# The Role of Oxidative Signaling through Na/K-ATPase in PNx-induced Anemia

> **NIH NIH R15** · MARSHALL UNIVERSITY · 2022 · $444,000

## Abstract

Summary
 Chronic kidney disease (CKD) is one of the most prominent conditions affecting
approximately 15% of US adults, and most end-stage kidney disease patients have anemia of
CKD. Although the causes of anemia of CKD are multifactorial, present clinical treatments could
only partially reverse anemia status, indicating other mechanisms. Accumulating evidence
suggests that anemia is also the result of accelerated eryptosis that shortens red blood cell (RBC)
lifespan, contributing to the development and progression of anemia of CKD.
 We have demonstrated that the Na/K-ATPase (NKA) α1 subunit, by its interaction with c-
Src under native resting condition, serves as a “receptor” for reactive oxygen species (ROS) and
acts as a feed-forward ROS amplifier. In a pole-ligation 5/6th PNx mouse model, we found that
PNx-induced uremic anemia was ameliorated by blocking NKA-Src signaling with a specific
peptide (pNaKtide) but not with the induction of hemeoxygenase-1. pNaKtide, which was
developed from the N domain of the NKA α1 subunit, binds to the α1-associated c-Src kinase
domain to prevent c-Src phosphorylation, ultimately prevents the ROS amplification. Our
preliminary in vivo data indicate that pNaKtide ameliorated PNx-induced anemia by blocking the
increases in oxidative stress and eryptosis. However, the PNx procedure, with or without
pNaKtide treatment, does not significantly affect plasma iron homeostasis.
 Our central hypothesis is that Accelerated eryptosis play a central role in PNx-induced
anemia through stimulating NKA-Src signaling. Specifically, we hypothesize that PNx-
mediated increases in cardiotonic steroids (CTS), uremic toxins, and oxidative stress stimulate
the NKA-Src signaling, which further induces oxidative stress that leads to the development and
progression of anemia. We further suggest that inhibition of the NKA-Src signaling could serve as
a therapy for anemia in CKD.
 Aim 1 tests the hypothesis that PNx-stimulated NKA-Src signaling increases oxidative
stress and stimulates eryptosis in vivo. We will define the role of adipocytes and the global NKA-
Src signaling in the 5/6th PNx-induced anemia in C57/BL6 mice and global c-Src knock-out mice.
Caveolin-1-null mice and NKA α1 knockdown mice will serve as an alternative.
 Aim 2 tests the hypothesis that the NKA-Src signaling stimulates oxidative stress and RBC
eryptosis in isolated RBCs. We will use isolated RBCs (from C57/BL6 and global c-Src knock-out
mice) to define the NKA-Src signaling complex in RBCs under native resting condition. Again,
caveolin-1-null mice and NKA α1 knockdown mice will serve as an alternative.
 Validation of our hypothesis would further explain the development and progression of
anemia under excessive oxidative stress such as hypertension, aging, obesity, and diabetes. In
addition, a clearer understanding of the molecular mechanisms would have pathophysiological
and therapeutic implications. Further, it also has the potential to provide the framework ...

## Key facts

- **NIH application ID:** 10498130
- **Project number:** 1R15HL164682-01
- **Recipient organization:** MARSHALL UNIVERSITY
- **Principal Investigator:** JIANG LIU
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498130

## Citation

> US National Institutes of Health, RePORTER application 10498130, The Role of Oxidative Signaling through Na/K-ATPase in PNx-induced Anemia (1R15HL164682-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10498130. Licensed CC0.

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