Biology subjects

Griendling, K. K.

Publications and source records attributed to Griendling, K. K..

3 recordsLinked to original sources

bioRxiv2025

Poldip2 deficiency attenuates disease severity in a mouse model of COVID-19

The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), with the infection resulting in lung inflammation, pulmonary vascular leakage and diffuse alveolar damage. Polymerase delta-interacting protein-2 (Poldip2) mediates lung inflammation and vascular permeability after lipopolysaccharide-induced acute respiratory distress syndrome; however, its role in regulating lung permeability, vascular inflammation and tissue damage following SARS-CoV-2 infection is completely unknown. Here, we assessed the role of Poldip2 in inflammation, immune cell infiltration and lung tissue damage in response to SARS-CoV-2 infection. Our data shows that while deletion of Poldip2 does not affect the susceptibility to SARS- CoV-2 infection, mice heterozygous for Poldip2 exhibit reduced lung tissue damage, reduced cytokine and chemokine induction and decreased infiltration of myeloperoxidase (MPO)-positive neutrophils into inflamed lung tissue. These data reveal that Poldip2 depletion mitigates inflammation and immune cell infiltration following SARS-CoV-2 infection, highlighting the therapeutic potential of Poldip2 inhibition to attenuate severe lung injury.

pathology↗

bioRxiv2021

Characterization of Poldip2 knockout mice: avoiding incorrect gene targeting

POLDIP2 is a multifunctional protein whose roles are only partially understood. Our laboratory previously reported physiological studies performed using a mouse gene trap model, which suffered from two limitations: perinatal lethality in homozygotes and constitutive Poldip2 inactivation. To overcome these limitations, we developed a new conditional floxed Poldip2 model. The first part of the present study shows that our initial floxed mice were affected by an unexpected mutation, which was not readily detected by Southern blotting and traditional PCR. It consisted of a 305 kb duplication around Poldip2 with retention of the wild type allele and could be traced back to the original targeted ES cell clone. We offer simple suggestions to rapidly detect similar accidents, which may affect genome editing using both traditional and CRISPR-based methods. In the second part of the present study, correctly targeted floxed Poldip2 mice were generated and used to produce a new constitutive knockout line by crossing with a Cre deleter. In contrast to the gene trap model, many homozygous knockout mice were viable, in spite of having no POLDIP2 expression. To further characterize the effects of Poldip2 ablation in the vasculature, an RNA-seq experiment was performed in constitutive knockout carotid arteries. Results support the involvement of POLDIP2 in multiple cellular processes and provide new opportunities for future in-depth study of its functions.

genetics↗

bioRxiv2019

VE-cadherin endocytosis controls vascular integrity and patterning during development

Tissue morphogenesis requires dynamic intercellular contacts that are subsequently stabilized as tissues mature. The mechanisms governing these competing adhesive properties are not fully understood. Using gain- and loss-of-function approaches, we tested the role of p120-catenin (p120) and VE-cadherin (VE-cad) endocytosis in vascular development using mouse mutants that exhibit increased (VE-cadGGG/GGG) or decreased (VE-cadDEE/DEE) internalization. VE-cadGGG/GGG mutant mice exhibited reduced VE-cad-p120 binding, reduced VE-cad levels, microvascular hemorrhaging, and decreased survival. By contrast, VE-cadDEE/DEE mutants exhibited normal vascular permeability but displayed microvascular patterning defects. Interestingly, VE-cadDEE/DEE mutant mice did not require endothelial p120, demonstrating that p120 is dispensable in the context of a stabilized cadherin. In vitro, VE-cadDEE mutant cells displayed defects in polarization and cell migration that were rescued by uncoupling VE-cadDEE from actin. These results indicate that cadherin endocytosis coordinates cell polarity and migration cues through actin remodeling. Collectively, our results indicate that regulated cadherin endocytosis is essential for both dynamic cell movements and establishment of stable tissue architecture.\n\nSummary StatementThis study uses mouse genetic and in vitro approaches to demonstrate that cadherin endocytosis is critical for the formation of blood vessels during development by promoting actin-dependent collective cell migration, whereas the inhibition of this endocytosis by p120 binding is essential for vessel stabilization.

cell biology↗