TRPC5 Channel Inhibition Protects Podocytes in Puromycin-Aminonucleoside Induced Nephrosis Models

Yiming Zhou; Choah Kim; Juan Lorenzo B Pablo; Fan Zhang; Ji Yong Jung; Li Xiao; Silvana Bazua-Valenti; Maheswarareddy Emani; Corey R Hopkins; Astrid Weins; Anna Greka

doi:10.3389/fmed.2021.721865

TRPC5 Channel Inhibition Protects Podocytes in Puromycin-Aminonucleoside Induced Nephrosis Models

Front Med (Lausanne). 2021 Sep 21:8:721865. doi: 10.3389/fmed.2021.721865. eCollection 2021.

Authors

Yiming Zhou^{1

2}, Choah Kim², Juan Lorenzo B Pablo², Fan Zhang¹, Ji Yong Jung^{1

3}, Li Xiao¹, Silvana Bazua-Valenti^{1

2}, Maheswarareddy Emani², Corey R Hopkins⁴, Astrid Weins⁵, Anna Greka^{1

2}

Affiliations

¹ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
² Center for the Development of Therapeutics (CDoT), Broad Institute of MIT and Harvard, Cambridge, MA, United States.
³ Department of Internal Medicine, Gachon University Gil Medical Center, College of Medicine, Incheon, South Korea.
⁴ Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, United States.
⁵ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.

Abstract

Podocyte injury and the appearance of proteinuria are key features of several progressive kidney diseases. Genetic deletion or selective inhibition of TRPC5 channels with small-molecule inhibitors protects podocytes in rodent models of kidney disease, but less is known about the human relevance and translatability of TRPC5 inhibition. Here, we investigate the effect of TRPC5 inhibition in puromycin aminonucleoside (PAN)-treated rats, human iPSC-derived podocytes, and kidney organoids. We first established that systemic administration of the TRPC5 inhibitor AC1903 was sufficient to protect podocyte cytoskeletal proteins and suppress proteinuria in PAN-induced nephrosis rats, an established model of podocyte injury. TRPC5 current was recorded in the human iPSC-derived podocytes and was blocked by AC1903. PAN treatment caused podocyte injury in human iPSC-derived podocytes and kidney organoids. Inhibition of TRPC5 channels reversed the effects of PAN-induced injury in human podocytes in both 2D and 3D culture systems. Taken together, these results revealed the relevance of TRPC5 channel inhibition in puromycin-aminonucleoside induced nephrosis models, highlighting the potential of this therapeutic strategy for patients.

Keywords: Rac1; TRPC5 channel; calcium signaling; kidney disease; podocyte.

Grants and funding

R01 DK099465/DK/NIDDK NIH HHS/United States