Nephrogenic diabetes insipidus is the definition of to the inability to concentrate urine as a result of a complete or partial change in the kidney's response to the arginine vasopressin hormone, leading to the release of a large volume of dilute urine. Protheragen, as a premier research service provider focused on enabling therapies for rare kidney diseases, offers comprehensive drug discovery and development services. We collaborate with biopharmaceutical companies and researchers to facilitate the drug development from target discovery to application, utilizing our integrated service platform and specialized know-how.
Overview of Nephrogenic Diabetes Insipidus
Diabetes insipidus is a renal disorder marked by the excretion of large amounts of hypotonic urine. It can be subdivided into two types, central and nephrogenic. Central diabetes insipidus is due to a lack of the hormone arginine vasopressin (AVP), which is stored in the pituitary gland or hypothalamus.
Fig.1 AVP's effect on water permeability in collecting duct principal cells. (Hureaux, M., and Vargas-Poussou, R., 2023)
On the other hand, nephrogenic diabetes insipidus is due to AVP resistance in the kidneys. In nephrogenic diabetes insipidus, the excretion of urine is uncontrollable, and there is a lack of ability to concentrate urine, which leads to polydipsia and polyuria, in the presence of normal or even elevated levels of AVP. In the absence of effective management, diabetes insipidus can cause severe complications like hypernatremia and dehydration, leading to increased morbidity and mortality rates.
Pathogenesis of Nephrogenic Diabetes Insipidus
Nephrogenic diabetes insipidus is associated with the incapacity to concentrate and reabsorb water within the collecting duct of the kidneys. In nephrogenic diabetes insipidus, the lack of responsiveness of the kidneys to AVP leads to a functional deficiency of the AQPs. As a result, diuresis with the excretion of large volumes of dilute urine is observed in the affected individuals. The primary forms of nephrogenic diabetes insipidus are due to mutations in the AVPR2 and AQP2 genes, which encode the key proteins. The secondary forms are associated with obstructive uropathy, biochemical changes, or the taking of certain drugs, especially lithium.
Fig.2 Schematic of the AVPR2 gene. (Hureaux, M., and Vargas-Poussou, R., 2023)
Therapeutics Development for Nephrogenic Diabetes Insipidus
| Therapeutics |
Targets |
Key Findings/Mechanism |
Research Stage |
| Thiazide diuretics |
Sodium transporters |
Reduces urine volume in individuals with nephrogenic diabetes insipidus. |
Approved |
| Hydrochlorothiazide |
NCC |
Reduces glomerular filtration rate while enhancing sodium and water reabsorption in the proximal tubule. |
Approved |
| Indomethacin |
COX |
COX inhibition leads to decreased prostaglandin synthesis, which decreases sodium and water excretion. |
Approved |
| Desmopressin |
V2 receptors |
This is a synthetic analog of vasopressin. |
Approved |
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's specialized services address the unique difficulties encountered in nephrogenic diabetes insipidus drug development. Our in-depth nephrogenic diabetes insipidus R&D solution begins with advanced diagnostics research and biomarker discovery, progressing through bespoke therapeutic discovery, tailored disease models development, rigorous preclinical studies, and pharmacokinetics and safety assessments, ensuring all drugs are safe and efficacious prior to further trials.
Therapeutic Development Platforms for Nephrogenic Diabetes Insipidus
Disease Models Development for Nephrogenic Diabetes Insipidus
Accurate disease models for nephrogenic diabetes insipidus pathophysiology and novel therapeutic evaluations are pivotal. We develop and validate diverse in vitro and in vivo models that accurately reproduce the genetics and phenotypes of the human nephrogenic diabetes insipidus. Our models support high-throughput screening and comprehensive mechanistic, efficacy, and safety profiling depending on the model system.
- Primary renal tubular cells
- AVPR2 mutant cell lines
- AQP2 knockout cells
- iPSC-derived kidney organoids
- And more
- AVPR2 knockout model
- AQP2 mutant model
- Lithium-induced nephrogenic diabetes insipidus model
- And more
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 integrates advanced deep disease biology expertise with comprehensive disease model systems for preclinical research and systems biology. Our specialists in rare kidney diseases offer strategic guidance and provide scientific solutions aligned with your project's goal. Reach out to us today for a discussion on how your therapeutic development program would benefit from our bespoke solutions.
Reference
- Hureaux, Marguerite, and Rosa Vargas-Poussou. "Genetic basis of nephrogenic diabetes insipidus." Molecular and cellular endocrinology 560 (2023): 111825.
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