Bartter syndrome is a rare genetic disorder belonging to a class of inherited renal tubulopathies; it is marked by the insufficient reabsorption of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle, resulting in a pronounced electrolyte imbalance. Protheragen is committed to advancing therapeutic solutions for rare kidney disorders, leveraging our deep expertise in renal physiology and ion channel biology to develop novel therapies for Bartter syndrome.
Introduction to Bartter Syndrome
Bartter syndrome includes a collection of rare disorders, all of which stem from an autosomal recessive inheritance, and involve the malfunctioning of the renal system tubules reabsorbing vital electrolytes. This disorder is marked by an electrolyte imbalance in the body, hypokalemia, which is low potassium in the blood, metabolic alkalosis, and an overproduction of renin and aldosterone. Common symptoms include a combination of excessive thirst and urination and stunted growth. There are different types of disorders that all stem from unique mutations in the SLC12A1, KCNJ1, CLCNKB, BSND, MAGED2 genes which produce the ion channels and transporters that are essential for the reabsorption of electrolytes in the thick ascending limb of the loop of Henle (TAL).
Pathogenesis of Bartter Syndrome
Fig.1 Proteins and channels implicated in the pathogenesis of Gitelman and Bartter syndromes. ((Nunez-Gonzalez, Carrera and Garcia-Gonzalez, 2021)
The genetic basis of Bartter syndrome is linked to abnormalities of electrolyte transport processes in the loops of Henle's thick ascending limb (TAL) of the nephron in the kidney. Disorders of the sodium-potassium chloride cotransporter (SLC12A1 NKCC2) and/or the renal outer medullary potassium channel (KCNJ1 ROMK) and/or chloride channels (CLC-NKB ClC-Kb) and/or the Barttin protein BSND cause failure of sodium-potassium-chloride cotransporter reabsorption. Excessive renal sodium loss is observed alongside hypokalemia and metabolic alkalosis. As a response to the renal sodium loss and hypovolemia due to the dehydration, the renin-angiotensin-aldosterone system will be activated. Alterations in electrolyte homeostasis due to the TAL dysfunction characterize Bartter syndrome.
Therapeutic Development for Bartter Syndrome
| Therapy Category |
Target/Approach |
Key Findings/Mechanism |
Development Stage |
| EP4 Receptor Antagonist |
PTGER4 |
Selectively blocks EP4 receptors; reduces hyperreninemia while avoiding gastrointestinal toxicity (I trial completed) |
Phase I |
| ENaC Blocker + Ibuprofen |
SCNN1 complex & PTGS2 (COX-2) |
Dual inhibition of Na+ reabsorption and COX; reduces potassium wasting |
Phase II |
| Phospholipid-Wrapped KCl |
N/A |
Slow-release formulation decreases diarrhea incidence by 80% versus conventional KCl |
Phase III |
| AAV-CLCNKB Gene Therapy |
CLCNKB gene |
Restores Cl- transport in thick ascending limb; normalizes tubular function in murine models |
Preclinical |
| iPSC-Derived Tubular Organoids |
SLC12A1 (NKCC2) |
Engrafts differentiated cells into damaged tubules; restores sodium reabsorption in preclinical models |
Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers comprehensive preclinical therapeutic development services, specializing in creating advanced disease models. Our focus is on elucidating the diverse genetic and physiological impacts of ion channel and transporter mutations that lead to renal salt wasting in Bartter syndrome.
Therapeutic Development Platform for Bartter Syndrome
Protheragen combines deep expertise in renal physiology, ion channel biology, and rare genetic disorders with advanced molecular and cellular technologies to address the multifaceted mechanisms leading to Bartter syndrome. Our comprehensive platform supports the development of various therapeutic modalities:
Disease Models Development for Bartter Syndrome
Developing innovative and comprehensive disease models is central to advancing preclinical research for Bartter syndrome. Our integrated platform effectively captures the ion transporter/channel dysfunction and electrolyte imbalances that cause Bartter syndrome, supporting extensive drug discovery and mechanism-based investigations focused on renal tubular function.
Cell-based & Organoid Models
- Bartter patient-derived iPSC line
- NKCC2-deficient thick ascending limb cell
- ROMK-deficient TAL cell
- ClC-Kb-deficient renal tubule cell
- Electrolyte transport-disrupted kidney organoid
Animal Models Development
- Slc12a1 (NKCC2) knockout mouse
- TAL-specific Kcnj1 (ROMK) KO mouse
- slc12a1 morpholino knockdown zebrafish
- Humanized CLCNKB mutation rabbit
- Kcnj1/Clcnka double KO mouse
Drug Pharmacokinetics & Safety Evaluation Services
In Vitro ADME Services
- Renal Clearance Assay
- Drug-Transporter Interaction Screening
- Metabolic Stability Assay
- CYP Inhibition Screening
- Plasma Protein Binding
Protheragen offers integrated preclinical development solutions specifically designed for research in kidney disorders like Bartter syndrome. Our expertise in disease model development, pharmacokinetics, and drug safety evaluation allows us to support your investigation from the initial stages to preclinical validation.
If you are interested in our services and advancing research for Bartter syndrome, please don't hesitate to contact us.
References
- Hoogstraten, C. A., J. G. Hoenderop, and J. H. F. de Baaij. "Mitochondrial Dysfunction in Kidney Tubulopathies." Annu Rev Physiol 86 (2024): 379-403.
- Nunez-Gonzalez, L., N. Carrera, and M. A. Garcia-Gonzalez. "Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Bartter and Gitelman Syndromes: A Primer for Clinicians." Int J Mol Sci 22.21 (2021).
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
