Paradoxes in magnesium transport in type 1 Bartter's syndrome and Gitelman's syndrome: a modeling analysis

• Published in: American journal of physiology. Renal physiology Vol. 327; no. 3; pp. F386 - F396
• Main Authors: Dutta, Pritha, Layton, Anita T
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.09.2024
• Subjects: Adaptation; Animal models; Animals; Bartter Syndrome - genetics; Bartter Syndrome - metabolism; Bartter's syndrome; Calcium - metabolism; Calcium transport; Computer Simulation; Female; Genetic disorders; Gitelman Syndrome - genetics; Gitelman Syndrome - metabolism; Gitelman Syndrome - physiopathology; Kidneys; Magnesium; Magnesium - metabolism; Male; Mathematical models; Models, Biological; Nephrons - metabolism; Preservation; Rats; Sex differences; Sex Factors; Sexual dimorphism; Solute Carrier Family 12, Member 1 - genetics; Solute Carrier Family 12, Member 1 - metabolism; Solute Carrier Family 12, Member 3 - genetics; Solute Carrier Family 12, Member 3 - metabolism; renal transport; Bartter’s syndrome; Gitelman’s syndrome; magnesium homeostasis; sex differences
• ISSN: 1931-857X; 1522-1466; 1522-1466
• DOI: 10.1152/ajprenal.00117.2024

Type 1 Bartter's syndrome and Gitelman's syndrome are characterized by mutations in two key renal Na transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg ) and calcium (Ca ) transport in the kidney, significant alterations in the transport of these two electrolytes are observed in type 1 Bartter's syndrome and Gitelman's syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rats to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg and Ca preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter patterns, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in type 1 Bartter's syndrome, nephron adaptations prevent salt wasting and favor Mg preservation but not Ca , whereas in Gitelman's syndrome, those adaptations favor Ca preservation over Mg . In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males. Although changes in Ca excretion in type 1 Bartter's syndrome and Gitelman's syndrome are well understood, Mg excretion displays an interesting paradox. This computational modeling study provides insights into how renal adaptations in these two disorders impact Ca and Mg transport along different nephron segments. Model simulations showed that nephron adaptations favor Mg preservation over Ca in Bartter's syndrome and Ca preservation over Mg in Gitelman's syndrome and are stronger in females than in males.