# Mechanisms and pathophysiologic impact of claudin-2 modulation

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $767,016

## Abstract

ABSTRACT
The incidence of immune mediated diseases, including inflammatory bowel disease, has grown exponentially
over the last decades. This has been linked to a variety of factors, including dietary preservatives and
processed food. Interest has recently turned to salt (NaCl) is a potential culprit. Abundant data show that high
salt diets can activate intestinal mucosal inflammation and increase severity up to a variety of experimental
disorders, including inflammatory bowel disease and multiple sclerosis, and experimental animals. Further,
some epidemiologic studies have correlated salt intake with frequency of immune-media disease. We recently
discovered that genetic or pharmacological inhibition of claudin-2, which forms a paracellular Na+ channel
within the intestinal epithelium, is an effective intervention in experimental, immune-mediated inflammatory
bowel disease. Our additional studies indicate that claudin-2 overexpression in transgenic mice promotes Th17
polarization of mucosal immune cells while claudin-2 deletion promotes Tregs development. A high salt diet
also activates mucosal IL-17 production in claudin-2 transgenic, but not knockout, mice. Thus, expression of
the paracellular Na+ channel protein claudin-2 synergizes with dietary salt to promote mucosal inflammation.
This is relevant to wide variety of inflammatory intestinal disorders, especially inflammatory bowel disease,
because claudin-2 expression is markedly upregulated in these settings. Thus, this is the potential of creating a
vicious cycle where claudin-2 and dietary salt promote inflammation and, in turn, the inflammation signals back
to the epithelium and causes further upregulation of claudin-2. High salt diets are also well-recognized to affect
the microbiota. We found that the effect of high salt diet on the microbiome was modified by claudin-2
overexpression or deletion. This suggests that the immune changes induced by claudin-2 expression or
deletion also modify the microbiome or, alternatively, microbial changes feedback to alter the immune system.
Examples of both mechanisms have been reported in other settings. Finally, is possible that claudin-2 and
dietary salt affect immune system and microbiota separately. Regardless of which affect his primary, these
data provide strong support for the conclusion that claudin-2 inhibitors should be developed as potential
therapeutic agents. Unfortunately, structural data and general understanding of how claudin-2 paracellular
channels are created and regulated are limited. Thus, the second aim of this proposal seeks to define
structure-function relationships in order to understand the molecular mechanisms that determine claudin-2
biology and to identify potential molecular interfaces to be targeted therapeutically.

## Key facts

- **NIH application ID:** 10882457
- **Project number:** 2R01DK061931-24
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** JERROLD R. TURNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $767,016
- **Award type:** 2
- **Project period:** 2001-09-29 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882457

## Citation

> US National Institutes of Health, RePORTER application 10882457, Mechanisms and pathophysiologic impact of claudin-2 modulation (2R01DK061931-24). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10882457. Licensed CC0.

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