Kidney Week

Abstract: TH-PO1089

Targeting Long Noncoding RNA MALAT1 Preserves Endothelial Cell Integrity and Protects against Kidney Fibrosis

Session Information

• CKD: Mechanisms - 1
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Zhao, Qiao, Leids Universitair Medisch Centrum, Leiden, Netherlands

Qiao Zhao, PhD

• van der Pluijm, Loïs, Leids Universitair Medisch Centrum, Leiden, Netherlands

Loïs van der Pluijm, MS, MSc

• Peled, Daniel, NYU Langone Health, New York, New York, United States

Daniel Peled, MD

• de Klerk, Juliette A., Leids Universitair Medisch Centrum, Leiden, Netherlands

Juliette A. de Klerk

• Slieker, Roderick, Leids Universitair Medisch Centrum, Leiden, Netherlands

Roderick Slieker, PhD

• 't Hart, Leen M., Leids Universitair Medisch Centrum, Leiden, Netherlands

Leen M. 't Hart, PhD

• Stam, Wendy, Leids Universitair Medisch Centrum, Leiden, Netherlands

Wendy Stam

• Duijs, Jacques, Leids Universitair Medisch Centrum, Leiden, Netherlands

Jacques Duijs

• Koudijs, Angela, Leids Universitair Medisch Centrum, Leiden, Netherlands

Angela Koudijs

• Rotmans, Joris I., Leids Universitair Medisch Centrum, Leiden, Netherlands

Joris I. Rotmans, MD, PhD

• Van Zonneveld, Anton Jan, Leids Universitair Medisch Centrum, Leiden, Netherlands

Anton Jan Van Zonneveld, PhD

• van Solingen, Coen, NYU Langone Health, New York, New York, United States

Coen van Solingen, PhD

• Bijkerk, Roel, Leids Universitair Medisch Centrum, Leiden, Netherlands

Roel Bijkerk, PhD

Background

Loss of integrity of the peritubular capillary network is directly associated with the development of kidney fibrosis and chronic kidney disease. Here, we aimed to identify long non-coding RNAs (lncRNAs) that could serve as a target to maintain vascular integrity and decrease kidney fibrosis.

Methods

We induced vascular injury and kidney fibrosis by ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) in VE-cadherin-ERT2;tdTomato mice to label and trace endothelial cells (ECs). Subsequently, we sorted Tomato-positive ECs by FACS and profiled for differentially expressed lncRNAs. We reprocessed transcriptomic datasets to assess kidney and circulating MALAT1 levels in patients with kidney fibrosis.

Results

In IRI and UUO, we found 417 and 587 lncRNAs differentially expressed (>2-fold, p<0.05) in the VE-cadherin-derived tomato-positive ECs, respectively. We identified the conserved lncRNA MALAT1 to be increased in ECs in both UUO (7.42-fold) and IRI (2.38 fold). Subsequent gapmer-mediated knockdown of MALAT1 in the UUO model protected against the development of kidney fibrosis, as illustrated by a ~50% decrease in collagen deposition and a concomitant decrease in interstitial α-SMA positive cells. This protective effect was associated with an increase in capillary density and reduced endothelial to mesenchymal transition. Transcriptomic analysis of kidney ECs isolated using FACS from gapmer-MALAT1 treated animals demonstrated that MALAT1 knockdown increased ECM-receptor and cell-cell interaction. Indeed, using the microvessel-on-a-chip platform and transendothelial electric resistance assays, we demonstrated that silencing MALAT1 resulted in increased barrier function, less vascular leakage and a decreased angiogenic response. In addition, MALAT1 knockdown in ECs decreased focal adherens junctions and maintained normal VE-cadherin distribution. Lastly, we found both kidney and circulating MALAT1 levels to be increased in patients with fibrotic kidney disease compared to healthy controls.

Conclusion

Taken together, we demonstrated that targeting MALAT1 preserves endothelial cell function and kidney health and may provide novel strategies to counteract the development of fibrosis.

Funding

• Private Foundation Support