Abstract: SA-PO315
A TRPC5 Inhibitor Protects Podocytes from Injury in a Minimal Change Disease Rat Model
Session Information
- Cellular Crosstalk in Glomerular Diseases - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Zhou, Yiming, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
- Zhang, Fan, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
- Watts, Andrew James baxter, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
- Vernon, Katherine Anne, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
- Greka, Anna, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
Background
Inhibition of the Rac1-TRPC5 disease pathway in podocytes using specific TRPC5 ion channel inhibitors has been shown to protect from podocyte injury and loss in two pre-clinical animal models: a transgenic rat model of FSGS and a spontaneous hypertensive rat model of FSGS. Since the Rac1-TRPC5 disease pathway has been implicated in the earliest cytoskeletal podocyte changes leading to the development of nephrotic range proteinuria, we asked whether TRPC5 inhibition can confer benefit in a rat model of minimal change disease (MCD).
Methods
We investigated the effect of the specific TRPC5 inhibitor AC1903 in a puromycin aminonucleoside (PAN)-induced rat model. PAN treatment has been shown to induced podocyte injury, foot process effacement and proteinuria with no glomerular histological changes in rats, which most closely resembles human MCD.
Results
We found that a single injection of 50 mg/kg PAN caused podocyte injury and led to a significant increase in proteinuria 7 days after a single injection of PAN. Treatment with AC1903 administered intraperitoneally (i.p.) twice daily significantly reduced the amount of proteinuria induced by PAN injection as measured in 24 hour urine collected in metabolic cages on day 7 post-PAN injection. In histologic analysis of rat kidney tissue, no glomuerular lesions or other obvious changes were found, whereas electron microscopy revealed severe foot process effacement (FPE) induced by single PAN injection. This was significantly ameliorated after treatment with AC1903. Western blotting from rat kidney lysates showed that treatment with AC1903 preserved synaptopodin and podocin abundance in PAN rats.
Conclusion
Taken together, these results show that inhibition of TRPC5 ion channels by AC1903 protects podocytes from injury in a rat model of MCD. Our data thus highlight the potential of this therapeutic strategy for the full spectrum of nephrotic syndrome from MCD to FSGS.
Funding
- NIDDK Support