Neonatal Hyperoxia Downregulates Claudin-4, Occludin, and ZO-1 Expression in Rat Kidney Accompanied by Impaired Proximal Tubular Development.

Xuewen Xu,Linlin Gao,Kai You,Chunfeng Liu,Xinyue Zhang,Joël R Drevet

doi:10.1155/2020/2641461

Xuewen Xu, Linlin Gao + Show 4 more

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https://doi.org/10.1155/2020/2641461

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Abstract

Hyperoxia is essential to manage in preterm infants but causes injury to immature kidney. Previous study indicates that hyperoxia causes oxidative damage to neonatal kidney and impairs renal development. However, the underlying mechanisms by which neonatal hyperoxia effects on immature kidney still need to be elucidated. Tight junction, among which the representative proteins are claudin-4, occludin, and ZO-1, plays a crucial role in nephrogenesis and maintaining renal function. Inflammatory cytokines are involved in the pleiotropic regulation of tight junction proteins. Here, we investigated how neonatal hyperoxia affected the expression of key tight junction proteins and inflammatory factors (IL-6 and TNF-α) in the developing rat kidneys and elucidated their correlation with renal injury. We found claudin-4, occludin, and zonula occludens-1 (ZO-1) expression in proximal tubules was significantly downregulated after neonatal hyperoxia. The expression of these tight junction proteins was positively correlated with that of IL-6 and TNF-α, while claudin-4 expression was positively correlated with injury score of proximal tubules in mature kidneys. These findings indicated that impaired expression of tight junction proteins in kidney might be a potential mechanism of hyperoxia-induced nephrogenic disorders. It provides new insights to further study oxidative renal injury and development disorders and will be helpful for seeking potential therapeutics for hyperoxia-induced renal injury in the future.

Highlights

Supplemental oxygen therapy is commonly administered in the management of premature infants with respiratory disorders [1, 2]
To evaluate inflammatory cytokine production after hyperoxia and to quantify the total expression of tight junction proteins in rat kidneys exposed to neonatal hyperoxia, we examined the expression of claudin-4, occludin, zonula occludens-1 (ZO-1), Interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) in the kidneys of newborn rats by western blotting (Figure 4(a))
Our current study demonstrated that neonatal hyperoxia downregulated ZO-1 expression in both neonatal and adult proximal tubules, which might impair the proliferation of proximal tubular cells during nephrogenesis

Summary

Introduction

Supplemental oxygen therapy (hyperoxia) is commonly administered in the management of premature infants with respiratory disorders [1, 2]. Increasing evidence from various clinical and experimental observations suggests that neonatal hyperoxia may cause oxidative damage and adversely affects glomerular and tubular maturity [3, 4]. These adverse effects are manifested by enlarged renal corpuscles, renal tubular injuries, and interstitial inflammation during the perinatal period, which might extend into adulthood and influence renal function [5, 6]. The paracellular permeability of collecting ducts, which play a crucial role in electrolyte reabsorption and secretion, is mainly regulated by tight junctions [11]

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