PMID- 29848510
OWN - NLM
STAT- MEDLINE
DCOM- 20190701
LR  - 20220716
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Print)
IS  - 0143-5221 (Linking)
VI  - 132
IP  - 12
DP  - 2018 Jun 29
TI  - Prorenin independently causes hypertension and renal and cardiac fibrosis in 
      cyp1a1-prorenin transgenic rats.
PG  - 1345-1363
LID - 10.1042/CS20171659 [doi]
AB  - Plasma prorenin is commonly elevated in diabetic patients and appears to predict 
      the development of diabetic nephropathy. However, the pathological role of 
      prorenin is unclear. In the present study, a transgenic, inducible, hepatic 
      prorenin-overexpressing rat model was generated and the effect of prorenin in 
      organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male 
      and female rats and non-transgenic littermates) were assigned to receive a diet 
      containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. 
      Plasma prorenin concentration was increased and mean arterial pressure (MAP) 
      increased from 80 +/- 18 to 138 +/- 17 (mmHg), whereas renal prorenin/renin protein 
      expression was unchanged, in transgenic rats fed with I3C diet. The intact 
      prorenin, not renin, in plasma and urine samples was further observed by Western 
      blot analysis. Importantly, transgenic rats with high levels of prorenin 
      developed albuminuria, glomerular and tubulointerstitial fibrosis associated with 
      increased expression of transforming growth factor beta (TGFbeta) 1 (TGFbeta1), 
      plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These 
      rats also exhibited cardiac hypertrophy determined by echocardiography, with 
      elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in 
      interstitial and perivascular regions was prominent, accompanied by the increase 
      in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide 
      (BNP), beta-myosin heavy chain (beta-MHC), TGFbeta1, PAI-1, and collagen in the heart 
      tissue. Furthermore, renal protein levels of p-NF-kappaB-p65 and monocyte 
      chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 
      8-isoprostane (8-IP), p-ERK, p-beta-catenin, and p-Akt were dramatically increased 
      in prorenin overexpressing rats. These results indicate that prorenin, without 
      being converted into renin, causes hypertension, renal and cardiac fibrosis via 
      the induction of inflammation, oxidative stress and the ERK, beta-catenin, and 
      Akt-mediated signals.
CI  - (c) 2018 The Author(s).
FAU - Zhou, Guangyu
AU  - Zhou G
AD  - Division of Nephrology, Department of Internal Medicine, University of Utah 
      Health, Salt Lake City, UT 84112, U.S.A.
AD  - Division of Nephrology, Department of Internal Medicine, Shengjing Hospital, 
      China Medical University, Shenyang 110004, China.
FAU - Wu, Jie
AU  - Wu J
AD  - Division of Nephrology, Department of Internal Medicine, University of Utah 
      Health, Salt Lake City, UT 84112, U.S.A.
FAU - Gu, Chunyan
AU  - Gu C
AD  - Division of Nephrology, Department of Internal Medicine, University of Utah 
      Health, Salt Lake City, UT 84112, U.S.A.
FAU - Wang, Bin
AU  - Wang B
AD  - Division of Nephrology, Department of Internal Medicine, University of Utah 
      Health, Salt Lake City, UT 84112, U.S.A.
FAU - Abel, E Dale
AU  - Abel ED
AD  - Division of Endocrinology, Metabolism and Diabetes, Department of Internal 
      Medicine, University of Utah Health, Salt Lake City, UT 84112, U.S.A.
AD  - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology 
      and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 
      52242, U.S.A.
FAU - Cheung, Alfred K
AU  - Cheung AK
AD  - Division of Nephrology, Department of Internal Medicine, University of Utah 
      Health, Salt Lake City, UT 84112, U.S.A.
FAU - Huang, Yufeng
AU  - Huang Y
AD  - Division of Nephrology, Department of Internal Medicine, University of Utah 
      Health, Salt Lake City, UT 84112, U.S.A. yufeng.huang@hsc.utah.edu.
AD  - Department of Pathophysiology, University of Nantong College of Medicine, Nantong 
      Shi, Jiangsu 226000, China.
LA  - eng
GR  - K01 DK077955/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180628
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - EC 3.4.23.15 (Renin)
SB  - IM
MH  - Albuminuria/blood/physiopathology
MH  - Animals
MH  - Cardiomegaly/diagnostic imaging/physiopathology
MH  - Echocardiography
MH  - Female
MH  - Fibrosis
MH  - Gene Expression
MH  - Hypertension/blood/*physiopathology
MH  - Kidney/*pathology
MH  - Male
MH  - Myocardium/metabolism/*pathology
MH  - Organ Size
MH  - Oxidative Stress/physiology
MH  - Rats, Transgenic
MH  - Renin/blood/genetics/*physiology
MH  - Signal Transduction/physiology
PMC - PMC6024026
OTO - NOTNLM
OT  - Prorenin
OT  - cardiac disease
OT  - hypertension
OT  - renal disease
OT  - renin
COIS- The authors declare that there are no competing interests associated with the 
      manuscript.
EDAT- 2018/06/01 06:00
MHDA- 2019/07/02 06:00
PMCR- 2018/06/28
CRDT- 2018/06/01 06:00
PHST- 2018/01/03 00:00 [received]
PHST- 2018/05/10 00:00 [revised]
PHST- 2018/05/25 00:00 [accepted]
PHST- 2018/06/01 06:00 [pubmed]
PHST- 2019/07/02 06:00 [medline]
PHST- 2018/06/01 06:00 [entrez]
PHST- 2018/06/28 00:00 [pmc-release]
AID - CS20171659 [pii]
AID - 10.1042/CS20171659 [doi]
PST - epublish
SO  - Clin Sci (Lond). 2018 Jun 28;132(12):1345-1363. doi: 10.1042/CS20171659. Print 
      2018 Jun 29.