Role of Renal Intercalated Cells in Alkali Sensing

Most people know that a major function of the kidneys is to remove waste products and excess fluid from the body via urine production. However, these are not the only functions of these important organs. The kidneys also accomplish the crucial task of keeping the blood pH within normal values. When the blood pH is too high, a condition called alkalosis ensues. Symptoms of alkalosis can include hand tremors, lightheadedness, muscle twitching and spasms, nausea, vomiting, numbness or tingling in the face, hands, or feet, and confusion, which can progress to stupor, coma, and even death. Thus, in conditions of alkalosis, the kidneys promptly activate mechanisms to eliminate bicarbonate in the urine. This will lower the blood pH towards normal values. The elimination of bicarbonate in the urine occurs via highly specialized kidney cells, the beta-intercalated cells. However, how beta-intercalated cells sense blood alkalosis and how they react is poorly understood. We hypothesize that a pH molecular sensor localized on the beta-intercalated cells can detect the blood pH and activate an intracellular signaling cascade, including second messengers like calcium and cellular enzymes as intermediate partners. We also believe that these intermediate partners can activate final effectors like ion transporters and channels that eliminate bicarbonate in the urine. Our research consortium includes scientists from Paracelsus Medical University of Salzburg, Austria, the University Claude Bernard of Lyon, and the University Jules Verne of Amiens, France. In tackling this project, we will use a complementary approach, including experiments in cell culture and mouse models, and employ modern molecular biology and cellular imaging techniques. We will verify if and how stimulation of the pH sensor activates the intermediate partners and the final effectors. We will also show that without the pH sensor, the intermediate partners, or the final effectors, the kidney cannot properly react to alkalosis. Also, when the kidney eliminates bicarbonate, it must reabsorb salt through the final effectors, potentially leading to elevated blood pressure. We hypothesize that the final effectors include at least two important ion transport macromolecules called pendrin and CFTR, which are also found in the inner ear and the lung, respectively. Malfunction of pendrin leads to hearing loss, and malfunction of CFTR causes a devastating lung disease called cystic fibrosis. Thus, our findings will shed light not only on the pathophysiology of the kidney in the context of alkalosis and hypertension but will also involve the inner ear and the lungs.

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