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McNaughton, K.

Publications and source records attributed to McNaughton, K..

2 recordsLinked to original sources
bioRxiv2026

Type A Intercalated Cell Dysfunction Disrupts Renal Epithelial/Immune Balance and Impairs Host Defense During UTI

Intercalated cells (ICs) of the renal collecting duct are traditionally recognized for their role in acid-base homeostasis, but growing evidence suggests they also participate in innate immune defense. Although ICs have been implicated in renal antimicrobial function, their specific role in coordinating immune responses during urinary tract infection (UTI) remains unclear. Using Ae1 R607H knock-in mice, a distal renal tubular acidosis (dRTA) model with A-intercalated cell (A-IC) dysfunction, we examined the renal response to uropathogenic Escherichia coli (UPEC). Mice with A-IC dysfunction exhibited higher bacterial loads 24 h post-infection and increased renal expression of antimicrobial peptides lipocalin-2 (Lcn2), galectin-3 (Lgals3), and cathelicidin-related antimicrobial peptide (Camp). Pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1{beta} (IL-1{beta}) were elevated at both transcript and protein levels, whereas tumor necrosis factor- (TNF-) increased only at the protein level. Interleukin-10 (IL-10) showed a modest rise in mRNA. Chemokines C-X-C motif chemokine ligand 2 (Cxcl2) and C-C motif chemokine ligand 2 (Ccl2) were also upregulated, accompanied by excessive neutrophil infiltration and a marked shift in renal myeloid-cell composition. A-IC dysfunction therefore disrupts epithelial-immune homeostasis, resulting in exaggerated inflammation and impaired immune resolution. These findings identify A-ICs as essential epithelial immunomodulators that integrate antimicrobial defense, cytokine regulation, and immune-cell recruitment during UTI.

physiology↗
bioRxiv2026

A Kidney Stone Associated CLDN4 Variant Impairs Tight Junction Stability and Paracellular Ion Permeability

Claudin-4 (CLDN4) is a key determinant of paracellular ion transport in the distal nephron, where it contributes to chloride permeability and transepithelial resistance. Although CLDN4 knockout mice exhibit hypercalciuria, the epithelial mechanism linking CLDN4 to calcium permeability and kidney stone disease remains unclear. We examined the molecular and functional effects of a kidney stone-associated CLDN4 variant P74L which was identified in two unrelated individuals with nephrolithiasis from the Bern Kidney Stone Registry. Using doxycycline-inducible epithelial cell models expressing human wild-type (WT) or mutant CLDN4, we show that the P74L variant displayed reduced protein stability, impaired junctional incorporation, and decreased surface expression. In contrast to WT CLDN4, whose overexpression increased transepithelial electrical resistance and restricted paracellular sodium, chloride, and calcium permeability, P74L CLDN4 failed to confer these effects. Expression of P74L CLDN4 was associated with reduced CLDN3 and CLDN7 messenger abundance without significant changes in CLDN8 or transcriptional regulation of other distal calcium (and other ion) transport genes. Together, these findings identify CLDN4 P74L as a loss-of-function variant that increases epithelial calcium permeability, possibly leading to increased calcium back-flux in the distal nephron relevant to nephrolithiasis.

physiology↗