Alteration of thyroid hormone signaling triggers the diabetes-induced pathological growth, remodeling, and dedifferentiation of podocytes
Valentina Benedetti, Angelo Michele Lavecchia, Monica Locatelli, Valerio Brizi, Daniela Corna, Marta Todeschini, Rubina Novelli, Ariela Benigni, Carlamaria Zoja, Giuseppe Remuzzi, Christodoulos Xinaris
Valentina Benedetti, Angelo Michele Lavecchia, Monica Locatelli, Valerio Brizi, Daniela Corna, Marta Todeschini, Rubina Novelli, Ariela Benigni, Carlamaria Zoja, Giuseppe Remuzzi, Christodoulos Xinaris
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Research Article Cell biology

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

Abstract

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 (DN-associated) podocyte pathology, and we identify TRα1 as a key regulator of the pathogenesis of DN. In ZSF1 diabetic rats, T3 levels progressively decreased during DN, and this was inversely correlated with metabolic and renal disease worsening. These phenomena were associated with the reexpression of the fetal isoform TRα1 in podocytes and parietal cells of both rats and patients with DN and with the increased glomerular expression of the TH-inactivating enzyme deiodinase 3 (DIO3). In diabetic rats, TRα1-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 TRα1 and DIO3 expression and induced cytoskeleton rearrangements, adult podocyte marker downregulation and fetal kidney marker upregulation, the maladaptive cell cycle induction/arrest, and TRα1-ERK1/2–mediated hypertrophy. Strikingly, T3 treatment reduced TRα1 and DIO3 expression and completely reversed all these alterations. Our data show that diabetic stress induces the TH-TRα1 axis to adopt a fetal ligand/receptor relationship pattern that triggers the recapitulation of the fetal podocyte phenotype and subsequent pathological alterations.

Authors

Valentina Benedetti, Angelo Michele Lavecchia, Monica Locatelli, Valerio Brizi, Daniela Corna, Marta Todeschini, Rubina Novelli, Ariela Benigni, Carlamaria Zoja, Giuseppe Remuzzi, Christodoulos Xinaris

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Figure 3

TRα1 reexpression is associated with reactivation of kidney developmental program in diabetic rats.

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TRα1 reexpression is associated with reactivation of kidney developmenta...
(A–C) Expression of fetal markers in kidneys of ZSF1 and lean rats at 6 months of age. Western blot and densitometric analysis of (A) Pax2, (B) Six2, and (C) GDNF protein levels in ZSF1 rats compared with lean rats (left). Representative images of TRα1 and (A) Pax2, (B) Six2, and (C) GDNF stainings on serial sections in lean and ZSF1 rats (right). Fetal markers were highly expressed in the glomerular tuft and parietal cells of ZSF1 rats. (D) Representative images of nestin-positive podocytes (green) expressing Pax2 (red; top) and Six2 (red; bottom) in kidney sections of diabetic rats. (E and F) Western blot and densitometric analysis of (E) Ret and (F) GFRα1 protein levels in ZSF1 rats compared with control rats (left). Representative images of (E) Ret and WT-1 and (F) GFRα1 and nestin stainings in lean and ZSF1 rats (right). Ret and GFRα1 (red) expression significantly increased in kidneys of ZSF1 rats compared with lean rats. Data are expressed as mean ± SEM. *P < 0.05, unpaired Student’s t test. n = 3–4 rats per group. Tubulin protein expression (A) or ponceau red staining (B, C, E, and F) was used as sample loading control. Scale bars: 20 μm. LCA, Lens culinaris agglutinin.