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Calcium oxalate crystal induced transcriptomic changes in renal epithelial cells.

ABSTRACT: Small molecule inhibiton of calcium oxalate induced transcriptomic changes of renal epithelial cells.

PROVIDER: PRJEB34728 | ENA |

REPOSITORIES: ENA

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Project description:Kidney stones (KS) are very common, excruciating, and are associated with tremendous healthcare cost, chronic kidney disease (CKD), and end stage renal disease (ESRD). Most KS are composed of calcium oxalate and very small increases in urine oxalate concentration increase the risk for stone formation. Besides its critical role in the pathogenesis of KS, emerging data suggest that disturbed oxalate homeostasis (hyperoxaluria and/or hyperoxalemia) contributes to CKD progression, CKD - and ESRD-associated cardiovascular diseases, progression of cyst growth in autosomal dominant polycystic kidney disease (ADPKD), and delayed graft function & poor renal allograft survival. This emphasizes the urgent need for plasma and urinary oxalate lowering therapies, and enhancing the bowel’s ability to secrete oxalate may effectively do so. We previously identified Oxalobacter formigenes (O. formigenes)-derived factors secreted in its culture conditioned medium (CM) which stimulated oxalate transport by human intestinal Caco2-BBE (C2) cells and reduced urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. Given their remarkable therapeutic potential, we now identified several proteins belonging to Sel1-like family as the major O. formigenes-derived secreted factors, and we determined the crystal structures for six proteins to better understand their function. Importantly, Sel1-14-derived small peptides P8 & P9 were identified as the major factors, with P8+9 closely recapitulate the CM’s effects, including acting through the oxalate transporters SLC26A2 & SLC26A6 and PKA activation. P8+9 also stimulate oxalate transport by human ileal and colonic organoids, confirming that these peptides work in human tissues. Collectively, the identification of these small peptides provide a great opportunity for developing a peptide-based novel therapeutic for hyperoxalemia, hyperoxaluria, and related disorders, impacting the outcomes of patients suffering from KS, primary hyperoxaluria, CKD, ADPKD, ESRD, and renal transplant recipients.

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Calcium oxalate crystal induced transcriptomic changes in renal epithelial cells.

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