabetic organs. Here we aim to investigate whether triiodothyronine (T3) administration can prevent diabetes-induced alterations of TH signalling and the associated cellular pathological remodelling in kidney and heart of Zucker diabetic fatty (ZDF) rats, an experimental model of type II diabetes. Immunofluorescence and western blot analyses showed that T3 administration reversed the diabetes-induced adoption of TH foetal profile and prevented the reactivation of foetal markers both in kidney and heart of ZDF rats. Moreover, T3 provision strongly reduced glomerular damage as well as glomerular and cardiac fibrosis. Electron microscopy analysis showed that T3 provision preserved glomerular and podocyte’s ultrastructure, and reversed cardiomyocyte damage (i.e., mitochondrial swelling, cristae fragmentation, myofibril disruption and Z line disappearance). Also, T3 treatment counteracted polyploidisation-induced hypertrophy of podocytes and cardiomyocytes in ZDF rats, normalising DNA content and restoring the physiological size and shape of cardiomyocytes, as assessed by DNA content evaluation and morphometric studies. To evaluate whether TH signalling could exert these effects also in humans, we optimised and used in vitro glucose-induced injury models for cell culture and hiPSC-derived cardiac and kidney organoids. Treatment with T3 reversed the marked increase in cell area of glucose-stressed podocyte and cardiomyocyte and normalised the altered long to short axis ratio in cardiomyocytes. Moreover, T3 administration strongly decreased fibrosis and alteration of Connexin-43 expression in cardiac spheroids as well as podocyte injury in kidney organoids. Our data highlight the key role that TH signalling plays in the dedifferentiation, morpho-phenotypical alterations and pathological growth of podocytes and cardiomyocytes in both animal and human models of diabetes and suggest that its activation, through T3 administration, can substantially counteract cellular pathological remodelling.