Overexpression of catalase prevents hypertension and tubulointerstitial fibrosis and normalization of renal angiotensin-converting enzyme-2 expression in Akita mice

Abstract

We investigated the relationship among oxidative stress, hypertension, renal injury, and angiotensin-converting enzyme-2 (ACE2) expression in type 1 diabetic Akita mice. Blood glucose, blood pressure, and albuminuria were monitored for up to 5 mo in adult male Akita and Akita catalase (Cat) transgenic (Tg) mice specifically overexpressing Cat, a key antioxidant enzyme in their renal proximal tubular cells (RPTCs). Same-age non-Akita littermates and Cat-Tg mice served as controls. In separate studies, adult male Akita mice (14 wk) were treated with ANG 1-7 (500 μg·kg⁻¹·day⁻¹ sc) ± A-779, an antagonist of the Mas receptor (10 mg·kg⁻¹·day⁻¹ sc), and euthanized at the age of 18 wk. The left kidneys were processed for histology and apoptosis studies. Renal proximal tubules were isolated from the right kidneys to assess protein and gene expression. Urinary angiotensinogen (AGT), angiotensin II (ANG II), and ANG 1-7 were quantified by specific ELISAs. Overexpression of Cat attenuated renal oxidative stress; prevented hypertension; normalized RPTC ACE2 expression and urinary ANG 1-7 levels (both were low in Akita mice); ameliorated glomerular filtration rate, albuminuria, kidney hypertrophy, tubulointerstitial fibrosis, and tubular apoptosis; and suppressed profibrotic and proapoptotic gene expression in RPTCs of Akita Cat-Tg mice compared with Akita mice. Furthermore, daily administration of ANG 1-7 normalized systemic hypertension in Akita mice, which was reversed by A-779. These data demonstrate that Cat overexpression prevents hypertension and progression of nephropathy and highlight the importance of intrarenal oxidative stress and ACE2 expression contributing to hypertension and renal injury in diabetes.

Angiotensin-(1–7) prevents systemic hypertension, attenuates oxidative stress and tubulointerstitial fibrosis, and normalizes renal angiotensin-converting enzyme 2 and Mas receptor expression in diabetic mice

“…Hyperglycaemia and Agt overexpression act in concert to elicit sHTN (systolic hypertension) and RPTC apoptosis in diabetic Agt-Tg mice [16]. More recently, we documented that RAS (renin-angiotensin system) blockade and Cat (catalase) overexpression in RPTCs prevent sHTN and tubular ROS generation, suppress RPTC apoptosis and normalize ACE2 expression in RPTCs of diabetic Akita Agt-Tg [17] and Akita Cat-Tg mice [18], supporting the view that enhanced ROS generation and RAS activation are pivotal in down-regulation of ACE2 expression and renal injury in diabetes.…”

“…Akita mice, an autosomal dominant model of spontaneous Type 1 diabetes in which insulin gene 2 is mutated, have decreased numbers of pancreatic islet β-cells and develop hyperglycaemia at 3-4 weeks of age, manifesting impaired renal function with increased oxidative stress markers in their RPTs (renal proximal tubules) by 30 weeks of age [20,21] and closely resembling those observed in Type 1 diabetes patients. Adult Akita mice (14 weeks of age) were treated subcutaneously with Ang-(1-7) (500 μg/kg of BW per day) with or without A779 (10 mg/kg of BW per day) and killed at 20 weeks of age (eight mice per group), as described previously [18]. Untreated non-Akita WT (wild-type) mice served as controls.…”

“…SBP was monitored in the morning with a BP-2000 tail-cuff pressure monitor (Visitech Systems) at least two or three times each week per animal, for 10 weeks [14][15][16][17][18][22][23][24][25][26]. The mice were habituated to the procedure for at least 15-20 min per day for 5-7 days before the first SBP measurements.…”

Effect of benazepril on the transdifferentiation of renal tubular epithelial cells from diabetic rats

“…Ang Ⅱ leads to abnormalities of renal blood flow dynamics in diabetic state and participates in tubulointerstitial fibrosis in a non-hemodynamic manner (20). By RAS and AT1 receptors, Ang II stimulates renal tubular epithelial cell hypertrophy, induces the synthesis of TGF-β1, and generates interstitial fibroblasts and tubular epithelial cells into myofibroblasts.…”

Angiotensin-(1-7): A Novel Peptide to Treat Hypertension and Nephropathy in Diabetes?

“…Ang 1-7 binds to MasR to trigger eNOS and Akt phosphorylation (21), and stimulate the release of NO and prostaglandins. Our group previously reported that overexpression of catalase or administration of Ang1-7 normalises oxidative stress and sHTN in Akita diabetic mice (a mouse model of type 1 diabetes) and that the effect of Ang 1-7 can be reversed after treatment with MasR antagonist A-779, indicating the anti-hypertensive effect of Ang 1-7 is mediated, at least in part, via suppression of oxidative stress in diabetes (7,22).…”