Kidney Week

Abstract: FR-PO213

A New Perspective on the Pathogenesis of Diabetic Nephropathy: Changes in Thyroid Hormone Signaling Trigger Diabetes-Induced Podocyte Pathology

Session Information

• Diabetic Kidney Disease: Basic - II
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Benedetti, Valentina, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Valentina Benedetti,

• Lavecchia, Angelo Michele, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Angelo Michele Lavecchia,

• Locatelli, Monica, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Monica Locatelli,

• Corna, Daniela, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Daniela Corna,

• Todeschini, Marta, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Marta Todeschini,

• Brizi, Valerio, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Valerio Brizi,

• Novelli, Rubina, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Rubina Novelli,

• Benigni, Ariela, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Ariela Benigni,

• Zoja, Carlamaria, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Carlamaria Zoja,

• Remuzzi, Giuseppe, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Giuseppe Remuzzi,

• Xinaris, Christodoulos, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy

Christodoulos Xinaris,

Background

In diabetic patients, hypothyroidism – both clinical and subclinical – is the most common diabetes-associated disorder, while thyroid dysfunction and low T₃ levels are strongly associated with worse renal clinical outcomes and increased mortality. Based on these data, we investigated the role of thyroid hormone (TH) signaling changes in diabetic nephropathy (DN).

Methods

ZSF1 rats were used as in vivo model of DN and human immortalized podocytes exposed to high glucose or H₂O₂ as in vitro model of diabetic stress. Rat systemic parameters were evaluated at different time-points. Immunohistochemical and western blot analysis were performed on rat renal tissue and human podocytes. Patient biopsies were analyzed using immunohistochemical assays.

Results

In ZSF1 rats, plasma T₃ levels decreased during DN, and this was inversely correlated with metabolic and renal disease worsening, and glomerular histological changes. We observed the re-expression of the fetal TH receptor (TR) isoform TRα1 in podocytes and parietal cells of diabetic rats and patients with DN, and increased glomerular expression of the TH-inactivating enzyme deiodinase 3 (DIO3). In ZSF1 rats, TRα1-positive cells also re-expressed fetal, mesenchymal and damage-related podocyte markers, such as Pax2, Six2, GDNF, desmin, Ret and GFRα1. Podocyte depletion and glomerular and podocyte hypertrophy were evident. In vitro studies showed that podocytes that were exposed to components typical of the diabetic milieu exhibited a significant increase in TRα1 and DIO3 expression, as well as cytoskeleton rearrangements, adult podocyte marker down-regulation and fetal kidney marker up-regulation, in addition to maladaptive cell cycle induction/arrest and TRα1-ERK1/2-mediated hypertrophy. Strikingly, T₃ administration significantly decreased TRα1 and DIO3 expression and reversed the above changes.

Conclusion

Our data show that diabetic stress induces the TH-TRα1 axis to adopt a fetal ligand/receptor relationship pattern that plays a key role in DN-associated podocyte pathology, and create a new perspective on the pathogenesis of DN, suggesting that TRα1 could be a new pharmacological target.

Funding

• Private Foundation Support