P0549ESSENTIAL ROLES OF TESTOSTERONE IN MALE KIDNEY MATURATION AND REPAIR AFTER INJURY

Abstract Background and Aims The newborn kidneys are structurally and functionally immature. They mature after birth to adapt to extra-uterine life, yet the comprehensive changes of the kidney have not been defined. We investigated the structural and functional changes in the kidney after weaning and examined the effect of testosterone in this maturation process in male mice. Method We performed phenotypic analysis of male mouse kidneys as well as those subjected to castration utilizing a combination of histological analysis, bulk transcriptome analysis, charged metabolite analysis by CE-TOFMS and brush border membrane vesicles LC-MS/MS analysis. Results Bulk transcriptome analysis of postnatal 3 and 8 week male kidneys showed the gene sets enriched in 8w included those associated with metabolic process and transporters in proximal tubule, and structural analysis revealed proximal tubule elongation and hypertrophy in 8 weeks. Most differentially expressed genes (DEGs) identified above were induced between postnatal day 28 and 40, a period of testosterone surge, and were closely correlated with DEGs between adult male and female kidneys. These structural and gene expression changes during maturation were mostly cancelled by castration before testosterone surge. Proximal tubules expressed androgen receptor, and some of these DEGs were upregulated or downregulated by the administration of testosterone in cultured proximal tubules. Consistent results with DEGs were also confirmed at protein levels and related metabolites in vivo. For instance, induction of cystine transporter SLC7A13 expression as well as the increase in cysteine and cysteine-glutathione disulphide-Divalent in the kidney were confirmed during this period. Fatty acid β-oxidation enzymes were also increased during this period. Some of the down-regulated genes across puberty were reactivated after injury and returned to the basal levels with repair. Conclusion Proximal tubules are the main site of maturation after weaning, and acquire the abilities to absorb and metabolize a variety of filtered substances and to increase energy metabolism, which were mainly driven by testosterone.