Nephrotic syndrome (NS) is usually treated with steroids, although steroid-resistant forms of NS exist. The mechanism of this steroid resistance is unclear, but now six novel genes mutated in NS have been identified by whole-exome sequencing and linkage analysis in 17 families with partially treatment-sensitive NS.
“We demonstrate that the six gene products physically or functionally interact and delineate two novel complexes that regulate the activity of RHO-like GTPases in NS and that are apparently sensitive to steroid treatment,” says Friedhelm Hildebrandt. The researchers showed that CDK20, MAGI2 and TNS2 interact with the RHOA GTPase-activating protein DLC1 to regulate the activity of RHOA. MAGI2, TNS2 and CDK20 overexpression or DLC1 knockdown in HEK293T cells increased active RHOA levels, whereas MAGI2, TNS2 and CDK20 knockdown or DLC1 overexpression reduced active RHOA levels. Notably, the effects of DLC1 or CDK20 (but not MAGI2 or TNS2) knockdown on active RHOA levels were reversed by steroid treatment. Importantly, MAGI2, CDK20 or DLC1 knockdown in human podocytes reduced their migration rate in vitro, suggesting that the pathogenic effects of NS mutations in this RHOA-regulatory module might occur through podocyte dysfunction.
Finally, the guanine nucleotide exchange factors ITSN1 and ITSN2 were shown to modulate the activity of the RHO-like GTPase CDC42 and regulate filopodia formation in human podocytes in vitro. Additionally, in the lipopolysaccharide (LPS) model of transient NS, recovery from podocyte injury was delayed in ITSN2-deficient mice compared with that in wild-type mice, suggesting that CDC42 is involved in the pathogenesis of NS.
“Our findings should enable the generation of functional assays to identify therapeutic targets for steroid-resistant NS, for which no effective treatment currently exists,” says Hildebrandt.
Ashraf, S. et al. Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nat. Commun. 9, 1960 (2018)
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Otto, G. RHO-like GTPases in nephrotic syndrome. Nat Rev Nephrol 14, 536 (2018). https://doi.org/10.1038/s41581-018-0030-6