Indirect podocyte injury manifested in a partial podocytectomy mouse model

In progressive glomerular diseases, segmental podocyte injury often expands, leading to global glomerulosclerosis by unclear mechanisms. To study the expansion of podocyte injury, we established a new mosaic mouse model in which a fraction of podocytes express human (h)CD25 and can be injured by the immunotoxin LMB2. hCD25⁺ and hCD25^- podocytes were designed to express tdTomato and enhanced green fluorescent protein (EGFP), respectively, which enabled cell sorting analysis of podocytes. After the injection of LMB2, mosaic mice developed proteinuria and glomerulosclerosis. Not only tdTomato⁺ podocytes but also EGFP⁺ podocytes were decreased in number and showed damage, as evidenced by a decrease in nephrin and an increase in desmin at both protein and RNA levels. Transcriptomics analysis found a decrease in the glucocorticoid-induced transcript 1 gene and an increase in the thrombospondin 4, heparin-binding EGF-like growth factor, and transforming growth factor-β genes in EGFP⁺ podocytes; these genes may be candidate mediators of secondary podocyte damage. Pathway analysis suggested that focal adhesion, integrin-mediated cell adhesion, and focal adhesion-phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin signaling are involved in secondary podocyte injury. Finally, treatment of mosaic mice with angiotensin II receptor blocker markedly ameliorated secondary podocyte injury. This mosaic podocyte injury model has distinctly demonstrated that damaged podocytes cause secondary podocyte damage, which may be a promising therapeutic target in progressive kidney diseases.NEW & NOTEWORTHY This novel mosaic model has demonstrated that when a fraction of podocytes is injured, other podocytes are subjected to secondary injury. This spreading of injury may occur ubiquitously irrespective of the primary cause of podocyte injury, leading to end-stage renal failure. Understanding the molecular mechanism of secondary podocyte injury and its prevention is important for the treatment of progressive kidney diseases. This model will be a powerful tool for studying the indirect podocyte injury.