de la Cruz Julia E, Michael Olugbenga S, Kanthakumar Praghalathan, Falayi Olufunke O, Iwhiwhu Samson A, Afolabi Jeremiah M, Kumar Ravi, Soni Hitesh, Adebiyi Adebowale
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA.
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
Ren Fail. 2025 Dec;47(1):2534018. doi: 10.1080/0886022X.2025.2534018. Epub 2025 Jul 24.
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.
尾加压素II（UII）系统由UII、UII相关肽（URP）及其共同受体UT组成。具有生物活性的UII可由其前体前UII原经丝氨酸蛋白酶弗林蛋白酶的蛋白水解切割产生。肾脏是UII的重要来源，据报道，慢性肾病婴儿的UII水平升高。在此，我们研究了UII系统在新生猪缺血再灌注（IR）诱导的急性肾损伤（AKI）过程中对肾功能丧失的作用。经动脉肾内输注猪UII可减少肾血流量并增加血管阻力，UT拮抗剂尿抑胃素可逆转这些作用。尽管IR并未改变全肾UT的表达，但它增加了弗林蛋白酶、UII、URP和血管UT的水平。尿抑胃素减轻了IR诱导的肾脏灌注不足、AKI生物标志物和循环细胞因子的升高以及肾脏组织学损伤。在原代新生猪近端肾小管上皮细胞（PTECs）中，化学IR（cIR）通过1小时缺血（ATP、葡萄糖和血清缺乏培养基）后再灌注（完全培养基恢复）进行模拟，增加了弗林蛋白酶和UII的产生。弗林蛋白酶抑制剂SSM 3三氟乙酸盐（SSM 3）抑制了cIR诱导的UII合成。此外，尿抑胃素和SSM 3均减轻了cIR诱导的PTEC损伤。这些发现表明，在新生猪中：（1）肾IR上调肾脏组织中的弗林蛋白酶、UII和URP以及微血管中的UT；（2）弗林蛋白酶促进肾上皮细胞中UII的生物合成；（3）抑制UT可预防缺血性AKI。
