Effect of calcium-sensing receptor activation in models of autosomal recessive or dominant polycystic kidney disease.

Abstract

BACKGROUND:

Antagonists of relevant Gs protein-coupled and agonists of relevant Gi protein-coupled receptors lower renal cAMP and inhibit growth of renal cysts in animal models of human ARPKD (PCK rat) and/or ADPKD (Pkd2(-/WS25) mouse). A calcium-sensing receptor (CaR) is expressed in various tubular segments and couples to Gq, thereby activating phospholipase Cgamma, InsP3 generation and calcium mobilization from intracellular stores, and Gi proteins. By both mechanisms, CaR activation could lower intracellular cAMP and inhibit renal cyst growth.

METHODS:

PCK rat and Pkd2(-/WS25) mouse littermates were fed rodent chow without or with R-568, a type 2 calcimimetic, at a concentration of 0.05% or 0.1% between 3 and 10 or 16 weeks of age. Histomorphometric analysis was performed with Meta-Morph software. Western analysis and immunohistochemical staining were performed using antibodies for aquaporin-2, urea transporter UT-A1 and CaR. Northern blot hybridization was used to quantify the expression of vasopressin V2 receptor and aquaporin 2 mRNAs. Cyclic AMP was measured using an enzyme immunoassay kit.

RESULTS:

R-568 had no effect on kidney weight, cyst volume, plasma BUN concentration or severity of the polycystic liver disease. A significant reduction in renal interstitial fibrosis was detected in PCK rats, but not in Pkd2(-/WS25) mice. R-568 administration, as anticipated, resulted in hypocalcemia and hyperphosphatemia, and significant increases in urine output, osmolar clearance, and urinary excretions of sodium, potassium and calcium.

CONCLUSIONS:

CaR activation had no detectable effect on cystogenesis in models of autosomal recessive or dominant polycystic kidney disease. The lack of protective effect could be due to the absence of CaR in the outer medullary and cortical collecting ducts, the reduction in extracellular calcium and the unaffected levels of renal cAMP and renal expression of cAMP-dependent genes. A possible beneficial effect on interstitial fibrosis deserves further study at more advanced stages of the disease.

• Authors: Xiaofang Wang, Peter C Harris, Stefan Somlo, Daniel Batlle, Vicente E Torres
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 24 Issue 2 Pg. 526-34 (Feb 2009) ISSN: 1460-2385 [Electronic] England
• PMID: 18826972 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Aqp2 protein, mouse
• Aqp2 protein, rat
• Aquaporin 2
• N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
• Phenethylamines
• Propylamines
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• RNA, Messenger
• Receptors, Calcium-Sensing
• Receptors, Vasopressin
• Cyclic AMP
• Protein Serine-Threonine Kinases
• Calcium

Topics

• Aniline Compounds (pharmacology)
• Animals
• Aquaporin 2 (genetics)
• Calcium (agonists)
• Cyclic AMP (metabolism)
• Disease Models, Animal
• Female
• Humans
• Kidney (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Mice, Mutant Strains
• Phenethylamines
• Polycystic Kidney, Autosomal Dominant (drug therapy, genetics, metabolism, pathology)
• Polycystic Kidney, Autosomal Recessive (drug therapy, genetics, metabolism, pathology)
• Propylamines
• Protein Serine-Threonine Kinases (deficiency, genetics)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Mutant Strains
• Receptors, Calcium-Sensing (agonists, metabolism)
• Receptors, Vasopressin (genetics)