Dataset Information

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

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-?) 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-?, 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.

SUBMITTER: Xu X

PROVIDER: S-EPMC7725566 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Xu Xuewen X Zhang Xinyue X Gao Linlin L Liu Chunfeng C You Kai K

Oxidative medicine and cellular longevity 20201202

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 cyt ...[more]

PMID: 33343804

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Project description:BackgroundThe tight junction proteins claudin-2 and claudin-10a form paracellular cation and anion channels, respectively, and are expressed in the proximal tubule. However, the physiologic role of claudin-10a in the kidney has been unclear.MethodsTo investigate the physiologic role of claudin-10a, we generated claudin-10a-deficient mice, confirmed successful knockout by Southern blot, Western blot, and immunofluorescence staining, and analyzed urine and serum of knockout and wild-type animals. We also used electrophysiologic studies to investigate the functionality of isolated proximal tubules, and studied compensatory regulation by pharmacologic intervention, RNA sequencing analysis, Western blot, immunofluorescence staining, and respirometry.ResultsMice deficient in claudin-10a were fertile and without overt phenotypes. On knockout, claudin-10a was replaced by claudin-2 in all proximal tubule segments. Electrophysiology showed conversion from paracellular anion preference to cation preference and a loss of paracellular Cl- over HCO3- preference. As a result, there was tubular retention of calcium and magnesium, higher urine pH, and mild hypermagnesemia. A comparison with other urine and serum parameters under control conditions and sequential pharmacologic transport inhibition, and unchanged fractional lithium excretion, suggested compensative measures in proximal and distal tubular segments. Changes in proximal tubular oxygen handling and differential expression of genes regulating fatty acid metabolism indicated proximal tubular adaptation. Western blot and immunofluorescence revealed alterations in distal tubular transport.ConclusionsClaudin-10a is the major paracellular anion channel in the proximal tubule and its deletion causes calcium and magnesium hyper-reabsorption by claudin-2 redistribution. Transcellular transport in proximal and distal segments and proximal tubular metabolic adaptation compensate for loss of paracellular anion permeability.

Dataset Information

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

Publications

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

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