Claudin-17 Deficiency in Mice Results in Kidney Injury Due to Electrolyte Imbalance and Oxidative Stress

Abstract

The multi-gene claudin (CLDN) family of tight junction proteins have isoform-specific roles in blood–tissue barrier regulation. CLDN17, a putative anion pore-forming CLDN based on its structural characterization, is assumed to regulate anion balance across the blood-tissue barriers. However, our knowledge about CLDN17 in physiology and pathology is limited. The current study investigated how Cldn17 deficiency in mice affects blood electrolytes and kidney structure. Cldn17–/– mice revealed no breeding abnormalities, but the newborn pups exhibited delayed growth. Adult Cldn17–/– mice displayed electrolyte imbalance, oxidative stress, and injury to the kidneys. Ingenuity pathway analysis followed by RNA-sequencing revealed hyperactivation of signaling pathways and downregulation of SOD1 expression in kidneys associated with inflammation and reactive oxygen species generation, demonstrating the importance of Cldn17 in the maintenance of electrolytes and reactive oxygen species across the blood-tissue barrier.

Claudin-10 in the Blood Brain Barrier Function of Cerebral Endothelial Cells and Transendothelial Invasion of Breast Cancer Cells

“…The organization and integrity of epithelial TJs depend on interactions between claudins, ZO scaffolding proteins, and the cytoskeleton (25). ZO-1 is a TJ protein that interacts with both occludin and claudins (32,33).…”

“…Prot-Bertoye et al reported that CLDN10 was colocalized with ZO-1 in the human kidney cortex (34). However, Anderson et al reported that although colocalized, the association between claudin, ZO-1, and actin is intermittent rather than continuous, and breaking and reannealing of claudin strands are independent of ZO-1 or actin interactions in fibroblasts (25).…”

“…A functional TJ requires the interactions between the membrane integral TJ proteins (claudins and occluding), the subcoat scaffolding proteins (Zonula Occludens, ZOs) and the cytoskeleton. Claudin association with actin dependents on ZO-1, but colocalization demonstrates intermittent rather than continuous association between claudin, ZO-1, and actin (25). To determine whether inhibiting CLDN10 had an impact on ZO-1, we measured the transcription levels of ZO-1 in the hCMEC/D3 cells.…”

Identification of Modifier Gene Variants Overrepresented in Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis Patients With a More Aggressive Renal Phenotype

“…However, claudins play a critical role on FHHNC and CLDN17 protein, but not RNA, has been described to be present in mouse and human proximal tubules 6 , therefore we decided to include it in our prioritized SKAT-O gene list. A crucial role for CLDN17 in renal function via the regulation of serum electrolytes and tissue reactive oxygen species levels has been recently reported 43 . Although promising, the functional impact on the FHHNC specific variants in NFU1, DMD, HPS5 and CLDN17 and how they contribute to faster renal progression towards kidney failure remains to be characterized.…”