Effect of growth and development on tissue vulnerability : a study on the perinatal rat kidney

The infant is more vulnerable than older children and adults to pathological processes, such as metabolic disturbances and kidney infection. We have speculated that the vulnerability of the infant kidney may be related to the fact that the kidney at this time is undergoing rapid growth and development. To test this hypothesis we have tried to establish whether the regulation of growth can be divided into age-specific periods. We found that the proliferative rate and incidence of apoptosis are high in the perinatal rat kidney.

The decrease in cell proliferation was most rapid after the weaning period and was preceded by a decline in apoptosis. In order to identify the growth periods when the infant kidney may be particularly susceptible to damage, we have studied the expression of one of the common factors for growth regulation, protein kinase C (PKC). The maturation of the rat kidney was accompanied by changes in the distribution of PKC isoforms, which continued after the weaning period until adulthood. PKC inhibition retarded growth in proximal tubular (PT) cells, but had a more marked effect on cells from infant than from adult rats. Exposure of PT cells to exogenous PKC inhibitors enhanced apoptosis.

To test the hypothesis that the vulnerability of the infant kidney may be related to the proliferative rate and degree of maturation we have developed experimental models for two common pediatric disorders, salt deficiency (SD) and pyelonephritis. The rat kidney, because of its centrifugal development, provides a good model for studying the effects of growth and maturation on tissue vulnerability. We compared the effect of SD on PT cells in the inner and outer cortices. In weaning, 20-day-old rats, SD inhibited DNA synthesis in the immature PT cells in the outer cortex, but not in the more mature cells in the inner cortex. In vitro studies showed that an increase in intracellular sodium did not stimulate the growth of renal cells.

Our findings suggest that sodium is a permissive factor for renal growth. Pyelonephritis is another example of a disease with a typical age- dependent natural history. In weaning rats, pyelonephritis markedly suppressed DNA synthesis and induced apoptosis in PT cells. Pyelonephritis had no effect on cell proliferation in adult PT cells. In conclusion, the rat kidney continues to undergo maturational changes postnatally with regard to the regulation of growth. Growth and maturation have a pronounced effect on tissue vulnerability. This may explain why diseases have more severe consequences in infancy.