Menendez-Castro Carlos, Cordasic Nada, Fahlbusch Fabian B, Woelfle Joachim, Hilgers Karl F, Hartner Andrea
Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
Department of Nephrology and Hypertension, University Hospital of Erlangen, Erlangen, Germany.
Mol Cell Pediatr. 2023 Aug 25;10(1):8. doi: 10.1186/s40348-023-00164-4.
Clinical studies suggest that female sex plays a protective role in the development and progression of kidney disease. Recent experimental studies indicate that in male rats early nephron loss under ongoing nephrogenesis is accompanied by severe long-term sequelae. In humans, nephron formation occurs mainly in the third trimester, ceasing with 36 weeks of gestation. Due to perinatal complications, preterm infants delivered during this vulnerable period may undergo acute nephron loss. In rats nephrogenesis persists until postnatal day 10, reflecting the situation of human preterms with persisting nephrogenesis. In our animal model of neonatal uninephrectomy, female and male rats were uninephrectomized at day 1 of life. Hypothesizing sex-dependent differences, long-term renal outcome was assessed after 1 year.
In both sexes, neonatal uninephrectomy was not followed by arterial hypertension at 1 year of age. Compensatory weight gain and glomerular hypertrophy of the remaining kidney occurred in uninephrectomized female and male animals. Selected markers of interstitial inflammation and fibrosis were regulated sex-dependently. The expression of monocyte chemoattractant protein-1 was increased in females, while tubulointerstitial infiltration by M1 macrophages was significantly higher in males after neonatal uninephrectomy. Neonatally uninephrectomized male rats had more glomerulosclerosis and podocyte damage compared to females, which was assessed by a semiquantitative score and desmin staining. RT-PCR revealed that after neonatal uninephrectomy in the remaining contralateral kidney of female rats the expression of candidate genes of renal development and function, i.e., wt-1, nephrin, synaptopodin, gdnf, and itga8 was higher than in males.
Based on these observations we conclude that female sex is protective in the long-term response of the kidney to acute nephron loss under active nephrogenesis.
临床研究表明，女性性别在肾脏疾病的发生和发展中起保护作用。最近的实验研究表明，在雄性大鼠中，持续肾发生过程中的早期肾单位丢失伴随着严重的长期后遗症。在人类中，肾单位形成主要发生在妊娠晚期，妊娠36周时停止。由于围产期并发症，在此脆弱期出生的早产儿可能会发生急性肾单位丢失。在大鼠中，肾发生持续到出生后第10天，反映了人类早产儿肾发生持续的情况。在我们的新生儿单侧肾切除动物模型中，雌性和雄性大鼠在出生第1天进行单侧肾切除。基于性别差异的假设，1年后评估长期肾脏结局。
在两性中，新生儿单侧肾切除术后1岁时均未出现动脉高血压。单侧肾切除的雌性和雄性动物的剩余肾脏出现代偿性体重增加和肾小球肥大。间质炎症和纤维化的选定标志物存在性别依赖性调节。单核细胞趋化蛋白-1的表达在雌性中增加，而新生儿单侧肾切除后雄性中M1巨噬细胞的肾小管间质浸润明显更高。与雌性相比，新生儿单侧肾切除的雄性大鼠有更多的肾小球硬化和足细胞损伤，这通过半定量评分和结蛋白染色进行评估。逆转录-聚合酶链反应显示，雌性大鼠新生儿单侧肾切除后，其对侧剩余肾脏中肾发育和功能候选基因（即wt-1、nephrin、synaptopodin、gdnf和itga8）的表达高于雄性。
基于这些观察结果，我们得出结论，在肾发生活跃的情况下，女性性别对肾脏对急性肾单位丢失的长期反应具有保护作用。
