PIK3R4 Interacts with KIM-1 and Regulates Cell Fate in Proximal Tubule Cells

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PIK3R4 Interacts with KIM-1 and Regulates Cell Fate in Proximal Tubule Cells

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Co-author 1

Yilong Li yli3253@uwo.ca Schulich School of Medicine and Dentistry Microbiology and Immunology London Canada -

Co-author 2

Elene Tutunea-Fatan etutunea@uwo.ca London Health Sciences Centre Research Institute Medicine London Canada -

Co-author 3

Shabitha Arumugarajah sarumug2@uwo.ca Schulich School of Medicine and Dentistry Microbiology and Immunology London Canada -

Co-author 4

Lakshman Gunaratnam lakshman.gunaratnam@lhsc.on.ca Schulich School of Medicine and Dentistry Medicine London Canada *

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Introduction

Kidney injury molecule 1 (KIM-1) is a phosphatidylserine receptor upregulated on the apical membrane of injured proximal tubule epithelial cells (PTECs). KIM-1 can sense dead cells by binding to PS that is exposed on the outer membrane of apoptotic cells. We previously showed that KIM-1 expression is crucial for mitigating tissue damage and promoting repair during AKI. Though KIM-1 can transduce intracellular signalling in PTECs, the mechanisms by which KIM-1 protects against AKI remains incompletely understood. This study aimed to identify novel KIM-1-interacting proteins to address this knowledge gap.

Methods

KIM-1 immunoprecipitates from human PTECs (HK-2) endogenously expressing KIM-1 were stimulated with apoptotic cells and analyzed using liquid chromatography tandem mass spectrometry. Proteins were identified using PEAKS DB proteomics software. Protein-protein interactions were confirmed using Western blot. KIM-1 and its putative interacting protein were silenced using siRNA. Protein knockdown was confirmed using western blot, and cell viability was assayed using kinetic live cell imaging using a BioTek Cytation 5 multimode reader.

Results

The co-immunoprecipitation of KIM-1 and phosphoinositide-3-kinase regulatory subunit 4 (PIK3R4) was confirmed by western blot and mass spectrometry analysis. PI3KR4 interacted with KIM-1 in HK-2 cells independent of apoptotic cell stimulation. Silencing KIM-1 in HK-2 cells increased PIK3R4 expression, whereas silencing PIK3R4 decreased KIM-1 expression. Moreover, silencing PIK3R4 did not affect HK-2 cell proliferation and cell death, but silencing KIM-1 led to increased cell proliferation and death. However, the simultaneous silencing of KIM-1 and PIK3R4 rescued proliferation and cell death.

Conclusion

Our study identified PIK3R4 as a novel and constitutive KIM-1-interacting protein in PTECs. A negative feedback loop in HK-2 cells regulates KIM-1 and PIK3R4 expression. PIK3R4 may be a potential activator of cell proliferation, which KIM-1 inhibits. Further study is required to understand the role of PI3KR4 in vivo during AKI.

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