Gianni Celsi

Sensitive periods for glucocorticoids' regulation of Na+,K+-ATPase mRNA in the developing lung and kidney

ABSTRACT: We have previously reported that in the infant rat renal cortex, a saturating dose of glucocorticoid hormones (GC) rapidly increases the abundance of Na+,K+-ATPase mRNA. We now show that this effect is dose dependent. In the renal cortex of 10-d-old rats, an increase in renal Na+,K+-ATPase mRNA occurs with 2.5 μg beta-methasone/100 g body weight. In subsequent experiments, performed 6 h after a saturating dose (60 μg/100 g body weight), we show that the effect is age dependent. The most marked effects on renal cortical α-mRNA were found at 10 d of age (5.3-± 0.9-fold). A significant increase was also found in 20-d-old rats (1.6-± 0.2-fold), but no effect was found in fetal and 5-d-old rats. Studies were also performed on the lung, where the most marked effect was noted in the perinatal period (2.0-± 0.1-fold 2 d before birth and 1.76 ± 0.2 at 5 d of age), but no effect on α-mRNA was found at 10 and 20 d. In one protocol, the effect of betamethasone on renal Na+K+-ATPase mRNAs abundance was determined in adult adrenalectomized rats. In these rats, betamethasone induced a significant 1.6-± 0.2-fold and 1.8-± 0.3-fold increase in renal Na+,K+-ATPase mRNA. This effect, however, was significantly smaller than the increase induced in intact 10-d-old rats. GC induction of Na+,K+-ATPase mRNA is age and tissue dependent and is dependent on factors other than GC-receptor availability. The GC-sensitive period appears to coincide with the physiologic need for organ maturation.

Influence of age on compensatory renal growth in rats.

ABSTRACT. Rats were nephrectomized (nx) or shamoperated (s) at the age of 5 days (young) or 55 days (adult). Nx and s rats from the same litters were studied at various times 5-75 days after surgery with determination of kidney weight and of renal cortical DNA and protein content. In some protocols protein and DNA content were determined in a more homogenous population of proximal tubular cells. In s rats body weight, kidney weight, renal cortical DNA content, and protein/DNA ratio increased until at least 80 days of age. Body growth was the same in nx and s rats. In young nx rats the remnant kidney was significantly enlarged 5 days after surgery. The difference in kidney size between nx and s rats increased continuously at least until the age of 80 days. The remnant kidney was 125 ± 9% enlarged 3 wk after nx and 175 ± 18% enlarged 8 wk after nx. Five days after nx there was no increase in cortical DNA content but a significant increase in protein/DNA ratio. From 2 wk after nx on, the DNA content was significantly higher in nx than in s rats but the protein/ DNA ratio was the same in nx and s rats. In adult nx rats, the remnant kidney was enlarged to the same extent 3 and 8 wk after surgery (130 ± 7 and 132 ± 8%, respectively). The increase in kidney weight 8 wk after nx was significantly smaller in adult than in young rats. The cortical DNA content and protein/DNA ratio were both moderately but significantly increased in adult rats 8 wk after nx. In conclusion this study has established age-dependent differences regarding the degree, the nature and the duration of compensatory renal growth. These differences can probably be attributed to the high mitotic capacity that is unique in the young kidney.

Influence of Different Protein Intake on Renal Growth in Young Rats

ABSTRACT. We have examined the effect of high protein intake on kidney growth and function in growing rats. The rats were kept on an isocaloric diet containing 12%, 21% and 50% protein, from weaning (16 days) until the time of investigation (18, 20, 24,40 or 80 days). There was no significant difference between the 12% and 21% protein groups in any of the parameters studied. 50% protein increased body weight (BW) and kidney weight (KW). The increase in kidney weight was already evident after 2 days and exeeded the increase in body weight in all age groups. At 24 days renal cortical DNA and the protein/DNA ratio were significantly increased in the 50% protein group. At 40 days the cortical DNA content, but not the protein/DNA ratio, was significantly increased in the 50% group. The glomerular filtration rate (GFR) was studied at 40 days. Total GFR as well as GFR/BW was significantly higher in the 50% group than in the 21% group. In one protocol the diet was discontinued at age 40 days and the rats were studied at age 80 days. In these rats all parameters of renal size and function were the same as in the rats that had had a normal (21%) protein intake from weaning. We conclude that in young rats high protein intake reversibly increases GFR out of proportion to BW and selectively and reversibly stimulates kidney growth by stimulating cell proliferation.

Use of Experimental Models to Study the Development of Renal Function

By use of animal experiments it has been demonstrated that renal cells are immature at birth. Membrane transport is quantitatively and qualitatively different. The control of fluid and electrolyte balance is therefore different in infancy. The increased filtered load at birth as well as hormones will induce tubule maturation. The use of animal experiments will in the future give an insight into how external factors influence growth and maturation.

Fetal Growth Retardation Correlates with Small Kidneys and Higher Blood Pressure in Adulthood • 1847

It has been suggested that impaired fetal kidney development may contribute to the onset of hypertension. This study was designed to investigate the outcome of adult subjects who were born preterm or growth retarded. Subjects(mean age± SEM 26±1 years, n=34) were randomly selected from the neonatal clinical records. They were allocated in 3 groups: born full term with approporiate birth weight, born full term with birth weight median. Gestational age was positively correlated to adult ERPF (r = 0.35, p median. All pathological 24-hours pressure profiles were in the group with renal volume < median. IGF-1 was lowest in the adults born full term but with low birth weights (207±73) and highest in the adults born preterm(258±40) (control adults: 231±21). No correlation was found between gestational age, birth weight or kidney volume with other variables. In conclusion, this study shows a weak but significant correlation between fetal growth retardation and renal function in adulthood. Adult renal volume and GFR are lower in adults who were born prematurely or small for age. Small renal volume in adulthood may be associated to the early onset of hypertension.

Na + ,K + -ATPase IS REGULATED BY GLUCOCORTICOIDS IN AN AGE AND TISSUE DEPENDENT MANNER

The adaptation of newborn mammals to extrauterine life is conditioned by increased expression of enzymes that are of importance for specialized tissue function. In the rat, maturation is accelerated around birth in the lung and around weaning in the kidney. The Na+, K+-ATPase enzyme is responsible for the active transport of ions across the membrane of each cell at the expense of 30% of total body O2 consumption. We have reported that in the infant rat renal cortex, glucocorticoids (GC) rapidly increases the abundance of the Na+, K+-ATPase mRNA, suggesting a direct transcriptional regulation. We have now compared the effect of a single injection of betamethasone, a synthetic highly specific GC, on the abundance of mRNA for the catalytic α and the regulatory β subunits in lung and kidney from fetal, infant and young rats. In the kidney the most prominent effects on the a mRNA was found at 10 days of age (5.3±0.9 fold). A significant increase was also found in 20-day-old rats (1.6±0.2 fold), but no effect was found in fetal and 5-day-old rats. In the lung the most prominent effect was found around birth, but no effect on α mRNA was found at 10 and 20 days. In the kidney there was a coordinate increase in α and β mRNA subunits, while in the lung, the β subunit was stimulated alone, in 10- and 20-day-old rats.Conclusion. GC induction of Na+, K+-ATPase genes is age- and tissue dependent. The GC sensitive period coincides with the physiological need for organ maturation.