WWC1 promotes podocyte survival via stabilizing slit diaphragm protein dendrin

Abstract

Previous studies have indicated that glomerular podocyte injury serves a crucial role in proteinuria during the process of chronic kidney disease. The slit diaphragm of podocytes forms the final barrier to proteinuria. Dendrin, a constituent of the slit diaphragm protein complex, has been observed to relocate from the slit diaphragm to the nuclei in injured podocytes and promote podocyte apoptosis. However, the exact mechanism for nuclear relocation of dendrin remains unclear. The expression of WWC1 in podocyte injury induced by lipopolysaccharides (LPS) or adriamycin (ADR) was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and the immunofluorescence assay. The role of WWC1 in podocyte apoptosis was detected by knockdown of WWC1 and flow cytometry. The mRNA and protein expression levels of apoptosis-associated genes Bcl-2-associated X (Bax) and Bcl-2 were measured by RT-qPCR and western blotting. The impact of WWC1 on dendrin nucleus relocation in vitro in podocytes was further evaluated by knockdown of WWC1. Expression of WWC1 significantly decreased in injured podocytes in vitro. The loss-of-function assay indicated that knockdown of WWC1 gene in vitro promoted podocyte apoptosis, accompanied with increased levels of the pro-apoptotic protein Bax and decreased levels of the anti-apoptotic protein Bcl-2. Furthermore, the relocation of dendrin protein was significantly promoted by knockdown of the WWC1 gene. In conclusion, the study indicated that loss of WWC1 may contribute to podocyte apoptosis by inducing nuclear relocation of dendrin protein, which provided novel insight into the molecular events in podocyte apoptosis.

MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes

“…Actually, recent basic and clinical research has also indicated that the nuclear translocation of dendrin induces podocyte apoptosis. [46][47][48][49] Additionally, other groups also demonstrated that MAGI-2 is a key molecule of Rap1 signaling, which is related to actin remodeling and secretion. 27 Taken together, MAGI-2 has three important functions for maintaining the filtration barrier: preventing podocyte apoptosis, regulating Rap1 signaling and stabilizing SD proteins.…”

The Effect of Interleukin-4 and Dexamethasone on RNA-Seq-Based Transcriptomic Profiling of Human Podocytes: A Potential Role in Minimal Change Nephrotic Syndrome

“…WW domain-containing protein 1 (WWC1), also known as kidney and brain scaffolding protein (KIBRA), is predominantly expressed in the kidney [ 47 ]. The knockdown of WWC1 in an in vitro model promoted podocyte apoptosis by inducing nuclear relocation of dendrin protein [ 48 ] and impaired directed cell migration [ 49 ]. Conversely, KIBRA has also been shown to promote podocyte injury by inhibiting YAP signaling, by disrupting actin cytoskeletal dynamics [ 50 ], and by interacting with synaptopodin [ 51 ].…”

Intrinsic disorder and amino acid specificity modulate binding of the WW2 domain in kidney and brain protein (KIBRA) to synaptopodin

“…Synaptopodin (SYNPO) is a 929-residue proline-rich actin cytoskeleton-associated protein, found in kidney podocytes and the dendrites of neurons (1,(20)(21)(22). In kidney podocytes, it is essential for the integrity of the podocyte actin cytoskeleton (23,24) and forms a WW domain-PPXY-mediated complex with KIBRA implicated in cell migration (4).…”