# The role of endothelin-1 in tubular injury in sickle cell disease

> **NIH NIH K99** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $152,777

## Abstract

1  Project Summary/Abstract
 2  Mentored Phase: Sickle cell disease (SCD), the most common hemoglobinopathy in US, is associated with
 3  high prevalence of end-stage kidney failure at the median 23 years of age. Due to the lack of kidney-targeted
 4  treatment the mean survival is less than 3 years. SCD milieu induces endothelin-1 (ET-1) and elevated ET-1
 5  levels in SCD patients correlate with microalbuminuria. I recently demonstrated that both ET receptor A (ETA)
 6  and dual ET receptor A and B (ETA+B) antagonists prevented the increase in glomerular permeability to albumin
 7  in a mouse model of SCD, but only the ETA receptor antagonist prevented albuminuria. These findings led me
 8  to the hypothesis that ET-1 via ETA receptor activation contributes to renal injury in SCD mice, while the ETB
 9  receptor provides tubular protection. Thus, the central hypothesis of the mentored phase is that in the SCD
10  milieu, elevated ET-1 and increased ETA receptor activity mediate tubular dysfunction leading to the
11  tubular injury in SCD mice, which is opposed by the ETB activity. The specific aim 1 of the mentored
12  phase will determine if increased ET-1 and the ETA receptor activity mediate tubular injury by decreased
13  tubular albumin uptake mechanism in SCD mice and if ETB receptor antagonism exacerbates ET-1 effects on
14  tubular albumin handling. With the use of new training in in vivo imaging techniques, I will track fluorescent-
15  labeled albumin to assess tubular albumin reabsorption in vehicle- or ET receptor antagonists treated SCD and
16  genetic control mice. We will also determine the direct effect of ET-1 and ET receptors on proximal tubule
17  albumin transporters in ex vivo and in vivo settings. Independent Phase: This phase will focus on an
18  independent line of investigation exploring mechanisms of renal iron handling that builds on previous training.
19  Evidence suggests that increased iron deposition in SCD is associated with albuminuria, both of which can be
20  attenuated by ETA receptor blockade. Although, ET-1 contributes to glomerulopathy in SCD, the relevance of
21  iron-induced toxicity and resultant tubular injury is unclear. Therefore, the overall hypothesis of the
22  independent phase is that elevated ET-1 leads to dysfunctional tubular iron handling, iron overload, and
23  tubular injury in SCD. This will be tested through in vitro experiments on cultured proximal tubules cells and
24  in vivo in SCD mice. The specific aim 2 will determine if impaired tubular iron handling in SCD leads to iron
25  overload via ET-1 induced increase in proximal tubule iron uptake and/or decrease in proximal tubule iron
26  removal. The specific aim 3 will determine mechanisms of iron toxicity that lead to tubular injury in SCD. This
27  will be tested by determining if renal iron-overload leads to tubular injury via oxidative stress and/or
28  mitochondrial dysfunction in SCD nephropathy. The goals of the proposed studi...

## Key facts

- **NIH application ID:** 9977263
- **Project number:** 5K99HL144817-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Malgorzata Kasztan
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $152,777
- **Award type:** 5
- **Project period:** 2019-07-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977263

## Citation

> US National Institutes of Health, RePORTER application 9977263, The role of endothelin-1 in tubular injury in sickle cell disease (5K99HL144817-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9977263. Licensed CC0.

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