# Cellular and Molecular Mechanisms of Renal Anemia

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Advanced chronic kidney disease (CKD) and end stage renal disease (ESRD) are characterized by the
inability of the diseased kidney to respond to hypoxia with adequate production of erythropoietin (EPO), the
glycoprotein hormone that is essential for the generation of red blood cells, and is furthermore associated
with absolute and functional iron deficiency. This leads to the development of anemia, a clinical hallmark of
advanced CKD, which is typically treated with recombinant human EPO and intravenous iron preparations.
The use of recombinant EPO not only represents a major cost factor in the care of patients with advanced
CKD and ESRD, but also is associated with significant cardiovascular risks prompting the FDA to issue
several black box warnings. While recombinant human EPO has been in use for over 25 years, the
pathogenesis of renal anemia is poorly understood. The long-term goals of this research project are to
understand the cellular and molecular mechanisms that underlie the pathogenesis of renal anemia.
 A key pathway in the oxygen-dependent regulation of renal EPO is the prolyl-4-hydroxylase (PHD) /
hypoxia-inducible factor (HIF) pathway. Over the last 10 years our laboratory and others have demonstrated
that HIF-2 regulates the hypoxic induction of EPO in kidney and liver. The pathogenesis of renal anemia is
intricately linked to renal fibrogenesis, as perivascular interstitial cells and pericytes are not only the cellular
sources of EPO in the kidney but also give rise to collagen-producing myofibroblasts. To understand the
regulation of renal EPO production in CKD on a cellular and molecular level unique genetic and
pharmacologic tools are used to dissect the PHD/HIF/EPO axis in normal and in injured kidneys.
 Under this grant we hypothesize that the PHD/HIF oxygen sensing system in conjunction with iron
responsive element binding protein (IRP) plays a critical role in regulating the differentiation state of EPO-
producing perivascular interstitial cells and pericytes. We propose that abnormal HIF-2 regulation generates
specific signals that modulate cell differentiation and function and thus has a crucial role in the pathogenesis
of renal anemia. Our studies aim at a) elucidating the role of the perivascular PHD/HIF-2 axis in anemia
development under renal injury conditions, b) at characterizing molecular phenotype that associates with
EPO-producing cells taking advantage of single cell RNA sequencing technology and c) at investigating the
role of IRP1 in the regulation of HIF-2 activity in renal interstitial cells and EPO production under baseline
and kidney injury conditions.

## Key facts

- **NIH application ID:** 9815323
- **Project number:** 5I01BX002348-06
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Volker Hans Haase
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-10-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815323

## Citation

> US National Institutes of Health, RePORTER application 9815323, Cellular and Molecular Mechanisms of Renal Anemia (5I01BX002348-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815323. Licensed CC0.

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