# Regulation of Renal Injury and Fibrosis by the Plasminogen Receptor, Plg-RKT

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2020 · —

## Abstract

Chronic kidney disease (CKD) has emerged as a silent killer that affects a large segment (15-20%) of the adult
population, and is a major risk factor for end-stage renal disease (ESRD), as well as acute kidney injury,
cardiovascular disease, and premature death. Progressive tubulointerstitial fibrosis is the final common
pathway for all kidney diseases leading to CKD. However, the molecular mechanisms and regulatory steps that
govern and modulate tubulointerstitial fibrogenesis are not fully understood. The response to tissue injury
involves an ordered sequence of partially overlapping phases: inflammatory, proliferation, and extracellular
matrix (ECM) remodeling. Previous work has focused on and demonstrated the key role of macrophages in the
response to renal injury, with distinct macrophage subsets regulating the balance of renal injury, inflammation,
repair, and fibrosis. Results also have shown a key role for tubular epithelial cells (TECs) in renal fibrogenesis.
TECs undergo marked phenotypic changes in acute injury and contribute to both inflammatory and pro-fibrotic
phases. Recent and very exciting work suggests a critical role for plasminogen (Plg) and the Plg activation
system in macrophage function and macrophage involvement in tissue repair, including promotion of key steps
in macrophage phagocytosis and signaling. Results also suggest a direct role for Plg in regulating TEC
function, including key TEC phenotypic changes and signaling in response to renal injury. This proposal is
based on our proteomics-based discovery of a new protein, the plasminogen receptor, Plg-RKT, which
markedly enhances the activation of the zymogen Plg to plasmin, as well as concentrates and localizes the
proteolytic activity of plasmin at specific sites on the cell surface. We have observed prominent expression of
Plg-RKT in macrophages and TECs. We have developed Plg-RKT-/- mouse models, and in recent studies
have demonstrated that Plg-RKT plays a major role in macrophage recruitment and function in response to
inflammatory stimulation. In addition, Plg-RKT-/- mice exhibit impaired tissue remodeling and impaired fibrin
degradation leading to fibrosis in several in vivo settings. Of note, in recent preliminary studies, we have
observed marked increases in renal fibrosis in Plg-RKT-/- mice compared to Plg-RKT+/+ mice in response to
acute renal injury. In addition, we have observed that Plg-RKT expression is substantially altered in response
to experimental renal injury, and in patients with CKD. The overall objectives of this proposal are to test the
hypothesis that Plg-RKT plays a major role in the modulation of renal fibrosis in response to renal injury, and to
delineate the specific mechanisms and pathways that mediate the effect of Plg-RKT on renal ECM remodeling
and repair. We will use a genetic approach to examine the role of cell-specific Plg-RKT in renal ECM
remodeling and the modulation of renal fibrosis in vivo. We will perform studies in Plg-RKT-/-...

## Key facts

- **NIH application ID:** 9898251
- **Project number:** 5I01BX003933-03
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** ROBERT J PARMER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898251

## Citation

> US National Institutes of Health, RePORTER application 9898251, Regulation of Renal Injury and Fibrosis by the Plasminogen Receptor, Plg-RKT (5I01BX003933-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898251. Licensed CC0.

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