Urotensin II system contributes to ischemic acute kidney injury in neonatal pigs
The urotensin II (UII) system comprises UII, UII-related peptide (URP), and their shared receptor UT. Bioactive UII can be generated from its precursor, prepro-UII, through proteolytic cleavage by the serine protease furin. The kidney serves as a significant source of UII, with elevated levels repor...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Renal Failure |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/0886022X.2025.2534018 |
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| author | Julia E. de la Cruz Olugbenga S. Michael Praghalathan Kanthakumar Olufunke O. Falayi Samson A. Iwhiwhu Jeremiah M. Afolabi Ravi Kumar Hitesh Soni Adebowale Adebiyi |
| author_facet | Julia E. de la Cruz Olugbenga S. Michael Praghalathan Kanthakumar Olufunke O. Falayi Samson A. Iwhiwhu Jeremiah M. Afolabi Ravi Kumar Hitesh Soni Adebowale Adebiyi |
| author_sort | Julia E. de la Cruz |
| collection | DOAJ |
| description | The urotensin II (UII) system comprises UII, UII-related peptide (URP), and their shared receptor UT. Bioactive UII can be generated from its precursor, prepro-UII, through proteolytic cleavage by the serine protease furin. The kidney serves as a significant source of UII, with elevated levels reported in infants with chronic kidney disease. Here, we investigated the contribution of the UII system to the loss of kidney function during ischemia-reperfusion (IR)-induced acute kidney injury (AKI) in neonatal pigs. Intra-arterial renal infusion of porcine UII reduced renal blood flow and increased vascular resistance, effects reversed by the UT antagonist urantide. Although IR did not alter whole-kidney UT expression, it increased furin, UII, URP, and vascular UT levels. Urantide attenuated IR-induced kidney hypoperfusion, elevations in AKI biomarkers and circulating cytokines, and histological kidney injury. In primary neonatal pig proximal tubule epithelial cells (PTECs), chemical IR (cIR), modeled by 1 h of ischemia (ATP-, glucose-, and serum-depleted medium) followed by reperfusion (restoration of complete medium), elevated furin and UII production. The furin inhibitor SSM 3 trifluoroacetate (SSM 3) suppressed cIR-induced UII synthesis. Moreover, both urantide and SSM 3 mitigated cIR-induced PTEC injury. These findings suggest that in neonatal pigs: (1) renal IR upregulates furin, UII, and URP in kidney tissue and UT in the microvasculature, (2) furin promotes UII biosynthesis in renal epithelial cells, and (3) UT inhibition protects against ischemic AKI. |
| format | Article |
| id | doaj-art-e405ed41d1d24f9ba977f2dae0c6d78c |
| institution | Matheson Library |
| issn | 0886-022X 1525-6049 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Renal Failure |
| spelling | doaj-art-e405ed41d1d24f9ba977f2dae0c6d78c2025-07-25T02:23:36ZengTaylor & Francis GroupRenal Failure0886-022X1525-60492025-12-0147110.1080/0886022X.2025.2534018Urotensin II system contributes to ischemic acute kidney injury in neonatal pigsJulia E. de la Cruz0Olugbenga S. Michael1Praghalathan Kanthakumar2Olufunke O. Falayi3Samson A. Iwhiwhu4Jeremiah M. Afolabi5Ravi Kumar6Hitesh Soni7Adebowale Adebiyi8Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USADepartment of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USADepartment of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USADepartment of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USADepartment of Physiology, University of Tennessee Health Science Center, Memphis, TN, USADepartment of Physiology, University of Tennessee Health Science Center, Memphis, TN, USADepartment of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USADepartment of Physiology, University of Tennessee Health Science Center, Memphis, TN, USADepartment of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USAThe urotensin II (UII) system comprises UII, UII-related peptide (URP), and their shared receptor UT. Bioactive UII can be generated from its precursor, prepro-UII, through proteolytic cleavage by the serine protease furin. The kidney serves as a significant source of UII, with elevated levels reported in infants with chronic kidney disease. Here, we investigated the contribution of the UII system to the loss of kidney function during ischemia-reperfusion (IR)-induced acute kidney injury (AKI) in neonatal pigs. Intra-arterial renal infusion of porcine UII reduced renal blood flow and increased vascular resistance, effects reversed by the UT antagonist urantide. Although IR did not alter whole-kidney UT expression, it increased furin, UII, URP, and vascular UT levels. Urantide attenuated IR-induced kidney hypoperfusion, elevations in AKI biomarkers and circulating cytokines, and histological kidney injury. In primary neonatal pig proximal tubule epithelial cells (PTECs), chemical IR (cIR), modeled by 1 h of ischemia (ATP-, glucose-, and serum-depleted medium) followed by reperfusion (restoration of complete medium), elevated furin and UII production. The furin inhibitor SSM 3 trifluoroacetate (SSM 3) suppressed cIR-induced UII synthesis. Moreover, both urantide and SSM 3 mitigated cIR-induced PTEC injury. These findings suggest that in neonatal pigs: (1) renal IR upregulates furin, UII, and URP in kidney tissue and UT in the microvasculature, (2) furin promotes UII biosynthesis in renal epithelial cells, and (3) UT inhibition protects against ischemic AKI.https://www.tandfonline.com/doi/10.1080/0886022X.2025.2534018Urotensin II systemfurinrenal ischemia-reperfusionacute kidney injuryneonatal pigs |
| spellingShingle | Julia E. de la Cruz Olugbenga S. Michael Praghalathan Kanthakumar Olufunke O. Falayi Samson A. Iwhiwhu Jeremiah M. Afolabi Ravi Kumar Hitesh Soni Adebowale Adebiyi Urotensin II system contributes to ischemic acute kidney injury in neonatal pigs Renal Failure Urotensin II system furin renal ischemia-reperfusion acute kidney injury neonatal pigs |
| title | Urotensin II system contributes to ischemic acute kidney injury in neonatal pigs |
| title_full | Urotensin II system contributes to ischemic acute kidney injury in neonatal pigs |
| title_fullStr | Urotensin II system contributes to ischemic acute kidney injury in neonatal pigs |
| title_full_unstemmed | Urotensin II system contributes to ischemic acute kidney injury in neonatal pigs |
| title_short | Urotensin II system contributes to ischemic acute kidney injury in neonatal pigs |
| title_sort | urotensin ii system contributes to ischemic acute kidney injury in neonatal pigs |
| topic | Urotensin II system furin renal ischemia-reperfusion acute kidney injury neonatal pigs |
| url | https://www.tandfonline.com/doi/10.1080/0886022X.2025.2534018 |
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