Alteration of thyroid hormone signaling triggers the diabetes-induced pathological growth, remodeling, and dedifferentiation of podocytes

Thyroid hormone (TH) signaling is a universal regulator of metabolism, growth, and development. Here, we show that TH-TH receptor (TH-TR) axis alterations are critically involved in diabetic nephropathy-associated (ON-associated) podocyte pathology, and we identify TR alpha 1 as a key regulator of the pathogenesis of DN. In Z5F1 diabetic rats, T-3 levels progressively decreased during ON, and this was inversely correlated with metabolic and renal disease worsening. These phenomena were associated with the reexpression of the fetal isoform TR alpha 1 in podocytes and parietal cells of both rats and patients with ON and with the increased glomerular expression of the TH-inactivating enzyme deiodinase 3 (DIO3). In diabetic rats, TR alpha 1-positive cells also reexpressed several fetal mesenchymal and damage-related podocyte markers, while glomerular and podocyte hypertrophy was evident. In vitro, exposing human podocytes to diabetes milieu typical components markedly increased TR alpha 1 and DIO3 expression and induced cytoskeleton rearrangements, adult podocyte marker downregulation and fetal kidney marker upregulation, the maladaptive cell cycle induction/arrest, and TR alpha 1-ERK1/2-mediated hypertrophy. Strikingly, T-3 treatment reduced TR alpha 1 and DIO3 expression and completely reversed all these alterations. Our data show that diabetic stress induces the TH-TR alpha 1 axis to adopt a fetal ligand/receptor relationship pattern that triggers the recapitulation of the fetal podocyte phenotype and subsequent pathological alterations.