Genetic insights into the mechanisms of proliferative glomerulonephritis
Gentzon Hall
Gentzon Hall
Published August 1, 2024
Citation Information: J Clin Invest. 2024;134(15):e183090. https://doi.org/10.1172/JCI183090.
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Commentary

Genetic insights into the mechanisms of proliferative glomerulonephritis

Abstract

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.

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Gentzon Hall

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Figure 1

PI3K signaling in podocyte health and disease.

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PI3K signaling in podocyte health and disease. (A) PI3K signaling is vit...
(A) PI3K signaling is vital for the maintenance of podocyte identity, structure, survival, and function. The PI3K/AKT signaling pathway and its downstream effectors regulate actin cytoskeletal dynamics and survival signaling via slit diaphragm proteins such as CD2AP, Nephrin, NEPH1, and podocin. (B) Derangements of PI3K signaling can lead to podocyte dysfunction and the loss of slit diaphragm integrity. The somatic gain-of-function mutation, p.H1047R, drives hyperactivation of p110α, podocyte hyperplasia, dedifferentiation, loss of slit diaphragm protein expression, and the loss of glomerular integrity. (C) Yamaguchi et al. (21) demonstrated that BYL719 (alpelisib) effectively reduced podocyte PI3K activation and glomerular injury in a patient with proliferative glomerulonephritis caused by the p.H1047R mutation and in experimental models of proliferative glomerulonephritis.