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Podocyte injury and the appearance of proteinuria are key features of several progressive kidney diseases. Genetic deletion or selective inhibition of TRPC5 channels with small-molecule inhibitors protects podocytes in rodent models of disease, but less is known about the human relevance and translatability of TRPC5 inhibition. Here, we investigate the effect of TRPC5 inhibition in puromycin aminonucleoside (PAN)-treated human iPSC-derived podocytes and kidney organoids. We first established that systemic administration of the TRPC5-specific blocker AC1903 was sufficient to protect podocyte cytoskeletal proteins and suppress proteinuria in PAN-induced nephrosis in rats, an established model of podocyte injury and progressive kidney disease. PAN treatment also triggered the Rac1-TRPC5 injury pathway in human iPSC-derived podocytes and kidney organoids. TRPC5 current was recorded in human iPSC-derived podocytes, and was blocked by AC1903. The TRPC5 blocker also reversed the effects of PAN-induced injury in human podocytes in both 2D and 3D culture systems. Taken together, these results revealed the relevance of the TRPC5-Rac1 pathway in human kidney tissue highlighting the potential of this therapeutic strategy for patients.

The root growth angle defines how roots grow towards the gravity vector and is among the most important determinants of root system architecture. It controls water uptake capacity, nutrient use efficiency, stress resilience and as a consequence yield of crop plants. We demonstrated that the ( ) mutant of barley exhibits steeper root growth of seminal and lateral roots and an auxin independent higher responsiveness to gravity compared to wild type plants. We cloned the gene by a combination of bulked segregant analysis and whole genome sequencing. Subsequent validation experiments by an independent CRISPR/Cas9 mutant allele demonstrated that encodes a STERILE ALPHA MOTIF domain containing protein. hybridization experiments illustrated that is expressed from the root cap to the elongation zone. Subcellular localization experiments revealed that localizes to the nucleus and cytoplasm. We demonstrated the evolutionary conserved role of in root growth angle control between barley and wheat by knocking out the orthologs in the A and B genomes of tetraploid durum wheat. By combining laser capture microdissection with RNA-seq, we observed that seven expansin genes were transcriptionally downregulated in the elongation zone. This is consistent with a role of in this region of the root where the effect of gravity sensing is executed by differential cell elongation. Our findings suggest that is an evolutionary conserved regulator of root growth angle in barley and wheat that could be a valuable target for root-based crop improvement strategies in cereals.