Differential localization patterns of claudin 10, 16, and 19 in human, mouse, and rat renal tubular epithelia

Abstract

Functional properties of the paracellular pathway depend critically on the set of claudins expressed at the tight junction. Two syndromes are causally linked to loss-of-function mutations of claudins: HELIX syndrome caused by genetic variations in the CLDN10 gene, and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis caused by genetic variations in the CLDN16 or the CLDN19 gene. All three genes are expressed in the kidney, particularly in the thick ascending limb (TAL). However, localization of these claudins in humans and rodents remains to be delineated in detail. We studied the segmental and subcellular expression of CLDN10, 16 and 19 in both paraffin-embedded and frozen kidney sections from adult human, mouse and rat, using immunohistochemistry and immunofluorescence, respectively. Here CLDN10 was present in a subset of medullary and cortical TAL cells, localizing to basolateral domains and tight junction in human and rodent kidney. A weak expression was detected at the tight junction of proximal tubular cells. CLDN16 was primarily expressed in a subset of TAL cells in cortex and outer stripe of outer medulla, restricted to basolateral domains and tight junctional structures in both human and rodent kidney. CLDN19 predominantly colocalized with CLDN16 in tight junctions and basolateral domains of TAL but was also found in basolateral and junctional domains in more distal sites. CLDN10 expression at tight junction almost never overlapped with that of CLND16 and CLDN19, consistent with distinct junctional pathways with different permeation profiles in both human and rodent kidney.

Impact of claudin‐10 deficiency on amelogenesis: Lesson from a HELIX tooth

“…Two isoforms of claudin‐10 are expressed in the kidney, 20 claudin‐10a and claudin‐10b. The expression of claudin‐10a, which is anion‐selective, is restricted to the proximal tubule 21 . Claudin‐10b, which is cation‐selective and may determine paracellular sodium permeability, 22,23 is expressed not only in the thick ascending limb of Henle's loop in the kidney 21 but also in other epithelia 24,25 …”

Molecular mechanisms underlying paracellular calcium and magnesium reabsorption in the proximal tubule and thick ascending limb

“…CLDN10 is most abundantly present in the junctions of the TAL in the ISOM, which is devoid of CLDN16. CLDN10 is also expressed in the tight junctions of the OSOM and cortical TAL opposite the junctions populated by CLDN16/CLDN19, forming a mosaic pattern 59,117,118,120 . Coupling between localization and permeability characteristics of TAL cell subtypes was elegantly demonstrated by perfusing TAL segments from the cortex, OSOM, and ISOM and then evaluating the claudin expression in the same tubules by immunohistochemistry 59 .…”

“…114 Similar findings were reported using single-cell RNA sequencing in cells isolated from the mouse kidney. 115 Importantly, the expression of CLDN16 and CLDN19 proteins has been localized primarily to the TAL, 59,110,111,[116][117][118] where they are enriched in the OSOM and cortical TAL segments. 59,117 Their expression is restricted to the tight junction as well as basolateral membrane domains of select TAL cells, where expression of CLDN16 and CLDN19 in the tight junction is likely involved in determining the permeability of the paracellular shunt.…”

“…115 Importantly, the expression of CLDN16 and CLDN19 proteins has been localized primarily to the TAL, 59,110,111,[116][117][118] where they are enriched in the OSOM and cortical TAL segments. 59,117 Their expression is restricted to the tight junction as well as basolateral membrane domains of select TAL cells, where expression of CLDN16 and CLDN19 in the tight junction is likely involved in determining the permeability of the paracellular shunt. Claudins localize along the TAL in a mosaic pattern, meaning that while CLDN16 and CLDN19 colocalize in the tight junctions of select TAL cells, other tight junctions predominantly contain CLDN10.…”

“…CLDN10 is also expressed in the tight junctions of the OSOM and cortical TAL opposite the junctions populated by CLDN16/CLDN19, forming a mosaic pattern. 59,117,118,120 Coupling between localization and permeability characteristics of TAL cell subtypes was elegantly F I G U R E 3 Proposed model of divalent cation reabsorption from the thick ascending limb (TAL). Calcium and magnesium are reabsorbed through a paracellular pore composed of claudin-16 (CLDN16) and claudin-19 (CLDN19).…”