TY - JOUR
T1 - TRPC5 Channel Inhibition Protects Podocytes in Puromycin-Aminonucleoside Induced Nephrosis Models
AU - Zhou, Yiming
AU - Kim, Choah
AU - Pablo, Juan Lorenzo B.
AU - Zhang, Fan
AU - Jung, Ji Yong
AU - Xiao, Li
AU - Bazua-Valenti, Silvana
AU - Emani, Maheswarareddy
AU - Hopkins, Corey R.
AU - Weins, Astrid
AU - Greka, Anna
N1 - Funding Information:
This work was supported by NIH/NIDDK grants DK099465 and DK095045 (AG).
Publisher Copyright:
© Copyright © 2021 Zhou, Kim, Pablo, Zhang, Jung, Xiao, Bazua-Valenti, Emani, Hopkins, Weins and Greka.
PY - 2021/9/21
Y1 - 2021/9/21
N2 - 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.
AB - 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.
KW - Rac1
KW - TRPC5 channel
KW - calcium signaling
KW - kidney disease
KW - podocyte
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U2 - 10.3389/fmed.2021.721865
DO - 10.3389/fmed.2021.721865
M3 - Article
C2 - 34621762
AN - SCOPUS:85116416242
SN - 2296-858X
VL - 8
JO - Frontiers in Medicine
JF - Frontiers in Medicine
M1 - 721865
ER -