Interplay of OSBPL7 and HIF-1α in Hyperoxia-Induced Podocyte Dysfunction

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https://storage.unitedwebnetwork.com/files/1099/5d8340a5f083f29fecb20d74ddb2c23a.pdf

Abstract Title

First Name *

Jeffrey

Last Name *

Pressly

Co-author 1

Joanne Duara jduara@med.miami.edu University of Miami Miller School of Medicine Pediatrics Division of Neonatology Miami

Co-author 2

Jeffrey Pressly jxp1865@med.miami.edu University of Miami Miller School of Medicine Internal Medicine Division of Nephrology Miami

Co-author 3

Ping Ping Chen pchen2@med.miami.edu University of Miami Miller School of Medicine Pediatrics Division of Neonatology Miami

Co-author 4

Rachel Njem rxn404@miami.edu University of Miami Miller School of Medicine Internal Medicine Division of Nephrology Miami

Co-author 5

Sandra Merscher smerscher@med.miami.edu University of Miami Miller School of Medicine Internal Medicine Division of Nephrology Miami

Co-author 6

Shu Wu swu2@med.miami.edu University of Miami Miller School of Medicine Pediatrics Division of Neonatology Miami

Co-author 7

Karen Young kyoung3@med.miami.edu University of Miami Miller School of Medicine Pediatrics Division of Neonatology Miami

Co-author 8

Alessia Fornoni Afornoni@med.miami.edu University of Miami Miller School of Medicine Internal Medicine Division of Nephrology Miami

Co-author 9

Co-author 10

Co-author 11

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

Preterm infants are increasingly susceptible to renal dysfunction, which has been correlated with podocyte derangement. Hyperoxia has been demonstrated to damage podocyte structure and function. The molecular pathways contributing to this phenomenon, particularly those involving Oxysterol-Binding Protein Like 7 (OSBPL7) and Hypoxia-Inducible Factor 1-alpha (HIF-1α), remain elusive. This study aims to unravel these molecular underpinnings

Methods

In vitro experiments were conducted on immortalized human podocytes subjected to either hyperoxic (85% O2) or normoxic conditions for 24 hours. In vivo, neonatal rats were exposed to hyperoxia (85% O2) or room air from postnatal day 1 to day 10. Molecular and structural changes were scrutinized using a comprehensive array of analytical techniques. RNA Sequencing (RNA-Seq) was performed on both human podocytes and rat kidney tissue. Co-immunoprecipitation assays were conducted to probe protein-protein interactions.

Results

Upon hyperoxia exposure, OSBPL7 expression decreased significantly in both human podocytes and in the kidney cortex of neonatal rats. A corresponding decrease in HIF-1α levels was observed in the neonatal rat kidney cortex. Importantly, co-immunoprecipitation assays revealed a binding interaction between OSBPL7 and HIF-1α in Human Embryonic Kidney (HEK) cells. RNA-Seq analyses indicated altered expression of key genes, including significant upregulation of podocyte injury markers CENPF and MKI67 in human podocytes. In the rat glomerular cortex, hyperoxia exposure led to increased expression of genes related to cellular stress and extracellular matrix remodeling, such as PAPPA2, Col2a1, and CYP24A

Conclusions

Our data illuminate the intricate relationship between OSBPL7 and HIF-1α in hyperoxia-induced podocyte injury. We establish for the first time a binding interaction between these two proteins and highlight their potential as therapeutic targets. These findings contribute to a deeper understanding of the molecular mechanisms leading to podocyte dysfunction and renal failure in the context of neonatal hyperoxia. This comprehensive analysis provides a strong foundation for subsequent research aimed at developing targeted therapeutic strategies for renal dysfunctions in neonatal settings.

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