Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade on Streptozotocin-Induced Diabetic Nephropathy

Abstract

The aim of this study was designed to investigate the possible beneficial effects of the angiotensin-converting enzyme (ACE) inhibitor, Quinapril (Q) and, the angiotensin (ang) II T 1 (AT1) receptor blocker, irbesartan (Irb), in streptozotocin (STZ)-induced diabetes in rats. The rats were randomly allotted into one of five experimental groups: A (control), B (diabetic untreated), C (diabetic treated with Q), D (diabetic treated with Irb), and E (diabetic treated with Q&Irb), each group containing 10 animals. Groups B-E received STZ. Diabetes was induced in four groups by a single intraperitoneal (i.p) injection of STZ (50 mg/kg, freshly dissolved in 5 mmol/L citrate buffer, pH 4.5). Two days after STZ treatment, development of diabetes in four experimental groups was confirmed by measuring blood glucose levels in a tail vein blood samples. Rats with blood glucose levels of 250 mg/dL or higher were considered to be diabetic. The rats in Q-, Irb-, and Q&Irb-treated groups were given Q (in a dose of 3 mg/kg body weight), Irb (5 mg/kg body weight), and Q&Irb (in a dose of 1.5 mg/kg + 2.5 mg/kg body weight) once a day orally by using intra-gastric intubation for 12 weeks starting two days after STZ injection. Treatment of Q and especially Irb reduced the glomerular size and thickening of capsular, glomerular, and tubular basement membranes; and increased amounts of mesangial matrix and tubular dilatation and renal function as compared with diabetics untreated. Notably, the better effects were obtained when Q and Irb given together. We conclude that Q, Irb, and especially Q+Irb therapy causes renal morphologic and functional improvement after STZ-induced diabetes in rats. We believe that further preclinical research into the utility of Q and Irb treatment, alone or its combination, may indicate its usefulness as a potential treatment in diabetic nephropathy (DNp).

Protective effects of thymoquinone on streptozotocin-induced diabetic nephropathy

“…Because a strong correlation exists between the magnitude of mesangial matrix expansion, degree of tubulointerstitial fibrosis and the progressive course of DNP, a role has implicitly arisen for ECM overproduction in the development and progressive nature of diabetic kidney disease (Mauer et al 1984). Sen et al (2008) evaluated whether Irb, ARB, alone or incombination with quinapril (Q), ACE inhibitor, has some additional effect on ACE inhibitor in renal function and structure in an animal model of DNP. Similar protective effects were seen all treatment groups in renal functional assesment.…”

Angiotensin‐Converting Enzyme Inhibition and Angiotensin AT1 Receptor Blockade Downregulate Angiotensin‐Converting Enzyme Expression and Attenuate Renal Injury in Streptozotocin‐Induced Diabetic Rats

“…On the other hand, ARBs selectively and completely block ANGII actions via AT1 receptors allowing ANGII binding to AT2 receptors with beneficial AT2‐mediated vasodilator, antiproliferative, and antifibrogenic effects . Clinical and experimental evidence supports that ACEIs and ARBs have renoprotective effects independent of their antihypertensive effects, leading to attenuation of progressive renal disease , but the mechanisms underlying their favorable effects are not fully understood.…”

The Dilemma of Dual Renin-Angiotensin System Blockade in Chronic Kidney Disease: Why Beneficial in Animal Experiments But Not in the Clinic?

“…However, in Lyon hypertensive rat there was an additive blood pressure lowering effect but no positive effects on the course of end-organ damage (Naelten et al 2005). In models of diabetic nephropathy the combination of ACEi and ARB also produced better organoprotective effects as compared with a single drug treatment; this was reported from studies of streptozotocin induced diabetes in rat (Sen et al 2008) as well as diabetic SHR animals (Cao et al 2001). Also other animals and conditions were treated successfully with the combination of ACEi and ARB, e.g.…”

“…However, this combination failed to improve survival or event-free time in human trials; on the other hand, adverse effects were more frequent (Fried et al 2008, Mia et al 2011, Onuigbo 2009, Parving et al 2012, Yusuf and ONTARGET Investigators 2008b, Rutkowski and Tylicky 2015. Conversely, in most animal experiments not only that it has been undoubtedly proved that the inappropriate activation of the intrarenal RAAS is the major culprit of the progression of chronic kidney disease, but the treatment with the combination of ACEi and ARB proved successful and reliable, usually superior to application of a single drug in the slowing the progression of chronic kidney disease and development of end-organ damage (Azizi and Ménard 2004, Carlstrom et al 2015, Cao et al 2001, Cortinovis et al 2016, Červenka and Heller 1996, Doleželová et al 2016, Ke et al 2000, Kobori et al 2007, Kujal et al 2014, Macconi 2010, Richer et al 1998, Sen et al 2008, Shen et al 1998, Sedláková et al 2017, Zoja et al 2006, Zoja et al 2002. Experimental work obviously aims to bring about some progress in future treatment of patients so the discrepancy between the effects in the experiment and the clinics appeared to preclude the translation of experimental results to human medicine.…”