Acta Diabetologica

, Volume 56, Issue 1, pp 97–104 | Cite as

Activation of angiotensin type 2 (AT2) receptors prevents myocardial hypertrophy in Zucker diabetic fatty rats

  • Giovanna CastoldiEmail author
  • Cira R. T. di Gioia
  • Francesca Roma
  • Raffaella Carletti
  • Giuseppina Manzoni
  • Andrea Stella
  • Gianpaolo Zerbini
  • Gianluca Perseghin
Original Article



Compound 21 (C21), selective AT2 receptor agonist, has cardioprotective effects in experimental models of hypertension and myocardial infarction. The aims of the study was to evaluate the effect of C21, losartan, or both in Zucker diabetic fatty (ZDF) rats (type 2 diabetes) on (1) the prevention of myocardial hypertrophy; (2) myocardial expression of phosphatase and tensin homolog (PTEN), a target gene of miR-30a-3p, involved in myocardial remodelling.


Experiments were performed in ZDF (n = 33) and in control Lean (8) rats. From the 6th to the 20th week of age, we administered C21 (0.3 mg/kg/day) to 8 ZDF rats. 8 ZDF rats were treated with losartan (10 mg/kg/day), 8 rats underwent combination treatment, C21+ losartan, and 9 ZDF rats were left untreated. Blood glucose and blood pressure were measured every 4 weeks. At the end of the study the hearts were removed, the apex was cut for the quantification of PTEN mRNA and miR-30a-3p expression (realtime-PCR). Myocardial hypertrophy was evaluated by histomorphometric analysis, and nitrotyrosine expression (as marker of oxidative stress) by immunohistochemistry.


ZDF rats had higher blood glucose (p < 0.0001) with respect to control Lean rats, while blood pressure did not change. Both parameters were not modified by C21 treatment, while losartan and losartan + C21 reduced blood pressure in ZDF rats (p < 0.05). miR-30a-3p expression was increased in ZDF rats (p < 0.01) and PTEN mRNA expression was decreased (p < 0.05). ZDF rats developed myocardial hypertrophy (p < 0.01) and increased oxidative stress (p < 0.01), both were prevented by C21 or losartan, or combination treatment. C21 or losartan normalized the expression of miR-30a-3p and PTEN.


Activation of AT2 receptors or AT1 receptor blockade prevents the development of myocardial hypertrophy in ZDF rats. This occurs through the modulation of the miR-30a-3p/PTEN interaction.


Diabetes Myocardial hypertrophy Angiotensin type 1 receptors Angiotensin type 2 receptors MicroRNA Zucker diabetic fatty rats Compound 21 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Animal studies were in conformity with the Institutional Guidelines in compliance with National laws and policies (D.L.n. 116, Gazzetta Ufficiale della Repubblica Italiana, suppl.40, Feb.18, 1992) and experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

Informed Consent

For this type of study (experimental study on animal model) it is not required.


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Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Dipartimento di Medicina e ChirurgiaUniversità degli Studi di Milano-BicoccaMonzaItaly
  2. 2.Dipartimento di Scienze Radiologiche, Oncologiche e Anatomopatologiche, Istituto di Anatomia PatologicaSapienza Universita’ di RomaRomeItaly
  3. 3.Dipartimento di Medicina Interna e RiabilitazionePoliclinico di MonzaMonzaItaly
  4. 4.Unità Complicanze del Diabete, Diabetes Research InstituteIstituto Scientifico San RaffaeleMilanItaly

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