# Counter regulatory mechanisms of cardiotonic steroids in cardio-renal syndrome

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2021 · $378,750

## Abstract

PROJECT SUMMARY
Patients with chronic kidney disease (CKD) often develop a “uremic” cardiomyopathy characterized by diastolic
dysfunction, left ventricular hypertrophy, and cardiac remodeling, despite contemporary therapies of
neurohormonal blockade. We have described a central mechanistic role of cardiotonic steroids (CTS) in
activating pro-inflammatory and pro-fibrotic pathways following renal insult that potentiate this uremic
cardiomyopathy. CTS are a family of steroid hormones including bufadienolides such as marinobufagenin and
telocinobufagin which are significantly elevated in volume expanded conditions such as CKD and can directly
lead to inflammation and cardiac fibrosis upon binding and signaling through the Na+/K+-ATPase.
Paraoxonases (PON) are hydrolytic lactonase enzymes that, depending on isoform, are either generated in the
liver and circulate bound to high-density lipoprotein or are expressed intracellularly at the tissue level. Our
preliminary experimental and clinical data demonstrate an association between diminished lactonase activities
of PON and cardiac disease severity and progression in CKD. Yet the underlying cardioprotective
mechanism(s) are largely unknown. Now, for the first time, we have identified novel mechanistic interactions
between paraoxonases and endogenous CTS. Interestingly, the lactonase activities of PON hydrolyze CTS to
their open-ring forms which, unlike native CTS, are incapable of stimulating collagen formation. Hence, the
overall goal of this proposal is to test the hypotheses that cardioprotection by PON can deter progressive cardiac
fibrosis and diastolic dysfunction in CKD, and that the mechanism occurs via modulation of pathogenetic
pathways induced by endogenous CTS. Our studies will define a novel endogenous substrate for PON and
establish for the first time a counter-regulatory mechanism of CTS activities in attenuating cardiac remodeling
following renal insult.

## Key facts

- **NIH application ID:** 10140132
- **Project number:** 5R01HL137004-05
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** David Joseph Kennedy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,750
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140132

## Citation

> US National Institutes of Health, RePORTER application 10140132, Counter regulatory mechanisms of cardiotonic steroids in cardio-renal syndrome (5R01HL137004-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10140132. Licensed CC0.

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