Norepinephrine released by intestinal Paneth cells exacerbates ischemic AKI.

Area of Science:

• Gastroenterology
• Nephrology
• Immunology

Background:

• Paneth cells in the small intestine are crucial in acute kidney injury (AKI) and remote organ dysfunction, partly via IL-17A.
• Norepinephrine from the intestine contributes to liver injury and systemic inflammation in sepsis.

Purpose of the Study:

• To investigate if small intestinal Paneth cells synthesize and release norepinephrine, exacerbating ischemic AKI.
• To explore the role of norepinephrine in AKI-induced organ damage and inflammation.

Main Methods:

• Assessed norepinephrine levels in portal venous and plasma after ischemic AKI in mice.
• Examined tyrosine hydroxylase (rate-limiting enzyme for norepinephrine synthesis) expression in murine and human Paneth cells.
• Measured norepinephrine release from small intestinal crypts post-AKI.
• Investigated IL-17A's role in norepinephrine release.
• Utilized Paneth cell-deficient mice (SOX9 villin Cre).
• Administered selective α-adrenergic antagonists (yohimbine, phentolamine) to mice post-AKI.

Main Results:

• Portal venous norepinephrine increased more than plasma norepinephrine after ischemic AKI, suggesting an intestinal source.
• Murine and human Paneth cells express tyrosine hydroxylase.
• Norepinephrine levels were higher in small intestinal crypts after ischemic AKI.
• Recombinant IL-17A stimulated norepinephrine release.
• Paneth cell-deficient mice showed reduced plasma norepinephrine after AKI.
• α-adrenergic antagonist treatment significantly reduced renal tubular necrosis, inflammation, apoptosis, and hepatic dysfunction.

Conclusions:

• Paneth cells are a significant source of norepinephrine release following ischemic AKI.
• Norepinephrine released by Paneth cells contributes to intestinal and liver injury, as well as systemic inflammation.
• Targeting norepinephrine may offer a therapeutic strategy for AKI and its complications.