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

Research Progress on the Pathological Mechanisms of Podocytes in Diabetic Nephropathy

“…Importantly, inhibition of Akt2 blocked TGF-β-induced podocyte hypertrophy [63]. In addition, TGF-β possesses an activation effect on the ERK pathway [67], and ERK1/2 activation is related to glomerular podocyte hypertrophy [68].…”

Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Targets

“…Recent studies in our lab have shown that podocytes and parietal epithelial cells in the glomeruli of patients and rats with DN re-expressed the fetal isoform TRα1, and that these cells were also positive for several fetal, mesenchymal and damage-related podocyte markers ( Benedetti et al, 2019 ). Notably, the simultaneous re-expression of TRα1 and fetal markers in the glomerulus was observed in almost all of the common rodent models of DN (i.e.…”

“…Apo-TRα1 binds DNA and represses the transcription of target adult genes (as happens in the fetus), leading to cell dedifferentiation, metabolic and structural remodeling, and cell cycle reactivation. The figure is modified from Benedetti et al, 2019. significance of this response, especially in humans, remains unknown.…”

“…TRβ is the predominantly adult isoform and regulates TH levels and the liver and kidney metabolism, and is also critical for the normal development of auditory and visual systems ( Brent, 2012 ; Mourouzis et al, 2020 ). TRα1 is highly expressed in developing organs, including the heart, brain and kidney, and plays a key role in cell proliferation prenatally, while after birth it regulates differentiation in various cell types ( Horn and Heuer, 2010 ; Pantos and Mourouzis, 2014 ; Benedetti et al, 2019 ). In the fetus, when the levels of the active form of TH L-triiodothyronine (T3) are low, TRα1 mainly acts as an apo-receptor (unliganded state) to repress adult genes (thus protecting the embryo from premature differentiation) and enhances cell proliferation and organ growth.…”

“…In addition, human podocytes exposed to typical components of the diabetic milieu in vitro (high glucose and H 2 O 2 ), exhibited markedly upregulated TRα1 and DIO3 expression. The adoption of this fetal profile of TH signaling was associated with cytoskeleton rearrangements, adult podocyte marker downregulation and fetal kidney marker upregulation, along with the induction of a maladaptive cell cycle, and TRα1-ERK1/2-mediated hypertrophy ( Benedetti et al, 2019 ).…”