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Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a significant complication of CKD associated with mortality, for which no curative treatment is currently available. In CKD-MBD, the kidney does not sufficiently respond to parathyroid hormone (PTH), leading to persistent hyperphosphatemia and decreased bioactive vitamin D. Therefore, enhancing PTH’s effect in the kidney is a promising approach to reverse CKD-MBD progression. This study aims to develop a novel treatment for CKD-MBD by selectively enhancing PTH receptor signaling. In proximal renal tubular cells, the a-subunit of heterotrimeric Gs protein (Gsa) mediates PTH receptor signaling to stimulate phosphate excretion and bioactive vitamin D synthesis. Gsa expression level in these cells is crucial for the PTH action because diminished Gsa expression leads to pseudohypoparathyroidism, characterized by renal PTH resistance with hyperphosphatemia, reminiscent of CKD-MBD. Thus, Gsa upregulation in proximal tubular cells should reverse CKD-MBD progression. Importantly, Gsa is “imprinted” specifically in proximal renal tubular cells; i.e., it is expressed only from the maternal allele. Paternal Gsa expression is silenced because of a competition-like mechanism between Gsa and an alternative upstream exon, A/B, which is actively transcribed only from the paternal allele. We aim to de-repress paternal Gsa expression by siRNA-mediated transcriptional silencing of A/B, thus making Gsa biallelically expressed. This project aims to obtain preclinical evidence of this novel approach to treating CKD-MBD. We will use human embryonic stem cell-derived proximal tubule-like cells and kidney organoids to test whether A/B silencing leads to enhanced PTH receptor signaling. Furthermore, employing an adenine-induced mouse CKD model, we will examine whether siRNA-mediated silencing of A/B improves CKD-MBD in vivo. Our strategy targeting Gsa imprinting has two advantages over conventional therapies. First, our approach to enhance PTH receptor signaling can simultaneously normalize several components of CKD-MBD: hyperphosphatemia, decreased bioactive vitamin D, and secondary hyperparathyroidism. Second, since Gsa imprinting operates in the proximal renal tubular cells in a tissue-specific manner, the increased Gsa expression will be confined to these cells. Therefore, adverse effects in other tissues where Gsa plays an important role, such as the heart, liver, and collecting ducts, are not anticipated. Our approach has the potential to bring innovative progress in the clinical care of CKD-MBD.
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