ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: SA-OR20

Differential Role of Endothelial Prolyl-Hydroxylase 1, 2, 3 in AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Tiwari, Ratnakar, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • An, Si Young, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Kapitsinou, Pinelopi P., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Recently, we showed that pre-ischemic inhibition of endothelial cell (EC)-HIF Prolyl Hydroxylase 2 (Phd2) protects against kidney ischemia-reperfusion injury (IRI). However, the role of post-ischemic inactivation of EC-Phd2 in kidney repair remains unclear. Further, recent single-cell RNA sequencing (scRNA-seq) data suggest a role for other EC-Phd isoforms (EC-Phd1 and EC-Phd3) in oxygen sensing. Here, we wished to address the role of post-ischemic inactivation of EC-Phd1, EC-Phd2, and EC-Phd3 in kidney repair.


Post-ischemic inactivation of EC-Phd1 (EC-Phd1KO), Phd2 (EC-Phd2KO), and Phd3 (EC-Phd3KO) was achieved by the Cdh5(PAC)CreER inducible system. To avoid compensatory effects between Phds, we generated mice with concurrent deletion of EC-Phd1, 2, and 3 (EC-Phd123KO) and induced recombination after IRI. Analysis was performed on day 14 post-IRI.


Post-ischemic inactivation of EC-Phd1 or EC-Phd2 failed to protect kidneys based on mRNA expression of kidney injury molecule 1 (Kim1) and profibrotic genes lysyl oxidase-like 2 (Loxl2), transforming growth factor-beta 1 (Tgfβ1), and smooth muscle actin (Acta2) and histopathological analysis (n=7-8). Surprisingly, the inactivation of EC-Phd3 following IRI exacerbated kidney damage and fibrosis as indicated by increased expression of Kim1, Tgf-β, and Acta2 and deposition of collagen (n=6-8; p< 0.05). Likewise, post-ischemic concurrent deletion of EC-Phd123 increased kidney damage and fibrosis assessed by histopathological analysis and increased expression of profibrotic genes and collagen deposition (n=7-8, p<0.05), respectively, compared to Cre-controls. These changes were associated with significant worsening of renal function assessed by blood urea nitrogen level and transdermal GFR measurements (n=7, p<0.05). scRNA-seq data of the EC-Phd123KO post-ischemic kidneys showed significant transcriptional alterations in the EC cluster compared to Cre- controls with prominent changes in metabolic genes. Significant transcriptional changes were also observed in tubular, fibroblast, and inflammatory cell clusters between the two genotypes.


Post-ischemic concurrent inactivation of Phd1, 2, and 3 significantly impaired renal function, induced fibrosis which was mainly driven by EC-Phd3 inactivation. We delineated a critical role for EC-Phd3 in post-ischemic AKI repair.


  • NIDDK Support