Gender-Specific Effects of Prenatal Betamethesone (Beta) Exposure and Unilateral Nephrectomy on the Intrarenal Renin-Angiotensin System (RAS) in Adult Sheep

The intrarenal renin angiotensin system (RAS) is activated in polycystic kidney disease. We have recently shown in the Pkd1 mouse that Gen 2 antisense oligonucleotide (ASO), which suppresses angiotensinogen (Agt) synthesis, is efficacious in slowing kidney cyst formation compared with lisinopril. The aim of this current study was to determine 1) if unilateral nephrectomy accelerates cystogenesis in Pkd1 mice (as previously shown in cilia knockout mice) and 2) whether Agt ASO can slow the progression in this accelerated cystic mouse model. Adult Pkd1 conditional floxed allele mice expressing cre were administered tamoxifen, resulting in global knockout of Pkd1. Three weeks after tamoxifen injection, mice underwent left unilateral nephrectomy. Mice were then treated with Agt ASO (75 mg/kg per week) or aliskiren (20 mg/kg per day)+Agt ASO or control for 8 wk. Unilateral nephrectomy accelerated kidney cyst formation compared with nonnephrectomized mice. Both Agt ASO and Aliskiren+Agt ASO treatments significantly reduced plasma and urinary Agt levels. Blood pressure was lowest in Aliskiren+Agt ASO mice among all treatment groups, and the control group had the highest blood pressure. All mice developed significant kidney cysts at 8 wk after nephrectomy, but Agt ASO and Aliskiren+Agt ASO groups had fewer kidney cysts than controls. Renal pAkt, pS6 levels, and apoptosis were significantly suppressed in those receiving Agt ASO compared with controls. These results indicate that suppressing Agt using an ASO slowed the progression of accelerated cystic kidney disease induced by unilateral nephrectomy in Pkd1 mice by suppressing intrarenal RAS, mammalian target of rapamycin pathway, and cell proliferation.

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Responses to converting-enzyme inhibition and hemorrhage in newborn lambs and adult sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1987.252.2.r306 ◽

1987 ◽

Vol 252 (2) ◽

pp. R306-R313

Author(s):

J. C. Rose ◽

S. M. Block ◽

K. Flowe ◽

M. Morris ◽

S. South ◽

...

Keyword(s):

Blood Pressure ◽

Enzyme Inhibition ◽

Age Groups ◽

Renin Angiotensin System ◽

Angiotensin Converting Enzyme Inhibition ◽

Converting Enzyme ◽

Angiotensin System ◽

Renin Angiotensin ◽

Adult Sheep ◽

Converting Enzyme Inhibition

We compared the cardiovascular and hormonal responses to angiotensin converting enzyme inhibition and hemorrhage of 20% of blood volume in chronically instrumented unanesthetized newborn lambs and adult sheep. Administration of the nonsulfhydryl-containing converting-enzyme inhibitor enalapril reduced mean arterial pressure in the newborn but not in the adult animals. Blood pressure fell in both age groups after hemorrhage, and the hemorrhage-induced fall in blood pressure, integrated over the period of hypovolemia, was more pronounced when converting-enzyme inhibition was present in the lambs. This was not observed in the adults. Cardiac output fell following hemorrhage in both age groups, and the fall was greater when enalapril was present in the lambs, but this was not the case in the adults. Hemorrhage increased plasma renin activity in both groups, and enalapril augmented this increase. Plasma concentrations of vasopressin and catecholamines increased following hemorrhage within and between groups. Taken together these data suggest that the renin-angiotensin system plays a more important role in the maintenance of cardiovascular homeostasis in newborn lambs than it does in adult sheep, and catecholamine and vasopressin responses to volume loss can occur in the presence of blockade of the renin-angiotensin system.

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