Biology subjects

Essuman, G.

Publications and source records attributed to Essuman, G..

4 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↗

bioRxiv2024

SLC4A1 MUTATIONS THAT CAUSE DISTAL RENAL TUBULAR ACIDOSIS ALTER CYTOPLASMIC PH AND CELLULAR AUTOPHAGY

Distal renal tubular acidosis (dRTA) is a disorder characterized by the inability of the collecting duct system to secrete acids during metabolic acidosis. The pathophysiology of dominant or recessive SLC4A1 variant related dRTA has been linked with the mis trafficking defect of mutant kAE1 protein. However, in vivo studies in kAE1 R607H dRTA mice and humans have revealed a complex pathophysiology implicating a loss of kAE1-expressing intercalated cells and intracellular relocation of the H+-ATPase in the remaining type-A intercalated cells. These cells also displayed accumulation of ubiquitin and p62 autophagy markers. The highly active transport properties of collecting duct cells require the maintenance of cellular energy and homeostasis, a process dependent on intracellular pH. Therefore, we hypothesized that the expression of dRTA variants affect intracellular pH and autophagy pathways. In this study, we report the characterization of newly identified dRTA variants and provide evidence of abnormal autophagy and degradative pathways in mouse inner medullary collecting duct cells and kidneys from mice expressing kAE1 R607H dRTA mutant protein. We show that reduced transport activity of the kAE1 variants correlated with increased cytosolic pH, reduced ATP synthesis, attenuated downstream autophagic pathways pertaining to the fusion of autophagosomes and lysosomes and/or lysosomal degradative activity. Our study elucidated a close relationship between the expression of defective kAE1 proteins, reduced mitochondrial activity and decreased autophagy and protein degradative flux.

physiology↗

bioRxiv2024

Urinary Sodium Wasting and Disrupted Collecting Duct Function in Mice with dRTA-Causing SLC4A1 Mutations

Distal renal tubular acidosis (dRTA) results in metabolic acidosis due to impaired urinary acidification and can also result in an unexplained urinary sodium-wasting phenotype. Here, we report the generation and characterization of a novel dRTA mutant mouse line, Ae1 L919X knockin (KI). Homozygous L919X KI mice exhibit typical dRTA features including a reduced ability to acidify urine in response to an acid load. This renal acidification defect was associated with a reduced number of Ae1-positive type A intercalated cells. To assess whether these mice exhibit urinary sodium-wasting as seen in some dRTA patients, homozygous KI L919X and the previously described R607H KI mice were fed a salt-depleted acid diet. In line with human patients, both mouse strains exhibited urinary sodium loss. Additionally, we identified increased expression of tight junction proteins claudin-4 and -10b, suggesting a compensatory paracellular pathway in the loop of Henle. Consistent with data from human patients, L919X KI mice displayed a milder phenotype than R607H KI mice. Our findings reveal that both mouse strains are appropriate models for dRTA with a urinary salt-wasting phenotype and a compensatory up-regulation of the paracellular pathway in the ascending limb of the loop of Henle.

physiology↗