Chronic angiotensin (17) injection accelerates STZ-induced diabetic renal injury¹

Abstract

Aim: The renin-angiotensin system (RAS) plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. In the past few years, angiotensin (Ang) (1-7) has been reported to counteract the effects of Ang II and was even considered as a new therapeutical target in RAS. The present study aimed to investigate the effect of Ang (1-7) administration on a diabetic animal model and the modulation on local RAS. Methods: Streptozotocin (STZ) injection-induced diabetic rats were used in the experiment. The animals were divided into 3 groups: (1) control; (2) STZ-induced diabetes; and (3) STZ-induced diabetes with chronic Ang (1-7) treatment [D+Ang (1-7)]. In the D+Ang(1-7) group, a dose of 25 µg·kg of Ang (1-7) was continually injected through the jugular vein by embedding miniosmotic pump for 6 weeks. Plasma glucose, ratio of kidney to body weight, and 24 h urine protein and serum creatinine were monitored by conventional measurement. Plasma and renal Ang II levels were measured by radioimmunoassay. Ang-converting enzyme (ACE), ACE2, Ang II type 1 (AT1) receptor, Ang II type 2 (AT2) receptor, Ang (1-7) Mas receptor, and TGF-β1 mRNA levels were measured by real time PCR; ACE, ACE2, and TGF-β1 protein levels were analyzed by Western blotting. Results:The renal function of diabetic rats was significantly retrogressed when compared with that of control rats. After the treatment by constant Ang (1-7) vein injection for 6 weeks, renal function was found to be even worse than diabetic rats, and both TGF-β1 mRNA and protein levels were elevated in the D+Ang(1-7) group compared with the diabetic rats. The real-time PCR result also showed an increase in ACE mRNA expression and decrease in ACE2 mRNA level in the D+Ang(1-7) group when compared with diabetic rats. The number of AT1 receptors increased in the Ang (1-7)-injected group, while the number of AT2 and Mas receptors decreased. Conclusion: Exogenous Ang (1-7) injection did not ameliorate STZinduced diabetic rat renal injury; on the contrary, it accelerated the progressive diabetic nephropathies.

Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

“…Thus, the beneficial effects of ACE2 observed in this study are most likely attributable to the net effect of decreased local Ang II level and increased local Ang-(1-7) level. Recent studies found that long-term ACE2 overexpression or Ang-(1-7) injection accelerated myocardial fibrosis or diabetic nephropathy (7,39,40). In this study, the outcome of ACE2 overexpression was assessed 4 weeks after gene transfer, and no detrimental effects were found, suggesting that our gene therapy offers a safe approach.…”

Attenuating effect of angiotensin-(1–7) on angiotensin II-mediated NAD(P)H oxidase activation in type 2 diabetic nephropathy of KK-Ay/Ta mice

“…This study also reported decreased urinary albumin excretion in response to ANG-(1-7) (6,7,13). Another study in the same streptozotocin-induced diabetic rat model showed that chronic injection of ANG-(1-7) accelerated diabetic renal injury (36). In db/db mice, glomerular expression of ACE2 was increased, and ACE2 inhibitor use showed increased glomerular staining for fibronectin and an extracellular matrix protein (42).…”

Adenosine 5′-triphosphate stimulates the increase of TGF-β1 in rat mesangial cells under high-glucose conditions via reactive oxygen species and ERK1/2

“…It is important to note, however, that NADPH oxidase is at least partially involved in ERK1/2 activation by ATP. Studies using neutralizing antibodies against TGF-β1 have provided convincing evidence that the prosclerotic and hypertrophic effects of high glucose levels are largely mediated by the production and activation of TGF-β1 by glomerular mesangial cells [24] . Activated ERK can activate Elk-1, a member of the ternary complex factors that enhances the expression of c-fos and promotes subsequent DNA binding of the transcription factor AP-1.…”