Innovative therapeutic approaches to treat chronic kidney disease

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Chronic kidney disease (CKD) has a worldwide prevalence of 10-15% and claims over 130,000 lives annually in the US. Systemic potassium deficiency hastens progression of CKD while higher dietary potassium is protective; however, the mechanistic link between CKD progression and potassium remains entirely unknown. Coordination of total body potassium homeostasis involves both the kidneys and skeletal muscle, with inwardly rectifying potassium (Kir) channels in both organs being critical molecular regulators of this process. I aim to understand how alterations in plasma potassium determine CKD progression. As multiple cell types are involved in the progression of CKD, my focus is on potassium-mediated signaling on proximal tubule epithelial cells and renal macrophages. Using a combination of whole animal kidney physiology, single cell RNA-seq, electrophysiology, and cell biology, I will determine how Kir channels in muscle, proximal tubule cells, and macrophages mediate kidney injury and if these pathways can be targeted as a novel approach to slow CKD progression. I propose to (1) determine how the basolateral potassium channel, Kir4.2, in the proximal tubule mediates kidney injury and metabolism, (2) determine how Kir2.2 in macrophages affect kidney injury, and (3) determine how Kir2.1 and Kir2.2 in skeletal muscle affect systemic potassium balance and in turn, kidney injury. Successful completion of this proposal will change our fundamental understanding of Kir channels as regulators of potassium signaling and identify Kir4.2, Kir2.1, Kir 2.2, and their related pathways as targets for CKD treatment. Further, it will define a muscle-kidney axis linked by plasma potassium as the signaling molecule. This project is my first as an independent investigator and will be supported by significant institutional support from Vanderbilt University Medical Center. This includes funding, laboratory space, and protected research time to establish my research program focused on potassium signaling via Kir channels and CKD.