Effects of Losartan Pretreatment in an Experimental Model of Ischemic Acute Kidney Injury

Abstract

Background/Aims: Contributions to the understanding of acute renal failure (ARF) pathogenesis have not been translated into an effective clinical therapy. We studied the effects of pretreatment with the angiotensin II type 1 (AT1) receptor blocker, losartan, on renal function, tissue injury, inflammatory response and serum aldosterone levels in a model of ischemic ARF. Methods: Rats underwent unilateral renal ischemia followed by 24 h of reperfusion (IR), and were pretreated or not with 8 (IRL8) or 80 (IRL80) mg/kg/day of losartan for 3 days. Results: IR kidneys showed marked renal dysfunction, epithelial damage, capillary congestion, increased myeloperoxidase (MPO) activity and increased TNF-α, IL1-β and IL-6 mRNA levels. IRL80 kidneys showed protection against dysfunction and tissue injury, associated with normal MPO activity and cytokine mRNA levels. The lower dose was not able to achieve the same degree of functional renoprotection and could not prevent an increase of MPO or proinflammatory cytokine mRNA levels. The high losartan dose completely prevented an increase of serum aldosterone levels induced by IR. Conclusion: Renoprotection of the high losartan dose would be mainly mediated by its anti-inflammatory actions. Our results show a potential pathophysiological role of AT1 activation in promoting renal dysfunction, structural injury, inflammation and aldosterone elevation after IR injury.

Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption

“…Studies in animal models of AKI render data in support of the notion that kidney renin-angiotensin system (RAS) activation contributes to the pathogenesis of AKI [150][151][152][153]. An increase in urine AGT is now considered as one of the most promising biomarkers of AKI progression in patients with acute decompensated heart failure [46,55,154,155].…”

Biomarkers of AKI

“…An unexplored area is the potential therapeutic benefit of shunting the RAS pathway from activation of angiotensin II receptor type 1 by angiotensin II to activation of the Mas receptor by angiotensin 1-7. Pretreatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aliskiren has been shown to mitigate renal ischemia-reperfusion injury in experimental models, primarily by reduction in postreperfusion inflammation (66)(67)(68). Additionally, one study reported a reduction in the severity of AKI at 48 hours postreperfusion when captopril was continuously administered through an intraperitoneal osmotic micropump implanted immediately after renal ischemia-reperfusion injury.…”

Urinary Angiotensinogen: A Promising Biomarker of AKI Progression in Acute Decompensated Heart Failure: What Does It Mean?

“…The increase in uAGT in AKI is of interest, because it likely reflects local activation of the RAS within the kidney. Studies in animal models of AKI provide evidence in support of the concept that activation of the kidney RAS contributes to the pathogenesis of AKI (13)(14)(15)(16).…”

“…Patients with AKI likely have a substantial inflammatory response (8), in part, caused by angiotensin II. Of note, in rodents exposed to renal I/R injury, RAS blockade using an ACE inhibitor or an angiotensin II type 1 receptor antagonist ameliorated inflammation within the kidney and alleviated the severity of AKI (13,14) This is not to say, of course, that blocking the proinflammatory and therefore, deleterious effects of RAS activation will overcome the generally considered beneficial hemodynamic actions of angiotensin II that help maintain systemic BP and attenuate the fall in GFR that occurs in AKI associated with decompensated heart failure.…”