Saturday, November 23, 2024
11/23/2024
Intrauterine growth restriction (IUGR) is associated with perinatal organ injury and the risk of developing cardiovascular, renal, and metabolic disorders in later life. Hence, elucidation of the mechanisms that cause early and progressive organ derangement in growth-restricted newborns is necessary to reduce infant and adult morbidity and mortality. Urotensin II (UII), a potent vasoactive peptide modulates renal function, and its levels are increased in infants with heart and kidney disease. Although its physiological and pathophysiological mechanisms are unresolved, recent evidence suggests that the UII system can promote neurotransmission, thereby altering organ function. Here, we propose a new concept that an increase in UII activity contributes to renal insufficiency in growth-restricted newborns. UII stimulates peripheral sympathoexcitation via Ca2+-dependent tyrosine hydroxylase phosphorylation, catecholamine biosynthesis, and neurotransmission. Sympathetic outflow elicited by UII triggers kidney injury in the neonates. These concepts will be investigated in newborn pigs and a preclinical porcine model of naturally-occurring human asymmetric IUGR. Using innovative procedures for translational research, we will study renal function in small-for-gestational-age neonatal pigs and elucidate the function and regulation of the UII system and the contribution of its components to 1) alterations in neonatal renal hemodynamics and 2) renal insufficiency in growth-restricted infants. We anticipate that our proposed studies will have a significant impact on understanding the pathophysiology of the immature kidney.
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