# Role of JNK and BNP in Septic Hypotension

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $76,965

## Abstract

ABSTRACT
Sepsis is the body's overwhelming immune response to infection that leads to organ failure and death.
Refractory hypotension despite administration of vasopressors and fluid resuscitation is the most severe
consequence of sepsis with a ~50% in-hospital mortality rate. Currently, there are no targeted therapies to
treat sepsis. Existing treatment guidelines focus on source control and supportive care, including early
administration of antibiotics and fluid resuscitation. Thus, novel genes and pathways that are involved in the
pathophysiology of sepsis are actively sought with the goal to identify new targets that may offer novel
therapeutic approaches. Cardiac dysfunction and hypotension in sepsis are associated with poor prognosis
and increased mortality. Elevated circulating levels of B-type natriuretic peptide (BNP) correlate with
myocardial stress in sepsis, as well as in other types of heart failure. Our data identified a signaling pathway
that increases BNP production, which leads to lower cardiac output. We have shown that activation of cJun N-
terminal kinase (JNK) contributes in the pathophysiology of sepsis. Our previous studies and new data show
that cardiac JNK activation, which we have shown to be involved in sepsis pathophysiology, increases BNP
expression in septic miceI. Our new data show that JNK inhibition increases blood pressure and tissue
perfusion in septic mice and this is associated with lower plasma BNP levels. Thus, our central hypothesis is
that activation of cardiomyocyte JNK and cJun mediates BNP upregulation in sepsis, and that inhibition of
circulating BNP will alleviate septic hypotension and improve survival. To address our hypothesis we have
designed the following specific aims: Aim 1 - To investigate the mechanism(s) that mediate plasma BNP
increase in sepsis. Aim 2 - To assess the role of BNP in reducing CO and promoting hypotension in septic
mice and patients. In summary, our goal is to elucidate the role of BNP in the pathophysiology of septic
hypotension and explore the therapeutic potential of treatment strategies aimed at regulating BNP expression
or neutralizing circulating BNP. Simultaneously, we will pursue clinical studies to evaluate the translational
impact of our findings. Thus, we anticipate our findings to constitute the basis for designing future clinical
applications aiming to alleviate septic hypotension and organ hypo-perfusion.

## Key facts

- **NIH application ID:** 10389857
- **Project number:** 3R01GM135399-01A1S1
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Konstantinos Drosatos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $76,965
- **Award type:** 3
- **Project period:** 2020-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389857

## Citation

> US National Institutes of Health, RePORTER application 10389857, Role of JNK and BNP in Septic Hypotension (3R01GM135399-01A1S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10389857. Licensed CC0.

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