Abstract: TH-PO105
Pubertal Surge of Sex Hormones Induces Kidney Maturation but Confers Ischemic Vulnerability to Postnatal Kidney
Session Information
- AKI: Inflammation, New Technologies, Omics
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Kitai, Yuichiro, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Sato, Yuki, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Yanagita, Motoko, Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Background
While neonatal kidney is still immature and maturation continues after birth, comprehensive studies on postnatal kidney maturation are limited, and how kidney maturation affects disease susceptibility has not been evaluated.
Methods
We set out to characterize female kidney maturation from infancy to adulthood by morphological analysis and comprehensive gene expression analysis. We also aimed to assess the impact of pubertal sex hormones on postnatal kidney maturation and disease susceptibility.
Results
Comprehensive analysis revealed the increase of transcripts encoding transporters and metabolic enzymes during puberty, associated with the elongation of brush borders of proximal tubules in the deep cortex. Upregulated transporters included solute carriers that transport sodium, organic anion, phosphate, glucose and amino acids, and the most enriched motif near the transcription start sites of these genes was the binding motif of hepatocyte nuclear factor 4a, a transcription factor essential for proximal tubule differentiation, presumably indicating the differentiation of proximal tubule during puberty. Notably, the maturation of adult mice was attenuated by the ovariectomy before puberty, whereas the administration of estrogen, but not progesterone reversed these changes. Unexpectedly, adult mice ovariectomized before puberty unexpectedly showed tolerance to renal ischemia, whereas adult mice ovariectomized after puberty were vulnerable to renal ischemia. Latter result was consistent with recent studies on the protective effects of estrogen against injury. Importantly, insulin-like growth factor 1 receptor (IGF-1R) protein in the kidney decreased during puberty, whereas kidneys of adult mice ovariectomized before puberty showed high expression of IGF-1R like infant kidney, indicating that pubertal sex hormone surge decreases IGF-1R expression. In vivo knockdown of IGF-1R in proximal tubules substantially reduced renal IGF-1R expression, and significantly attenuated ischemic tolerance of adult mice ovariectomized before puberty, implying that IGF-1R signaling in proximal tubule contributes to the tolerance of these mice.
Conclusion
Pubertal sex hormones accelerate kidney maturation but paradoxically confer ischemic vulnerability to postnatal kidney, possibly by inhibiting IGF-1R signaling in proximal tubules.