Temporal relationship between renal cyst development, hypertension and cardiac hypertrophy in a new rat model of autosomal recessive polycystic kidney disease.
METHODS
We have examined the hypothesis that cyst formation is key in the pathogenesis of cardiovascular disease in a Lewis polycystic kidney (LPK) model of autosomal-recessive polycystic kidney disease (ARPKD), by determining the relationship between cyst development and indices of renal function and cardiovascular disease.


RESULTS
In the LPK (n = 35), cysts appear at week 3 (1.1 +/- 0.1 mm) increasing to week 24 (2.8 +/- 2 mm). Immunostaining for nephron-specific segments indicate cysts develop predominantly from the collecting duct. Cyst formation preceded hypertension (160 +/- 22 vs. Lewis control 105 +/- 20 mm Hg systolic blood pressure (BP), n = 12) at week 6, elevated creatinine (109 +/- 63 vs. 59 +/- 6 micromol/l, n = 16) and cardiac mass (0.7 vs. 0.4% bodyweight, n = 15) at week 12, and left ventricular hypertrophy (2,898 +/- 207 vs. 1,808 +/- 192 mum, n = 14) at week 24 (all p < or = 0.05). Plasma-renin activity and angiotensin II were reduced in 10- to 12-week LPK (2.2 +/- 2.9 vs. Lewis 11.9 +/- 4.9 ng/ml/h, and 25.0 +/- 19.1 vs. 94.9 +/- 64.4 pg/ml, respectively, n = 26, p < or = 0.05). Ganglionic blockade (hexamethonium 3.3 mg/kg) significantly reduced mean BP in the LPK (52 vs. Lewis 4%, n = 9, p < or = 0.05).


CONCLUSIONS
Cyst formation is a key event in the genesis of hypertension while the sympathetic nervous system is important in the maintenance of hypertension in this model of ARPKD.
Phillips
Jacqueline K
JK
Division of Health Sciences, School of Veterinary and Biomedical Science, Murdoch University, Perth, Australia. j.k.phillips@murdoch.edu.au
Hopwood
Deborah
D
Loxley
Rhonda A
RA
Ghatora
Kamaljit
K
Coombes
Jason D
JD
Tan
Ying Sin
YS
Harrison
Joanne L
JL
McKitrick
Douglas J
DJ
Holobotvskyy
Vasyl
V
Arnolda
Leonard F
LF
Rangan
Gopala K
GK
D000818:Animals; D000911:Antibodies, Monoclonal; D015415:Biomarkers / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006977:Hypertension, Renal / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D007679:Kidney Medulla / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D007686:Kidney Tubules, Distal / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D017044:Polycystic Kidney, Autosomal Recessive / Q000150:complications / Q000235:genetics / Q000473:pathology*; D011237:Predictive Value of Tests; D051381:Rats; D011917:Rats, Inbred Lew; D011922:Rats, Mutant Strains; D012084:Renin-Angiotensin System / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D013565:Sympatholytics / Q000494:pharmacology; D013997:Time Factors; D014508:Urea / Q000097:blood
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D013565:Sympatholytics; D014508:Urea; D003404:Creatinine