ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy

Amrisha Verma, Zhiying Shan, Bo Lei, Lihui Yuan, Xuan Liu, Takahiko Nakagawa, Maria B. Grant, Alfred S. Lewin, William W. Hauswirth, Mohan K. Raizada, Qiuhong Li

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Despite evidence that hyperactivity of the vasodeleterious axis (ACE/angiotensin II (Ang II)/AT1 receptor) of the renin-angiotensin system (RAS) is associated with the pathogenesis of diabetic retinopathy (DR) use of the inhibitors of this axis has met with limited success in the control of this pathophysiology. We investigated the hypothesis that enhancing the local activity of the recently established protective axis of the RAS, ACE2/Ang-(1-7), using adeno-associated virus (AAV)-mediated gene delivery of ACE2 or Ang-(1-7) would confer protection against diabetes-induced retinopathy. Genes expressing ACE2 and Ang-(1-7) were cloned in AAV vector. The effects of ocular AAV-ACE2/Ang-(1-7) gene transfer on DR in diabetic eNOS -/- mice and Sprague-Dawley (SD) rats were examined. Diabetes was associated with approximately tenfold and greater than threefold increases in the ratios of ACE/ACE2 and AT1R/Mas mRNA levels in the retina respectively. Intraocular administration of AAV-ACE2/Ang-(1-7) resulted in significant reduction in diabetes-induced retinal vascular leakage, acellular capillaries, infiltrating inflammatory cells and oxidative damage in both diabetic mice and rats. Our results demonstrate that DR is associated with impaired balance of retinal RAS. Increased expression of ACE2/Ang-(1-7) overcomes this imbalance and confers protection against DR. Thus, strategies enhancing the protective ACE2/Ang-(1-7) axis of RAS in the eye could serve as a novel therapeutic target for DR.

Original languageEnglish (US)
Pages (from-to)28-36
Number of pages9
JournalMolecular Therapy
Volume20
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Fingerprint

Diabetic Retinopathy
Dependovirus
Renin-Angiotensin System
Genes
Retinal Vessels
Angiotensin Type 1 Receptor
Angiotensin Receptors
Sprague Dawley Rats
Retina
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Verma, A., Shan, Z., Lei, B., Yuan, L., Liu, X., Nakagawa, T., ... Li, Q. (2012). ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy. Molecular Therapy, 20(1), 28-36. https://doi.org/10.1038/mt.2011.155

ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy. / Verma, Amrisha; Shan, Zhiying; Lei, Bo; Yuan, Lihui; Liu, Xuan; Nakagawa, Takahiko; Grant, Maria B.; Lewin, Alfred S.; Hauswirth, William W.; Raizada, Mohan K.; Li, Qiuhong.

In: Molecular Therapy, Vol. 20, No. 1, 01.2012, p. 28-36.

Research output: Contribution to journalArticle

Verma, A, Shan, Z, Lei, B, Yuan, L, Liu, X, Nakagawa, T, Grant, MB, Lewin, AS, Hauswirth, WW, Raizada, MK & Li, Q 2012, 'ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy', Molecular Therapy, vol. 20, no. 1, pp. 28-36. https://doi.org/10.1038/mt.2011.155
Verma, Amrisha ; Shan, Zhiying ; Lei, Bo ; Yuan, Lihui ; Liu, Xuan ; Nakagawa, Takahiko ; Grant, Maria B. ; Lewin, Alfred S. ; Hauswirth, William W. ; Raizada, Mohan K. ; Li, Qiuhong. / ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy. In: Molecular Therapy. 2012 ; Vol. 20, No. 1. pp. 28-36.
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