# Meprin Metalloproteases in Kidney Injury

> **NIH NIH SC1** · NORTH CAROLINA AGRI & TECH ST UNIV · 2020 · $360,000

## Abstract

ABSTRACT
Acute kidney injury (AKI) is associated with high morbidity and mortality rates, and significantly impacts the
quality of life for patients and their families. The cost of treating acute kidney disease in the United States runs
in the tens of billions of dollars annually. However, treatment outcomes for AKI are poor in part because
underlying mechanisms are not fully understood. Ischemia/reperfusion (IR) is the leading cause of AKI and is
associated with inflammation in the initiation, tissue repair, and chronic phases. However, the genes which
modulate inflammation in IR are not fully defined. The proximal kidney tubules are the most susceptible to AKI
IR-induced injury. Meprins, zinc metalloproteases of the astacin family, are the most abundantly expressed
proteins in the brush border membranes (BBMs) of proximal kidney tubules. Meprins are made up of two
subunits, α and β, which form two highly similar protein isoforms; meprin A (a homooligomer of α-α subunits or
a heterooligomer of α-β subunits) and meprin B (a homooligomer of β-β subunits). Disruption of the meprin
genes and administration meprin inhibitors protect mice from IR-induced AKI, suggesting that meprins
exacerbate kidney injury. The mechanisms by which meprins enhance IR-induced kidney injury are not fully
understood. The meprin protein isoforms have common and distinct substrates. Studying the interactions
between meprins and their targets in the kidney will increase understanding of how they impact cell function
and the pathology of kidney disease. Known meprin substrates include several mediators of inflammation such
as (i) proinflammatory cytokines e.g. interleukins (IL-1β, IL-6, IL-18) and chemokines e.g. monocyte chemo-
attractant protein-1 (MCP-1). Proteolytic processing by meprins inactivates IL-6, but activates IL-1β and IL-18.
Additional support for a role for meprins in inflammation came from recent studies demonstrating that meprin α
mediates the release of the anti-inflammatory peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) from
thymosin β4. It is not known if the Ac-SDKP release plays a role in modulating IR-induced kidney injury. A
long-term consequence of inflammation is fibrosis, suggesting that there is an imbalance in extracellular matrix
(ECM) protein metabolism. Since meprins cleave and/or degrade several ECM proteins (e.g. nidogen-1,
laminin, fibronectin, and collagen), they could alleviate the fibrosis associated with IR-induced kidney injury.
Meprins also proteolytically process proteins that mediate cell signaling pathways involved in ECM metabolism
(e.g. the protein kinase A pathway). Proteolytic processing by meprins reduces the kinase activity of three
isoforms of the catalytic subunit of PKA (PKA Cα, Cβ1, and Cβ2). The proposed studies will utilize meprin
knock out mice to determine the mechanisms by which meprins modulate inflammation and the progression of
IR-induced renal injury in the initiation, reparative, and chronic phases. Th...

## Key facts

- **NIH application ID:** 9974554
- **Project number:** 5SC1GM118271-04
- **Recipient organization:** NORTH CAROLINA AGRI & TECH ST UNIV
- **Principal Investigator:** Elimelda Moige Ongeri
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,000
- **Award type:** 5
- **Project period:** 2017-08-18 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974554

## Citation

> US National Institutes of Health, RePORTER application 9974554, Meprin Metalloproteases in Kidney Injury (5SC1GM118271-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9974554. Licensed CC0.

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