Abstract: SA-PO198

Deiodinase 3 Downregulation: A Thyroid Hormone Associated Renoprotective Mechanism

Session Information

  • Glomerular: Cell Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Glomerular

  • 1003 Glomerular: Cell Biology

Authors

  • Tardi, Nicholas J., Rush University Medical Center, Chicago, Illinois, United States
  • Chen, Chuang, Rush University, Chicago, Illinois, United States
  • Dande, Ranadheer, Rush University Medical Center, Chicago, Illinois, United States
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
Background

Deiodinase 3 (D3) is a membrane-bound, catabolic enzyme that regulates cellular metabolism by deactivating tri-iodothyronine (T3), the metabolically active thyroid hormone. As evident by the embryonic lethality of D3 knockout animals, proper regulation of thyroid hormone activity is vital in nearly all cell types. In the kidney, hyperthyroidism increases renal filtration pressure and absorption capacity, while hypothyroidism thickens the glomerular basement membrane and reduces filtration rate. Despite the prevalence of overlapping complications of thyroid hormone disorders and kidney disease, a unifying mechanism regulating T3 homeostasis in the kidney is absent. Though well studied in endocrine tissues, the role of D3 in local regulation of thyroid hormone in renal tissue has not been addressed. To fill this void, we initially assayed for deiodinase expression in podocytes, as they have a significant role in energy metabolism; having mechanisms that respond to both glomeruli derived and circulating changes in hormone levels. After discovering D3 was highly expressed in podocytes and downregulated in injury models, we aimed to determine the significance of D3 dysfunction in glomerular kidney disease.

Methods

The T3 regulatory capacity of D3 was analyzed via cleavage assay using a radioisotope labeled substrate in cultured podocytes treated with puromycin aminonucleoside (PAN). The role of D3 in proteinuric kidney disease was evaluated using podocyte specific D3 KO mice. Glomerular D3 expression was measured in renal biopsies from kidney disease patients by immunofluorescence.

Results

D3 expression and activity was downregulated in response to PAN induced podocyte injury in vitro. D3 expression was prominently diminished at the cell membrane, yet remained concentrated in the golgi and perinuclear region where metabolically active T3 resides. Podocyte specific D3 KO mice responded poorly to LPS-induced acute kidney injury, resulting in heavy proteinuria compared to control. D3 expression in glomeruli of kidney disease patients suffering from minimal change disease, diabetic nephropathy, or focal segmental glomerulosclerosis showed unique profiles amongst diseases.

Conclusion

Our data shows D3 downregulation in podocytes as a response to injury, and suggests D3 may have a renoprotective role in thyroid hormone associated kidney disease.