Activation of angiotensin-converting enzyme 2 ameliorates metabolic syndrome-induced renal damage in rats by renal TLR4 and nuclear transcription factor κB downregulation

Abstract

BackgroundMetabolic syndrome (MetS) is an independent risk factor for chronic kidney disease (CKD) through many mechanisms, including activation of the renin–angiotensin system. The deleterious effects of angiotensin II (Ang II) can be counterbalanced by angiotensin-converting enzyme 2 (ACE2). Diminazene aceturate (DIZE), an anti-trypanosomal drug, can activate ACE2.ObjectiveThis study aimed to investigate the possible reno-protective effects of DIZE in MetS rats with elucidation of related mechanisms.Materials and methodsThirty adult male Wistar albino rats were divided equally into control, MetS, and MetS + DIZE groups. Body weight, systolic blood pressure (SBP), and urinary albumin levels were measured. Serum levels of fasting blood glucose (FBG), insulin, uric acid, lipid profile, urea, and creatinine were measured. Homeostasis Model Assessment Index (HOMA-IR) was estimated. Subsequently, renal levels of ACE2, Ang II, malondialdehyde (MDA), reduced glutathione (GSH), and tumor necrosis factor-α (TNF-α) were measured with histopathological and immunohistochemical assessment of TLR4 and NF-κB in renal tissues.ResultsMetS caused dyslipidemia with significant increases in body weight, SBP, FBG, serum insulin, HOMA-IR, uric acid, urea, creatinine, urinary albumin, and renal levels of Ang II, MDA, and TNF-α, whereas renal ACE2 and GSH were significantly decreased. Renal TLR4 and NF-κB immunoreactivity in MetS rats was upregulated. DIZE supplementation of MetS rats induced significant improvements in renal function parameters; this could be explained by the ability of DIZE to activate renal ACE2 and decrease renal Ang II levels with downregulation of renal TLR4 and NF-κB expression.ConclusionDIZE exerts a reno-protective effect in MetS, mainly by downregulating renal TLR4 and NF-κB levels.

Effects of Taxifolin in Spontaneously Hypertensive Rats with a Focus on Erythrocyte Quality

“…Basic biometric parameters, as well as concentrations of angiotensin peptides, were measured in order to determine the condition of all experimental animals with emphasis on the main effects of systemic ACE2 inhibition and TAX treatment. The increase in BW gain following the ACE2 inhibition observed in this experiment is consistent with data showing a BW decrease after the administration of an ACE2 activator [22] as well as the documented negative correlation between circulating ACE2 levels and BW in rats [23]. We observed a decrease in BW gain following the TAX treatment mainly in ACE2-inhibited SHRs to values comparable to TAX-treated control SHRs.…”

Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3)

“…In rat models, studies have shown that vascular ACE2 overexpression protects the kidneys against aging-induced renal dysfunction, 28 and the activation of ACE2 has been reported to have a renoprotective effect. 29 Recently, a large-scale study on the association between plasma ACE2 and the risk of CVD has been published. 30 However, there are still few clinical reports on the association between ACE2 and the prognosis of CKD, especially DKD, and our current report provides an important perspective.…”

Cardiovascular complications are resolved by tuna protein hydrolysate supplementation in rats fed with a high-fat diet

“…Adipocyte hypertrophy is present in MS rats and is the major source of inflammatory cytokines and a peptide hormone, leptin; research reports that leptin can enhance RAS 14 , 15 . Hyperactivity of RAS contributes to metabolic disorder-related complications 16 , 17 . Moreover, an increase in RAS components including angiotensin-converting enzyme (ACE), angiotensin II (ang II), and angiotensin II receptor type 1 (AT 1 R) in local tissue and circulation were seen in diet-induced MS in rats 18 .…”