# Novel Peptide Therapeutics for Cardiorenal Protection in Heart Failure

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $397,500

## Abstract

PROJECT SUMMARY
We advance innovative cardiorenal protective peptide therapeutics for heart failure (HF). Studies will
investigate NPA7, a novel, multivalent and first-in-class peptide, engineered by the applicants to co-target two
biological pathways. These two targets are the natriuretic peptide/particulate guanylyl cyclase-A
receptor/cGMP and Angiotensin1-7/MasR/cAMP systems. We hypothesize that NPA7 mediates cardiorenal
protective properties via these complementary pathways and has synergistic actions beyond pGC-A and
MasR activation alone. Importantly, we also hypothesize that NPA7 is highly effective in a state of an
overactive intrarenal renin-angiotensin-aldosterone system (RAAS) as NPA7 may suppress aldosterone
production/release, antagonize AT1, suppress renin and inhibit angiotensinogen (AGT) in the kidney.
Preliminary studies in experimental HF reveal that beyond sodium retention and congestion, there is activation
of deleterious molecular pathways in the kidney for inflammation, apoptosis, and fibrosis, which may result in
progressive worsening renal function and structure with poor outcomes. While multifactorial mechanisms may
be involved in progressive renal structural and functional impairment in chronic HF, Angiotensin II (ANG II) is a
fundamental mediator. Here NPA7, via pGC-A and MasR, may activate complementary RAAS inhibiting and
antagonizing mechanisms with amplified cardiorenal protection. We also advance the concept that urinary
AGT (uAGT), which drives the renal generation of ANG II, may serve as a novel pathophysiological biomarker
for intrarenal RAAS activation, independent of circulating RAAS. Indeed, a major long-term goal is the
development of uAGT as a novel urinary biomarker for intrarenal RAAS to aid in the identification of high-risk
HF patients that may benefit from NPA7 therapy. Aim 1: Determine the cardiorenal protective properties of
NPA7 in human renal tubular cells, cardiomyocytes and renal and myocardial fibroblasts in vitro. Aim 2:
Determine cardiorenal protective and intrarenal RAAS suppressing properties of chronic NPA7 therapy in a
large animal model of chronic HF that exhibits myocardial pump failure, reduced renal perfusion with
congestion and markedly activated intrarenal RAAS compared to ACEi. Aim 3: Determine uAGT levels in
high-risk chronic HF patients and its association with impaired renal function and its predictive power for future
HF hospitalization and death.

## Key facts

- **NIH application ID:** 9990840
- **Project number:** 5R01HL134668-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** John C Burnett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990840

## Citation

> US National Institutes of Health, RePORTER application 9990840, Novel Peptide Therapeutics for Cardiorenal Protection in Heart Failure (5R01HL134668-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990840. Licensed CC0.

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