# Molecular and Cellular Pathogenesis of Kidney Disease in Sickle Cell Disorders

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $351,746

## Abstract

PROJECT SUMMARY/ABSTRACT
Kidney disorders comprising acute kidney injury (AKI), chronic kidney disease (CKD) and end-stage renal
disease (ESRD) account for significant morbidity and mortality in sickle cell disease (SCD). AKI, a potent risk
factor for CKD and ESRD, develops primarily in SCD patients hospitalized with vasoocclusive pain crisis (VOC)
or acute chest syndrome (ACS). These characteristic SCD events are associated with rapid drop in hemoglobin
implying acute intravascular hemolysis releasing free circulating heme as a potential trigger for AKI. However,
the precise mechanisms of this association have not been investigated per se, and therefore targeted therapies
based on mechanistic models have not emerged for kidney injuries in SCD. Excess circulating heme is primarily
scavenged by hemopexin (Hx) and delivered to liver for degradation by heme oxygenase-1 (HO-1). Due to
chronic hemolysis, Hx is depleted in SCD. We reasoned that during acute intravascular hemolysis in SCD,
excess extracellular heme will preferentially bind to alpha-1-microglobulin (A1M), a secondary plasma heme
scavenger, which carries free heme to the kidneys. Consequently, renal proximal tubular epithelial cells
(RPTECs) will be exposed to high amount of toxic heme. Induction of intracellular HO-1 normally protects
RPTECs from heme toxicity and averts AKI. We have recently discovered that both patients and mice with SCD
have elevated plasma A1M compare to normal controls. This discovery leads to the development of a clinically
relevant model of AKI in humanized sickle mice by modest elevation of circulating heme through intravenous
injection of purified heme (hemin). Pilot data suggests that SCD patients with higher A1M/Hx ratio posses the
risk of developing AKI following VOC. Heme suppresses hepatocyte nuclear factor 4 alpha (HNF4a) expression
associated with reduced hemopexin expression in liver following acute hemolysis. Preliminary data also showed
that persistent exposure to excess heme renders RPTECs refractory to HO-1 induction during acute hemolysis
in SCD. Moreover, we found that heme induces kruppel-like factor 9 (KLF9) associated with amplification of
mitochondrial ROS (mtROS) that triggers renal tubular epithelial cell death. Based on these data we
hypothesized that enhanced clearance of circulating heme to the kidneys and impaired induction of HO-1 in the
renal tubular epithelium during intravascular hemolysis in SCD trigger tubular cell death and AKI development.
We will test this hypothesis with three specific aims that integrate experiments with cultured and primary human
RPTECs, murine models and clinical biorepository samples including serum, plasma and urine from multiple
cohorts of SCD patients.
Aim 1 will determine whether altered concentration of circulating heme scavenger proteins, can serve as risk
factor for AKI in individuals with SCD. This aim will also determine if multiple hemolytic events develop CKD.
Aim 2 will test the hypothesis that h...

## Key facts

- **NIH application ID:** 10318643
- **Project number:** 5R01DK124426-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Samit Ghosh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,746
- **Award type:** 5
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318643

## Citation

> US National Institutes of Health, RePORTER application 10318643, Molecular and Cellular Pathogenesis of Kidney Disease in Sickle Cell Disorders (5R01DK124426-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10318643. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*