<p>The chloride (Cl⁻) channel ClC-5 is a vesicular Cl⁻/H⁺ exchanger belonging to the CLC family of voltage-gated Cl⁻ channels. In mammals and humans, ClC-5 is involved in protein endocytosis and intracellular vesicular transport in the proximal tubule (PT) of the kidney. ClC-5 has also been identified in the amphibian kidneys, but little is known about its intrarenal distribution and physiological role. Our study aimed to perform a morphofunctional characterization of ClC-5 in the kidneys of the grass frog (<i>Rana temporaria</i>) and the lake frog (<i>Pelophylax ridibundus</i>) during receptor-mediated endocytosis, as well as under conditions of hypernatremia, dehydration, and hypervolemia. We used methods of immunocytochemistry, immunohistochemistry, confocal microscopy, and quantification of fluorescent signal intensity. The distribution of ClC-5 along the nephron and its intracellular pattern in glomerular and tubular cells were demonstrated. The colocalization of ClC-5 and the endocytic receptor megalin in the same PT cell compartments, together with a time-dependent increase in ClC-5 amount during lysozyme reabsorption, indicates the involvement of this channel in receptor-mediated endocytosis in frogs. ClC-5 expression in epithelial cells was increased in dehydrated and hypernatremic frogs, but not in hypervolemic ones. Hypernatremia and hypervolemia led to an increased number of ClC-5-containing glomeruli. These results demonstrate that the renal expression pattern of ClC-5 is similar in frogs and mammals. Increased ClC-5 expression is associated with functional changes resulting from modifications of epithelial transport owing to renal osmotic and ionic regulation.</p>