Histone H1 has been implicated in transcriptional regulation, in some instances by inhibiting thyroid receptorDNA interactions. We have shown a postnatal increase in renal cortical Na,KATPase abundance and activity in guinea pig and demonstrated a potential role for thyroid hormones in mediating this increase. Therefore, we wish to understand the ontogeny of H1 histones in the kidney around the time of birth. SDS polyacrylamide gel electrophoresis(SDSPAGE) of renal cortical homogenates revealed a 32 kDa protein band greatly more abundant in renal cortex from nearterm guinea pig fetuses (> 60 days gestation; term is 68 days) than from postnatal cortex. An 11amino acid fragment from this band was sequenced and found to be from a histone H1. Immunoblots of renal cortical homogenates from fetal (F), newborn (NB) and adult guinea pigs (n=6/group) were probed with an antihistone H1 antibody as well as antiserum to guinea pig outer medullary Na,KATPaseαβheterodimer. The abundances of these proteins were inversely related, with histone H1/Na,KATPase declining with maturation (F 1.9±0.5; NB 0.7±0.1; adults 0.02±0.01). This decline was largely accounted for simply by postnatal tubular cell hypertrophy. We isolated nuclei from renal cortex of the 3 groups, measured total histone H1 in silverstained SDSPAGE gels of nuclei and noted, however, that there was still a maturational decline in histone H1 abundance; F had 32±13% greater total histone H1 than NB and 26±12% greater than adults, while the abundance of the nucleosome core histones (H2H4) in these gels did not change with maturation (n=23/group). We also measured histone H1 isoform abundances in nuclei preps from the 3 groups. Similar to prior studies of the postnatal development of the mouse and rat kidneys, we noted a maturational decline in the ratio of histone H1A/histone H1° abundances in guinea pig renal cortical nuclei, (F 4.6±0.2; NB 2.6±0.3; adults 2.1±0.2, n=23/group). We conclude that there are maturational decreases in total H1 histone and shifts in histone H1 isoforms. We speculate that these changes may influence the maturation of renal tubular function. Glucocorticoid and thyroid receptors and response elements are known to interact with histone H1, and so the abundance of histone H1 isoforms may be a critical determinant of how the developing kidney responds to hormonal stimuli.