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Increased Kinin Levels and Decreased Responsiveness to Kinins During Aging

¹ Instituto de Ciencias Biomédicas, Programa de Biología Celular y Molecular and Centro FONDAP de Estudios Moleculares de la Célula, Facultad de Medicina, Universidad de Chile, Santiago.
² Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago.
³ Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.

Address correspondence to Felipe Sierra, PhD, Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096. E-mail: Sierraf{at}nia.nih.gov

Kinins are vasoactive peptides released from precursors called kininogens, and serum levels of both T- and K-kininogens increase dramatically as rats age. Kinin release is tightly regulated, and here we show that serum kinin levels also increase with age, from 63 ± 16 nmol/L in young Fisher 344 rats to 398 ± 102 nmol/L in old animals. Both K- and T-kininogens contribute sequentially to this increase, with the increase in middle-aged animals being driven primarily by K-kininogen, whereas the further augmentation in older rats occurs by increasing T-kininogen. By measuring ERK activation, we show that aorta endothelial cells from old animals are hyporesponsive to exogenous bradykinin. However, if serum kinin levels are experimentally decreased by lipopolysaccharide treatment, then the endothelial response to bradykinin is re-established. These results indicate that serum levels of kinins increase with age, whereas the responsiveness of target cells to kinins is reduced in these same animals.