Cldn5, also known as claudin-5, is an essential component of tight junctions. It is crucial for the integrity of the blood-brain barrier (BBB), ensuring CNS homeostasis and protection from damage [1,2,3]. It limits the passive diffusions of ions and solutes at the BBB, which is composed of brain microvascular endothelial cells, pericytes, and astrocytes [2].

In podocyte-specific Cldn5 knockout mice, deletion of Cldn5 exacerbates podocyte injury and proteinuria in a diabetic nephropathy mouse model. Mechanistically, Cldn5 deletion reduces ZO1 expression, induces nuclear translocation of ZONAB, down-regulates WNT inhibitory factor-1 (WIF1) expression, and activates the WNT signaling pathway [4]. In zebrafish models, variants in Cldn5 analogous to those in human patients with a syndrome of seizures, microcephaly, and brain calcifications result in an aberrant function of Cldn5, disrupting the blood-brain barrier and impairing neuronal function [3].

In conclusion, Cldn5 is vital for maintaining the integrity of the BBB and has a significant impact on CNS-related diseases such as those associated with BBB disruption, neurodevelopmental disorders, and cognitive decline [2,3,5]. In the kidney, it plays a role in regulating podocyte function and WNT signaling, affecting kidney disease progression [4]. Studies using gene knockout models in mice and zebrafish have been instrumental in revealing these functions, providing insights into the pathogenesis of related diseases.