Genetic insights into the mechanisms of proliferative glomerulonephritis

Glomerular visceral epithelial cells (i.e., podocytes) are an essential component of the tripartite glomerular filtration barrier. Healthy podocytes are terminally differentiated cells with limited replicative capacity; however, inappropriate cell cycle reentry can be induced in podocytes by various injurious stimuli. In this issue of the JCI, Yamaguchi et al. report on a somatic mosaic gain-of-function mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic α subunit (p110α, encoded by PIK3CA). The study reveals that activating mutations of p110α can drive podocyte proliferation in PIK3CA-related overgrowth syndrome (PROS). They also showed that selective, small-molecule inhibitors of p110 may be useful for the treatment of proliferative glomerulonephritis.