Effects of renal ischemia injury on brain in diabetic and non-diabetic rats: Role of angiotensin II type 2 receptor and angiotensin-converting enzyme 2.

Abstract

Clinically, patients with diabetes mellitus (DM) are more susceptible to ischemic renal injury (IRI) than non-diabetic (ND) patients. Besides, IRI predisposes distant organ dysfunctions including, neurological dysfunction, in which the major contributor remains renin-angiotensin system (RAS). Interestingly, the role of depressor arm of RAS on IRI-associated neurological sequalae remains unclear. Hence, this study aimed to delineate the role of angiotensin II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) under the same. ND and Streptozotocin-induced DM rats with bilateral IRI were treated with AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator-Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) either alone or as combination therapy. Effect of IRI on neurological functions were assessed by behavioural, biochemical, and histopathological analysis. Immunohistochemistry, ELISA and qRT-PCR experiments were conducted for evaluation of the molecular mechanisms. We found that in ND and DM rats, IRI causes increased hippocampal MDA and nitrite levels, augmented inflammatory cytokines (granulocyte-colony stimulating factor, glial fibrillary acidic protein), altered protein levels of Ang II, Ang-(1-7) and mRNA expressions of At1r, At2r and Masr. Treatment with C21 and Dize effectively normalised above-mentioned pathological alterations. Moreover, the protective effect of C21 and Dize combination therapy was better than respective monotherapies, and more likely, exerted via augmentation of protein and mRNA levels of depressor arm components. Thus, AT2R agonist and ACE2 activator therapy prevents the development of IRI-associated neurological dysfunction by attenuating oxidative stress and inflammation, upregulating depressor arm of RAS in brain under ND and DM conditions.

• Authors: Nisha Sharma, Anil Bhanudas Gaikwad
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 882 Pg. 173241 (Sep 05 2020) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 32565336 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Imidazoles
• Nitrites
• Receptor, Angiotensin, Type 2
• Sulfonamides
• Thiophenes
• Malondialdehyde
• Angiotensin-Converting Enzyme 2
• diminazene aceturate
• compound 21
• Diminazene

Topics

• Angiotensin-Converting Enzyme 2 (metabolism)
• Animals
• Brain (drug effects, metabolism)
• Diabetes Mellitus, Experimental (metabolism)
• Diminazene (analogs & derivatives, pharmacology)
• Hyperglycemia (metabolism)
• Imidazoles (pharmacology)
• Kidney Diseases (metabolism)
• Kidney Tubules (drug effects, metabolism)
• Male
• Malondialdehyde (metabolism)
• Nitrites (metabolism)
• Rats, Wistar
• Receptor, Angiotensin, Type 2 (agonists, metabolism)
• Reperfusion Injury (metabolism)
• Sulfonamides (pharmacology)
• Thiophenes (pharmacology)