# Paneth cells and acute kidney injury

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $360,000

## Abstract

Ischemic acute kidney injury (AKI) is a major clinical problem with a very high morbidity and mortality rate.
Patients with AKI frequently develop remote organ dysfunction including liver and intestinal injury. These
extra-renal organ injuries contribute significantly to the overall mortality from AKI. Indeed, most patients who
develop AKI do not die due to AKI but succumb from extra-renal complications. Impeding progress for
effective therapy, the mechanisms of remote organ injury after ischemic AKI remain obscure. The goal of this
proposal is to determine the mechanisms and develop effective treatment for remote organ injury due to
ischemic AKI. Recently, we demonstrated that small intestinal Paneth cells play an important role in hepatic
and intestinal dysfunction and systemic inflammation after renal ischemia reperfusion (IR) injury in mice. We
also demonstrated that Paneth cell-derived IL-17A plays a critical role in generating intestinal and hepatic
injury after ischemic AKI. However, the mechanisms that trigger Paneth cell degranulation and dysregulation
after renal IR remain obscure. Our long-term goal is to elucidate these mechanisms enabling the development
of therapeutic drugs for AKI-induced extra-renal organ dysfunction.
 Exciting preliminary data generated for this proposal suggest that Toll-like receptor-9 (TLR9) activation may
play a role in kidney IR-induced Paneth cell degranulation and IL-17A induction leading to an intestinal
inflammatory response and subsequent liver injury. Furthermore, our preliminary data suggest that Paneth
cells produce large quantities of norepinephrine in response to IL-17A that further propagates inflammatory
response and tissue injury. Finally, preliminary studies suggest that a selective A2b adenosine receptor (AR)
agonist induced anti-inflammatory IL-10 generation in Paneth cells and attenuated intestinal and hepatic injury
after renal IR. Furthermore, an A2bAR agonist reduced Paneth cell production of IL-17A and norepinephrine
after renal IR. Based on these preliminary findings, we hypothesize that ischemic AKI leads to TLR9-mediated
Paneth cell degranulation and IL-17A induction leading to Paneth cell-derived norepinephrine synthesis and
intestinal and hepatic injury. We will further elucidate the mechanisms and potential therapy for hepatic and
intestinal injury after ischemic AKI by testing the following 3 specific aims.
 Aim #1: To determine the mechanisms of Paneth cell dysregulation and degranulation after renal IR.
Aim #2: To demonstrate that Paneth cells synthesize and release norepinephrine as a major mediator
of hepatic and intestinal injury induced by renal IR.
Aim #3: To develop therapy to reduce AKI induced hepatic and intestinal injury.
 In summary, our translational proposal aims to provide a novel understanding of the mechanisms of remote
organ injury after ischemic AKI. Our proposal also aims to identify novel therapies to reduce systemic
complications from ischemic AKI.

## Key facts

- **NIH application ID:** 9888364
- **Project number:** 5R01DK109544-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** H. Thomas Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,000
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888364

## Citation

> US National Institutes of Health, RePORTER application 9888364, Paneth cells and acute kidney injury (5R01DK109544-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9888364. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*