Methods and compositions for treating nephrogenic diabetes insipidus
Inventors
Kishore, Bellamkonda K. • Carlson, Noel G. • Kohan, Donald E. • Nelson, Raoul D.
Assignees
US Department of Veterans Affairs • University of Utah
Publication Number
US-9901624-B2
Publication Date
2018-02-27
Expiration Date
2025-10-21
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Abstract
Disclosed are compositions and methods for treating nephrogenic diabetes insipidus and for induction of diuretic effect.
Core Innovation
The invention relates to compositions and methods for treating nephrogenic diabetes insipidus (NDI) and for the induction of diuretic effects by targeting purinergic P2Y2 receptors. Specifically, the use of P2Y2 receptor antagonists to treat NDI by decreasing prostaglandin E2 (PGE2) production or release and thereby restoring normal water channel (AQP2) protein levels in the kidney medullary collecting duct is disclosed. The methods encompass treatment of both acquired and inherited forms of NDI, characterized by low AQP2 abundance despite normal or elevated arginine vasopressin (AVP) levels.
The problem being solved is the vasopressin-resistant polyuria characteristic of acquired NDI conditions such as lithium-induced nephropathy, hypokalemic nephropathy, hypercalcemia, and post-obstructive uropathy. In these disorders, excessive production and release of PGE2 in the kidney medullary collecting duct antagonize the AVP-stimulated water reabsorption by promoting AQP2 retrieval from the apical membrane. Current treatments using prostaglandin synthesis inhibitors like indomethacin have limitations due to side effects and lack of specificity. This invention addresses the need for targeted therapies that inhibit the purinergic receptor-mediated PGE2 production pathway to ameliorate polyuria associated with NDI.
The compositions include selective antagonists of P2Y2 purinergic receptors that reduce purinergic-stimulated PGE2 release, thereby improving AVP responsiveness. Methods described include administration of P2Y2 antagonists alone or in combination with prostaglandin synthesis inhibitors, phospholipase inhibitors, cAMP elevating agents, protein kinase C inhibitors, MAP kinase inhibitors, diuretics like thiazides and amiloride, and prostaglandin transporter blockers. Additionally, P2Y2 agonists are disclosed for use as diuretics in conditions of fluid retention, leveraging their ability to regulate free water absorption without electrolyte imbalance. The invention also covers methods of screening for P2Y2 antagonists by monitoring PGE2 and AQP2 levels in kidney cells.
Claims Coverage
The claims include two independent claims directed to methods of treating and modulating nephrogenic diabetes insipidus using compositions targeting P2Y2 purinergic receptors, with multiple dependent claims detailing combinations and specific applications of these methods.
Use of P2Y2 purinergic receptor antagonists to treat nephrogenic diabetes insipidus
A method of treating NDI by administering a composition that acts as an antagonist of the P2Y2 purinergic receptor, aiming to reduce polyuria and restore AQP2 water channel function in the medullary collecting duct.
Combination therapy involving P2Y2 antagonists and prostaglandin synthesis inhibitors
The method includes using P2Y2 receptor antagonists in combination with inhibitors of prostaglandin synthesis, including non-specific cyclooxygenase inhibitors like indomethacin, rofecoxib, or flurbiprofen, to improve treatment efficacy and allow dose reduction of prostaglandin synthesis inhibitors.
Combination therapies with diuretics and phospholipase or kinase inhibitors
Methods of treatment wherein P2Y2 antagonists are combined with thiazides, optionally with amiloride, inhibitors of arachidonic acid release (such as cPLA2 inhibitors), protein kinase C inhibitors, MAP kinase inhibitors, or phosphodiesterase inhibitors to modulate the signaling pathways involved in NDI.
Use of P2Y2 antagonists to decrease renal PGE2 levels and disrupt purinergic-prostanoid interactions
The P2Y2 antagonist decreases levels of PGE2 in the kidney by inhibiting purinergic receptor-mediated production or release, thereby lowering the antagonism of AVP activity and enhancing AQP2 abundance in the collecting duct.
Treatment of various forms of NDI including acquired and inherited types
Methods apply to treating acquired NDI conditions such as lithium-induced nephropathy, hypokalemic nephropathy, hypercalcemia-induced NDI, and post-obstructive uropathy, as well as inherited forms associated with genetic defects in vasopressin V2 receptor or AQP2 water channel.
Identification and use of specific P2Y2 receptor antagonists
Use of specific antagonists like suramin, reactive blue 2, acid blue 129, acid blue 80, and PPADS for targeting P2Y2 receptors in treatment methods.
The claims predominantly cover methods of treating or modulating nephrogenic diabetes insipidus by administering P2Y2 purinergic receptor antagonists alone or in combination with prostaglandin synthesis inhibitors and other agents to reduce PGE2-mediated inhibition of vasopressin signaling, restore AQP2 levels, and ameliorate polyuria. The claims span various forms of NDI, specific antagonists, and combination therapies enhancing efficacy and reducing side effects.
Stated Advantages
The methods provide a targeted approach to inhibit purinergic receptor-mediated PGE2 production, which is implicated in the pathogenesis of acquired NDI.
Combination therapies allow for using lower doses of prostaglandin synthesis inhibitors, potentially reducing their known side effects.
Use of P2Y2 agonists offers a novel diuretic mechanism acting on medullary collecting duct independent of salt transport, thus avoiding electrolyte imbalances common with traditional diuretics.
Apyrase administration can prevent lithium-induced increase in urine output by decreasing PGE2 formation through degradation of extracellular ATP, representing a novel therapeutic approach.
Documented Applications
Treatment of nephrogenic diabetes insipidus including acquired forms such as lithium-induced nephropathy, hypokalemic nephropathy, hypercalcemia-induced NDI, post-obstructive uropathy, chronic kidney disease-induced NDI, sickle cell disease-induced NDI, low protein diet-induced NDI, and drug-induced NDI.
Use of P2Y2 receptor agonists as diuretics for treating water retention conditions such as congestive heart failure, chronic liver disease, hepato-renal syndrome, and tumors associated with fluid retention and dilutional hyponatremia.
Screening of compounds for P2Y2 antagonist activity by measuring reduction in PGE2 levels or increase in AQP2 levels in kidney cells.
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