Deletion of podocyte Rho-associated, coiled-coil-containing protein kinase 2 protects mice from focal segmental glomerulosclerosis

• Published in: Communications biology Vol. 7; no. 1; p. 402
• Main Authors: Matoba, Keiichiro, Nagai, Yosuke, Sekiguchi, Kensuke, Ohashi, Shinji, Mitsuyoshi, Etsuko, Shimoda, Masayuki, Tachibana, Toshiaki, Kawanami, Daiji, Yokota, Tamotsu, Utsunomiya, Kazunori, Nishimura, Rimei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-04-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 13/89; 14/28; 14/63; 38/77; 631/80/86/2341; 692/4022/1585/2759/1523; 82/80; Animal models; Animals; Biomedical and Life Sciences; Doxorubicin - pharmacology; Glomerulosclerosis, Focal Segmental - genetics; Glomerulosclerosis, Focal Segmental - prevention & control; Kinases; Life Sciences; Mice; Mice, Knockout; Podocytes - metabolism; Protein Serine-Threonine Kinases - metabolism; Protein-serine/threonine kinase; Sclerosis; Sclerosis - metabolism; Sclerosis - pathology; Signal transduction; Therapeutic targets
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06127-3

Focal segmental glomerulosclerosis (FSGS) shares podocyte damage as an essential pathological finding. Several mechanisms underlying podocyte injury have been proposed, but many important questions remain. Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) is a serine/threonine kinase responsible for a wide array of cellular functions. We found that ROCK2 is activated in podocytes of adriamycin (ADR)-induced FSGS mice and cultured podocytes stimulated with ADR. Conditional knockout mice in which the ROCK2 gene was selectively disrupted in podocytes (PR2KO) were resistant to albuminuria, glomerular sclerosis, and podocyte damage induced by ADR injection. In addition, pharmacological intervention for ROCK2 significantly ameliorated podocyte loss and kidney sclerosis in a murine model of FSGS by abrogating profibrotic factors. RNA sequencing of podocytes treated with a ROCK2 inhibitor proved that ROCK2 is a cyclic nucleotide signaling pathway regulator. Our study highlights the potential utility of ROCK2 inhibition as a therapeutic option for FSGS.
ROCK2 activation in podocytes contributes to FSGS. Disrupting ROCK2 in podocytes protects against damage, highlighting its potential as a therapeutic target.