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Evaluation of podocyte Rac-1 induced kidney disease by modulation of TRPC5

Onur K. Polat, Elena Isaeva, Ke Zhu, Manuel Noben, Yashwanth Sudhini, Beata Samelko, Varsha S. Kumar, Changli Wei, Mehmet M. Altintas, Stuart E. Dryer, Sanja Sever, Alexander Staruschenko, Jochen Reiser
doi: https://doi.org/10.1101/2021.05.25.445694
Onur K. Polat
1Department of Medicine, Rush University Medical Center, Chicago, IL
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Elena Isaeva
2Department of Physiology, Medical College of Wisconsin, Milwaukee, WI
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Ke Zhu
1Department of Medicine, Rush University Medical Center, Chicago, IL
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Manuel Noben
1Department of Medicine, Rush University Medical Center, Chicago, IL
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Yashwanth Sudhini
1Department of Medicine, Rush University Medical Center, Chicago, IL
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Beata Samelko
1Department of Medicine, Rush University Medical Center, Chicago, IL
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Varsha S. Kumar
1Department of Medicine, Rush University Medical Center, Chicago, IL
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Changli Wei
1Department of Medicine, Rush University Medical Center, Chicago, IL
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Mehmet M. Altintas
1Department of Medicine, Rush University Medical Center, Chicago, IL
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Stuart E. Dryer
3Department of Biology and Biochemistry, University of Houston, Houston, TX
4Department of Biomedical Sciences, University of Houston College of Medicine, Houston, TX
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Sanja Sever
5Division of Nephrology, Massachusetts General Hospital, Boston, MA
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Alexander Staruschenko
2Department of Physiology, Medical College of Wisconsin, Milwaukee, WI
6Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI
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Jochen Reiser
1Department of Medicine, Rush University Medical Center, Chicago, IL
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  • For correspondence: jochen_reiser@rush.edu
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Abstract

Background Transient receptor potential channel 5 (TRPC5) is a non-selective cationic ion channel expressed in brain, kidney and other organs where its activation underlies podocyte injury in chronic kidney diseases. Specifically, it has been suggested that a podocyte TRPC5 plasma membrane relocation and channel activation following injury results from activation of Rac-1, propagating podocyte dysfunction and proteinuria. However, previous TRPC5 transgenic mouse studies had questioned a pathogenic role for TRPC5 in podocytes. This investigation was designed to specifically evaluate podocyte Rac-1 activation in the context of functional TRPC5 or a TRPC5 pore mutant to assess effects on proteinuria.

Materials and Methods We employed single cell patch-clamp studies of cultured podocytes and studied proteinuria in transgenic mouse models to characterize the effects of TRPC5 following podocyte Rac-1 activation.

Results Inhibition of TRPC5 by small molecules reportedly ameliorated proteinuria in murine models of proteinuric kidney diseases. In order to directly examine TRPC5 function following Rac-1-induced podocyte injury, we analyzed TRPC5 inhibition in podocyte specific Rac-1 (active) transgenic mice. In addition, we generated a double-transgenic mouse constitutively overexpressing either TRPC5 (TRPC5WT) or a TRPC5 dominant-negative pore mutant (TRPC5DN) in concert with podocyte specific and inducible activation of active Rac-1 (Rac-1Dtg). In electrophysiological experiments, active TRPC5 was detected in primary podocytes overexpressing TRPC5 but not in podocytes with endogenous TRPC5 expression, nor with Rac-1 overexpressing podocytes. TRPC5 inhibition did not change proteinuria in mice with active podocyte Rac-1, nor did an increase or loss of TRPC5 activity affected podocyte injury in Rac-1Dtg animals. Administration of TRPC5 inhibitors, ML204 and AC1903, did not alleviate podocyte Rac-1 induced proteinuria.

Conclusion TRPC5 inhibition did not modify podocyte Rac-1 induced proteinuria in mice.

Significance Statement TRPC5 is a calcium conducting ion channel involved in a plethora of biological functions in the brain, kidney and other organs. In proteinuric kidney diseases, others proposed a model that links activation of small GTPase Rac-1 in podocytes to activation of TRPC5 channels propagating cellular injury and eventually leading to progressive kidney disease. To test this hypothesis, we have developed a novel transgenic mouse model that employs podocyte Rac-1 activation in the presence or absence of a functional TRPC5 channel. Our data shows that transgenic mice with activated Rac-1 in podocytes did not enhance endogenous TRPC5 expression or its activity. Furthermore, TRPC5 blockade or activation did not modify Rac-1 induced proteinuria in mice.

Competing Interest Statement

S.S. and J.R. are co-founders and shareholders of Walden Biosciences, a biotechnology company that develops novel kidney-protective therapies.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 25, 2021.
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Evaluation of podocyte Rac-1 induced kidney disease by modulation of TRPC5
Onur K. Polat, Elena Isaeva, Ke Zhu, Manuel Noben, Yashwanth Sudhini, Beata Samelko, Varsha S. Kumar, Changli Wei, Mehmet M. Altintas, Stuart E. Dryer, Sanja Sever, Alexander Staruschenko, Jochen Reiser
bioRxiv 2021.05.25.445694; doi: https://doi.org/10.1101/2021.05.25.445694
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Evaluation of podocyte Rac-1 induced kidney disease by modulation of TRPC5
Onur K. Polat, Elena Isaeva, Ke Zhu, Manuel Noben, Yashwanth Sudhini, Beata Samelko, Varsha S. Kumar, Changli Wei, Mehmet M. Altintas, Stuart E. Dryer, Sanja Sever, Alexander Staruschenko, Jochen Reiser
bioRxiv 2021.05.25.445694; doi: https://doi.org/10.1101/2021.05.25.445694

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