Regulation of paracellular transport in the distal nephron

Abstract

Purpose of review: Claudins play a major role in the regulation of paracellular electrolyte reabsorption in the kidney. This review describes the recent findings of the physiological function of claudins underlying the paracellular transport mechanisms for Cl(-) reabsorption in the collecting duct.

Recent findings: There are two parallel mechanisms for transepithelial Cl(-) reabsorption in the collecting duct that utilize the Na-driven Cl-bicarbonate exchanger (NDCBE) and the claudin-based paracellular channel. Histological studies have demonstrated the renal localization of claudin-3, claudin-4, claudin-7, and claudin-8 in the collecting duct. Molecular analyses using several collecting duct cell models have come to the conclusion that claudin-4 functions as a paracellular Cl(-) channel. The channel function of claudin-4 is conferred by a charged lysine residue (K65) in its extracellular loop. Claudin-8 is required for paracellular Cl(-) permeation through its interaction with and recruitment of claudin-4 during tight junction assembly. Claudin-7 provides the basic barrier function to the collecting duct. Genetic ablation of claudin-7 in animals results in systemic dehydration owing to the loss of extracellular ions and fluid in the kidney.

Summary: The paracellular pathway in the collecting duct is an important route for transepithelial Cl(-) reabsorption that determines the extracellular NaCl content and the blood pressure. In the collecting duct cells, claudin-4 and claudin-8 interact to form a paracellular Cl(-) channel, whereas claudin-7 maintains the transepithelial resistance. Different subsets of the claudin family proteins fulfill diverse aspects of the tight junction function that will be fundamental to understanding the physiology of the paracellular pathway.

Figure 1

Ion transport mechanism in the collecting duct. The membrane voltage (V_m) trace depicts the virtual measurement by an electrode that is pushed from the basolateral side through the cell to the luminal side. In this example, the basolateral membrane voltage is −70 mV and the luminal membrane voltage is −45 mV, resulting in a transepithelial V_te of −25 mV with respect to the basolateral side. V_te drives Cl⁻ transport through the paracellular channel. The ENaC mediated salt reabsorption is sensitive to amiloride; the NDCBE-pendrin mediated salt reabsorption is sensitive to thiazide.