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Norepinephrine released by intestinal Paneth cells exacerbates ischemic AKI.

Small intestinal Paneth cells play a critical role in acute kidney injury (AKI) and remote organ dysfunction by synthesizing and releasing IL-17A. In addition, intestine-derived norepinephrine is a major mediator of hepatic injury and systemic inflammation in sepsis. We tested the hypothesis that small intestinal Paneth cells synthesize and release norepinephrine to exacerbate ischemic AKI. After ischemic AKI, we demonstrate larger increases in portal venous norepinephrine levels compared to plasma norepinephrine in mice consistent with an intestinal source of norepinephrine release after renal IR. We demonstrate that murine small intestinal Paneth cells express tyrosine hydroxylase mRNA and protein, a critical rate-limiting enzyme for the synthesis of norepinephrine. We also demonstrate mRNA expression for tyrosine hydroxylase in human small intestinal Paneth cells. Moreover, freshly isolated small intestinal crypts express significantly higher norepinephrine levels after ischemic AKI compared to sham-operated mice. Suggesting a critical role of IL-17A in Paneth cell-mediated release of norepinephrine, recombinant IL-17A induces norepinephrine release in small intestine of mice. Furthermore, mice deficient in Paneth cells (SOX9 Villin Cre mice) have reduced plasma norepinephrine levels after ischemic AKI. Finally, supporting a critical role for norepinephrine in generating ischemic AKI, treatment with selective alpha-adrenergic antagonists yohimbine and phentolamine protect against murine ischemic AKI with significantly reduced renal tubular necrosis, inflammation and apoptosis, and less hepatic dysfunction. Taken together, we identify the Paneth cells as a critical source of norepinephrine release that may lead to intestinal and liver injury and systemic inflammation after AKI.