Table 1.

Experimental and clinical models of the (pro)renin receptor in blood pressure regulation

Experimental studies	Species	Promoter/Cre	Blood pressure (BP)	Phenotypic characteristics	Organ specific effects	Reference
Global
Over-expression of PRR	Mice	CAG promoter (embryonic stem cells)	No change	Renal expression ↑ 25-80 fold Cardiac expression ↑ 400 fold	No proteinuria No cardiac dysfunction	44
Over-expression of human PRR	Rats	CAG promoter (embryonic stem cells)	No change	No change	Proteinuria Glomerulosclerosis	45
PRR KO	Mice	ROSA26-creERT2	Not reported	Early lethality and weight loss	Pathology in colon, bone marrow and liver	18
Kidney
Podocyte PRR KO	Mice	podocin-Cre	Not reported	Nephrotic syndrome, early post-natal lethality	Severe renal injury	16,17
HRP in 2-kidney 1-clip Goldblatt	Rat	-	No change	HRP did not change plasma renin or aldosterone levels	No change in cardiac or renal injury	107
PRO20 infusion in inner medulla	Rat	-	↓ Ang-II infused hypertension (100 ng/kg/min)	-	↓ proteinuria and glomerulosclerosis following Ang-II	25
PRR shRNA injected to renal medulla	Rat	-	No change	-	Reduced α-ENaC abundance	31
Renal tubule PRR KO	Mice	Pax8-rtTA/LC1- Cre (inducible)	↓ Ang-II infused hypertension (600 ng/kg/min)	Urinary concentration defect	Reduced α-ENaC abundance	33
CD specific PRR KO	Mice	AQP2-Cre	↓ Ang-II infused hypertension (300 ng/kg/min)	-	Reduced α-ENaC abundance	34
CD specific PRR KO	Mice	Hoxb7-Cre	↓ basal systolic BP ↓ Ang-II infused hypertension (400 ng/kg/min)	Renal hypoplasia and ↓ renal function	Reduced cleaved α-ENaC and γ-ENaC abundance	35
Renal tubule PRR KO	Mice	Pax8-rtTA/LC1- Cre (inducible)	No change in BP with Ang-II infusion (1000 ng/kg/min)	↑ lysosomal proteins and autophagosome markers	↓ ability to excrete acid load	36
CD cell specific PRR KO	Mice	AQP2-Cre Principal cell specific	No change in BP	Urinary concentration defect	Reduced α-ENaC abundance	39
CD cell specific PRR KO	Mice	B1-ATPase-Cre Intercalated cell specific	No change in BP	Lower body weight	No change in ENaC abundance	39
Macula densa specific PRR KO	Mice	nNOS/CreERT2	↓ BP at baseline and following low Na+ + RAS blocker	↓ plasma renin concentration	↓ cyclooxygenase-2 and prostaglandin E synthase	40
Nephron progenitor cells	Mice	Six2GFPCre	Hypertension at 2 months of age	Homozygous deletion – early lethality	↓ glomeruli number and thickening of basement membrane	41
Cardiovascular system
Cardiomyocyte PRR KO	Mice	α MHC-Cre	Not reported	Lethal heart failure within 3 weeks of birth	Autophagic vacuoles in cardiomyocytes	15
Cardiomyocyte specific PRR overexpression	Mice	α MHC promoter	Not reported	170-fold ↑ PRR mRNA and 5-fold ↑ PRR protein	No change in cardiac function at baseline and following injury	47
Cardiomyocyte specific PRR overexpression	Rats	Adenovirus mediated gene delivery	Not reported	2-3 fold ↑ PRR protein	↓ left ventricular ejection fraction	51
Vascular smooth muscle cell PRR KO	Mice		No change in BP	Non-atherogenic sclerosis of aorta	VSMC autophagic cell death	52
Vascular smooth muscle cell PRR overexpression	Rats	Smooth muscle cell myosin heavy chain gene	Hypertension at 6 months of age	Tachycardia	-	53
Brain
Supra-optic nucleus PRR knock-down	Rats (SHR)	Adenovirus mediated gene delivery	↓ age associated hypertension	↓ heart rate	↓ plasma vasopressin levels	57
ICV PRR shRNA infusion	Mice	Overexpressing human renin and angiotensinogen	↓ BP	↓ sympathetic tone ↑ baroreflex sensitivity	↓ Ang-II type 1 receptor and vasopressin levels in brain	58
Neuron specific PRR KO	Mice	Nefh-Cre	↓ BP in ICV infusion of prorenin/ DOCA-salt	↓ sympathetic tone ↑ baroreflex sensitivity	↓ brain Ang-II levels	20
ICV PRO20 infusion	Mice	-	↓ BP Ang-II and DOCA-salt hypertension	↓ sympathetic tone ↑ baroreflex sensitivity	↓ brain hypothalamic Ang- II levels with DOCA-salt	6
Adipose tissue
Adipose tissue PRR KO	Mice	Adiponectin-Cre	↑ BP at baseline and following high fat diet	Lipodystrophy	↑ plasma sPRR	21
Clinical Studies	Species	Controls	Blood pressure	Other pertinent findings
Pre-eclamptic women	Human	Normotensive pregnant women	↑ BP	↑ placental PRR and ↑ plasma sPRR BP correlated with placental PRR but not plasma sPRR		67
Pre-eclamptic and diabetic women	Human	Healthy pregnant controls	Not reported	↑ plasma sPRR in diabetes but not preeclamptic or healthy controls		68
Japanese cohort of 1100 participants	Human	-	↑ BP in men with IVS5+169C > T polymorphism	-		69
Caucasian cohort	Human	-	↑ BP in men with IVS5+169C > T polymorphism	-		70

KO - knock out; Ang-II – Angiotensin-II; ENaC – epithelial Na channel; RAS – renin angiotensin system blocker; ICV – intracerebroventricular; sPRR- soluble PRR; DOCA-salt – Deoxycorticosterone acetate;