Ameliorative effect of AT2R and ACE2 activation on ischemic renal injury associated cardiac and hepatic dysfunction

Area of Science:

• Cardiovascular Science
• Renal Physiology
• Endocrinology

Background:

• Ischemic renal injury (IRI) can lead to damage in the heart and liver.
• The renin-angiotensin system (RAS) plays a complex role in regulating blood pressure and organ function.
• Diabetes mellitus (DM) can exacerbate organ damage following IRI.

Purpose of the Study:

• To investigate the role of the RAS depressor arm in cardio-hepatic dysfunction following IRI.
• To evaluate the therapeutic potential of targeting the RAS depressor arm in non-diabetic (ND) and diabetic mellitus (DM) rats with IRI.

Main Methods:

• Developed DM in rats using Streptozotocin.
• Induced bilateral IRI and allowed 24 hours of reperfusion.
• Administered AT2R agonist (Compound 21) and/or ACE2 activator (Dimetindene Aceturate) to ND and DM rats.

Main Results:

• IRI induced cardio-hepatic injuries, characterized by oxidative stress, inflammation, and altered RAS component expression (ACE, ACE2, Ang II, Ang-(1-7), AGT).
• Concomitant therapy with an AT2R agonist and ACE2 activator significantly mitigated IRI-induced cardio-hepatic dysfunction.
• This combined therapy inhibited oxidative stress, downregulated inflammation, and enhanced the RAS depressor arm in both ND and DM rats.

Conclusions:

• The depressor arm of the RAS is crucial in mitigating IRI-associated cardio-hepatic sequelae.
• Combined AT2R agonist and ACE2 activator therapy offers a protective strategy against cardio-hepatic dysfunction in IRI, even under diabetic conditions.
• Targeting the RAS depressor arm presents a promising therapeutic avenue for managing complex organ damage following ischemic events.