Investigating the Urinary Salt Losing Phenotype in R607H and L919X Mutant Mice with Distal Renal Tubular Acidosis
Notice bibliographique
Résumé
Introduction: The renal collecting duct consists of two cell types: principal and intercalated cells (ICs, alpha- and beta-type). These cells play a crucial role in regulating fluid, electrolyte, and acid-base homeostasis. Specifically, alpha-ICs promote secretion of protons into the urine through an apical proton ATPase while enabling the reabsorption of bicarbonate into the blood via the basolateral protein, kidney anion exchanger 1 (kAE1). Genetic mutations that impact IC cell function can lead to a condition called distal renal tubular acidosis (dRTA). Patients with dRTA typically exhibit alkaline urine, metabolic acidosis, electrolyte imbalances, and urinary ion loss. Study Objective and Hypothesis: Some dRTA patients continue to exhibit impaired conservation of sodium, despite sustained correction of their acidosis. The mechanisms that lead to this impairment need further investigation. Our lab has two dRTA kAE1 knock in (KI) mouse models, L919X (LX) and R607H (RH), that recapitulate classical metabolic acidosis seen in human patients. We hypothesize that these mice serve as an effective model for studying the cause behind the persistent urinary ion loss. The objectives of our work are to 1) determine whether our mouse models accurately reflect the urinary ion loss seen in dRTA patients, 2) comprehensively characterise the previously unpublished mouse line, kAE1 KI L919X, and 3) elucidate the mechanism behind this urinary salt loss. Methods: To test our hypothesis, we fed wild-type (WT) and dRTA mutant mice a low NaCl, acid, or combination (NaCl + acid) diet, to mirror conditions previously studied in human patients. We collected urine and plasma from the mice to measure ion concentrations and pH. We harvested and processed their kidney and gut tissues for analysis through qRT-PCR, immunoblot, and immunofluorescence to investigate acid-base and salt transports in the collecting duct and thick ascending limb. We aimed to identify potential alterations in these transporters between WT and KI mice. Results: On the low NaCl diet, there were little differences between WT and KI mice, either in comparison to each other or relative to their baseline conditions. However, the combination diet revealed a urinary salt losing phenotype in the RH and LX KI mice. These KI mice also displayed hypernatremia, hyperchloremia, and a failure to secrete potassium and to properly concentrate their urine. qRT-PCR analysis of whole kidney tissues revealed a surprising increase in the paracellular transport pathways, including claudin-4 and claudin-10b in the KI compared to WT. Initial immunoblots indicate a concordant upregulation and downregulation of protein expression that aligns with transcriptional changes seen at the mRNA level. Conclusion: Our current findings suggest a defective collecting duct function in the KI mice, thus validating our hypothesis. Additionally, there appears to be a compensatory mechanism at play in earlier nephron segments to rescue ion homeostasis. The results from this research may contribute to improved treatment options for patients that suffer with this severe disease. It will also deepen the understanding of the interconnected and complex functions of the nephron, aiding in treatment of other major conditions like hypertension or end-stage renal disease. Canadian Institutes of Health Research (CIHR), Canada Graduate Scholarship - Master's CIHR, and Kidney Foundation of Canada. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
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