# Renal endothelium and the development of chronic kidney disease in sickle cell disorders

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $608,926

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic kidney disease (CKD), widespread among individuals with sickle cell disease (SCD), is a significant
contributor to morbidity and early mortality. The progressive deterioration of renal health in SCD is associated
with chronic intravascular hemolysis. However, the mechanistic approach to interpreting the hemolysis-driven
pathogenesis of CKD in SCD is limited and therefore targeted therapies based on mechanistic models are
lacking. Progressive loss of renal function, represented by increased albuminuria and reduced glomerular
filtration rate (GFR), is associated with microvascular congestion in humans and mice with SCD. We postulated
that circulating cell-free heme, a product of hemolysis, may instigate persistent endothelial damage that ensues
CKD development. Endothelial protein C receptor (EPCR) maintains endothelial barrier integrity. We discovered
an age-dependent as well as heme-induced loss of EPCR from renal microvascular endothelium in SCD (SS)
mice. Concomitantly, the cleaved soluble form of EPCR (sEPCR) was elevated in the plasma associated with
albuminuria. Using super-resolution ultrasound imaging, we found that younger SS mice challenged with the
repetitive infusion of minimal doses of heme and the older SS mice without heme challenge incur substantial
renal microvascular rarefaction. Heme induces endothelial P-selectin that promotes vascular congestion. Our
pilot data show that reduced EPCR expression is associated with increased P-selectin on renal microvascular
endothelium in the SS mice. Proteinase 3 (PR3), expressed on neutrophils, can degrade EPCR. In our repeated
heme-challenged younger SS mice compared to vehicle-injected mice, we noticed increased expression of PR3
in plasma as well as in accumulated neutrophils from the kidneys. Moreover, we found that heme induces
acetylation of histone 4 Lys 16 residues (H4K16ac) which are known to promote the biosynthesis of PR3. Based
on these preliminary data, we hypothesize that heme-induced P-selectin and PR3 concurrently result in the loss
of EPCR leading to endothelial disintegration, microvascular congestion, and CKD development in SCD. We will
test this hypothesis with three specific aims that integrate experiments with human renal endothelial cells and
neutrophils in vitro, murine models, and clinical samples from multiple cohorts of SCD patients.
Aim 1 will determine that repeated low-dose heme insults promote renal endothelial P-selectin that suppresses
EPCR leading to vascular damage and development of CKD in mice with SCD. Aim 2 will test whether heme-
activated PR3 facilitates EPCR cleavage and expedite CKD in SCD. Aim 3 will determine whether sEPCR and
specific genetic variants of EPCR can indicate the risk of CKD in SCD patients.

## Key facts

- **NIH application ID:** 10805454
- **Project number:** 5R01DK132145-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Samit Ghosh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,926
- **Award type:** 5
- **Project period:** 2023-03-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805454

## Citation

> US National Institutes of Health, RePORTER application 10805454, Renal endothelium and the development of chronic kidney disease in sickle cell disorders (5R01DK132145-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10805454. Licensed CC0.

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