Non-neuronal Tph1 ablation does not alter basal kidney function but mitigates ischemic kidney insufficiency in adult rats

The tryptophan hydroxylase (Tph) gene family encodes the rate-limiting enzymes for serotonin (5-hydroxytryptamine, 5-HT) biosynthesis, a signaling molecule with diverse physiological and pathophysiological actions. Mammals express two isoforms: Tph1, which produces peripheral non-neuronal 5-HT, and Tph2, which drives neuronal 5-HT synthesis. Although both isoforms catalyze the hydroxylation of L-tryptophan to 5-hydroxytryptophan, their distinct expression patterns underlie discrete biological roles. Tph1 is enriched in peripheral tissues, including enterochromaffin cells and kidney proximal tubules, where 5-HT modulates gut motility, secretion, vascular tone, and epithelial ion transport. In contrast, Tph2 expression is largely confined to central and enteric neurons and sustains serotonergic neurotransmission. Here, we investigated the contribution of Tph1-derived peripheral 5-HT to kidney function at baseline and during ischemia–reperfusion (IR) injury using adult transgenic rats harboring a CRISPR-engineered 1-bp deletion in exon 4 of the Tph1 gene. Basal plasma and urinary L-tryptophan concentrations were unchanged in Tph1 knockout (KO) versus wild-type (WT) rats, whereas plasma 5-HT and urinary 5-hydroxyindoleacetic acid (5-HIAA) were markedly reduced, confirming substantial loss of peripheral 5-HT output. Despite this deficit, indices of baseline renal function and systemic hemodynamics were preserved: mean arterial pressure and heart rate (telemetry), transdermal glomerular filtration rate, renal blood flow, renal vascular resistance, plasma creatinine, blood urea nitrogen, and kidney morphology did not differ between KO and WT animals. These findings indicate that non-neuronal 5-HT is dispensable for maintaining resting renal hemodynamics and filtration in adult rats. In contrast, Tph1 ablation conferred significant protection during renal IR injury. A 35-minute period of renal ischemia followed by 24 hours of reperfusion increased renal Tph1 mRNA and protein expression and augmented 5-HT production in WT kidneys, without altering intestinal Tph1 expression or intestinal 5-HT levels, indicating a kidney-specific upregulation of peripheral 5-HT in response to renal ischemic stress. Under these conditions, KO rats exhibited improved renal perfusion and attenuated systemic hemodynamic instability compared with WT counterparts. Histological assessment further revealed reduced tubular dilatation, cast formation, and necrosis in KO kidneys. Collectively, these results identify Tph1-derived peripheral serotonin as a previously unrecognized mediator of renal ischemic insufficiency and implicate peripheral 5-HT signaling in microvascular dysfunction and tubular injury that exacerbate ischemic acute kidney injury in adult rats. Therapeutic strategies that selectively target peripheral 5-HT biosynthesis or signaling may therefore represent a novel approach to mitigating ischemia-related kidney insufficiency in adults. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.