Effect of calcium-sensing receptor activation in models of autosomal recessive or dominant polycystic kidney disease.
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.
Wang
Xiaofang
X
Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Harris
Peter C
PC
Somlo
Stefan
S
Batlle
Daniel
D
Torres
Vicente E
VE
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics; D002118:Calcium / Q000819:agonists; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010627:Phenethylamines; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017044:Polycystic Kidney, Autosomal Recessive / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011437:Propylamines; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000235:genetics
D000814:Aniline Compounds; C496024:Aqp2 protein, mouse; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D044169:Receptors, Calcium-Sensing; D017483:Receptors, Vasopressin; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D002118:Calcium