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Effect of acetazolamide on potassium reabsorption in the proximal tubule

Grant number: 18/23134-6
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): January 01, 2019
Effective date (End): December 31, 2021
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Gerhard Malnic
Grantee:Beatriz Santos Silva
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acetazolamide is a diuretic that acts by inhibiting the carbonic anhydrase enzyme present in the proximal tubule of the nephron. The enzyme carbonic anhydrase acts by converting water and CO2 into carbonic acid (H2CO3), which ionizes into H+ and HCO3-, so its inhibition reduces the concentration of both and leads to the excretion of Na+ and water. Potassium (K+) is the main ion of the intracellular medium being responsible for the maintenance of some basic cell functions, such as maintenance of membrane potential. The kidneys are responsible for the reabsorption and secretion of K+ along the nephron, which uses specific transport mechanisms in each segment. The proximal tubule reabsorbs most of the potassium filtered through the paracellular pathway by two fundamental mechanisms: solvent drag and electrodiffusion. The drag of K+ by water occurs along the entire proximal tubule. As fluid flows into the proximal tubule, the luminal voltage changes from negative to positive. In the final proximal tubule, the transepithelial voltage is sufficiently positive to provide a favorable force for K+ resorption by the low-resistance paracellular pathways. The claudins are proteins necessary for the formation of tight and leaky junctions that are blocking junctions present in the cellular membrane of epithelial cells that seal them together and are responsible for regulating the permeability of water and solutes in the paracellular pathway. Although the literature describes the existence of 29 claudin isoforms in mammals that regulate this barrier function, claudin 2 (CLDN2) forms paracellular channels for small cations such as sodium and potassium in the intestine and proximal renal tubule. We hope, with this project, to identify the role of CLDN2 in the regulation of potassium reabsorption in the proximal tubule in animals treated with acetazolamide, since the exact mechanism is not known. In this sense, this project intends to investigate the transport of K+ from the tubular lumen to the peritubular capillaries in the proximal tubule of rats through tubular microperfusion in vivo and to identify the role of CLDN2 in the tubular reabsorption of potassium.