Urotensin II and renal insufficiency in growth-restricted infants.

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.

Grant Number: 5R01DK127625-06
NIH Institute/Center: NIH
Principal Investigator: Adebowale Adebiyi