Heterozygosity for inverted formin-2 (INF2) mutations causes focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth disease. A key question is whether the disease is caused by gain-of-function effects on INF2 or loss of function (haploinsufficiency). Despite established roles in multiple cellular processes, neither INF2 knockout mice nor mice with a disease-associated point mutation display an evident kidney or neurologic phenotype. Here, we compared responses to puromycin aminonucleoside (PAN)–induced kidney injury between INF2 R218Q and INF2 knockout mice. R218Q INF2 mice are susceptible to glomerular disease, in contrast to INF2 knockout mice. Colocalization, coimmunoprecipitation analyses, and cellular actin measurements showed that INF2 R218Q confers a gain-of-function effect on the actin cytoskeleton. RNA expression analysis showed that adhesion and mitochondria-related pathways were enriched in the PAN-treated R218Q mice. Both podocytes from INF2 R218Q mice and human kidney organoids with an INF2 mutation (S186P) recapitulate adhesion and mitochondrial phenotypes. Thus, gain-of-function mechanisms drive INF2-related FSGS and explain this disease’s autosomal dominant inheritance.

Kidney diseases often lack optimal treatments, causing millions of deaths each year. Thus, developing appropriate model systems to study human kidney disease is of utmost importance. Some of the most promising human kidney models are organoids or small organ-resembling tissue collectives, derived from human-induced pluripotent stem cells (hiPSCs). However, they are more akin to a first-trimester fetal kidney than an adult kidney. Therefore, new strategies are needed to advance their maturity. They have great potential for disease modeling and eventually auxiliary therapy if they can reach the maturity of an adult kidney. In this review, we will discuss the current state of kidney organoids in terms of their similarity to the human kidney and use as a disease modeling system thus far. We will then discuss potential pathways to advance the maturity of kidney organoids to match an adult kidney for more accurate human disease modeling.