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

Shi, Yixuan; Lo, Chao‐Sheng; Padda, Ranjit S.; Abdo, Shaaban; Chénier, Isabelle; Filep, János G.; Ingelfinger, Julie R.; Zhang, Shaoling; Chan, John S.D.

doi:10.1042/cs20140329

Cited by 79 publications

(68 citation statements)

References 47 publications

(154 reference statements)

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“…24,25 Additionally, many studies have reported oxidative stress and inflammation in the kidneys of Akita Ins2+/C96Y C57BL/6 mice, which play an important role in the pathogenesis of diabetic nephropathy. [26][27][28][29][30] However, the genetic background of Akita mutation mice contributes to the severity of albuminuria and histological changes. Gurley et al 31 studied the effect of breeding the Ins2+/C96Y mutation into the DBA/2 and 129/SvEv strains on susceptibility to diabetic nephropathy.…”

Section: Genetic Models Of Type 1 Diabetes In Micementioning

confidence: 99%

Rodent models of diabetic nephropathy: their utility and limitations

Kitada¹,

Ogura²,

Koya³

2016

IJNRD

191

153

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Diabetic nephropathy is the most common cause of end-stage renal disease. Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and many type 1 and type 2 diabetic rodent models have been established for the study of diabetes and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26 mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 diabetes. In addition, db/db mice, KK-Ay mice, Zucker diabetic fatty rats, Wistar fatty rats, Otsuka Long-Evans Tokushima Fatty rats and Goto-Kakizaki rats serve as rodent models of type 2 diabetes. An animal model of diabetic nephropathy should exhibit progressive albuminuria and a decrease in renal function, as well as the characteristic histological changes in the glomeruli and the tubulointerstitial lesions that are observed in cases of human diabetic nephropathy. A rodent model that strongly exhibits all these features of human diabetic nephropathy has not yet been developed. However, the currently available rodent models of diabetes can be useful in the study of diabetic nephropathy by increasing our understanding of the features of each diabetic rodent model. Furthermore, the genetic background and strain of each mouse model result in differences in susceptibility to diabetic nephropathy with albuminuria and the development of glomerular and tubulointerstitial lesions. Therefore, the validation of an animal model reproducing human diabetic nephropathy will significantly facilitate our understanding of the underlying genetic mechanisms that contribute to the development of diabetic nephropathy. In this review, we focus on rodent models of diabetes and discuss the utility and limitations of these models for the study of diabetic nephropathy.

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Section: Genetic Models Of Type 1 Diabetes In Micementioning

confidence: 99%

Rodent models of diabetic nephropathy: their utility and limitations

Kitada¹,

Ogura²,

Koya³

2016

IJNRD

191

153

View full text Add to dashboard Cite

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“…NADPH oxidase is a membrane-bound enzyme complex, which triggers ROS production through generation of superoxide radicals. Our lab found that administration of Ang 1-7 limits the activation of NADPH oxidase by attenuating the mRNA and protein expressions of NOX4, a crucial component of the NADPH oxidase complex in diabetic RPTs (7). Furthermore, Ang 1-7 also normalises the expression of antioxidant enzymes catalase and HO-1, and oxidative stress inducible proteins Nrf2 and HO-1 in diabetic RPTs (7,15).…”

Section: Ang 1-7 Limits Ros Generation and Normalises Antioxidant Patmentioning

confidence: 98%

“…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).…”

Section: Ang 1-7 Reduces Systemic Hypertension (Shtn)mentioning

confidence: 99%

“…Furthermore, Ang 1-7 also normalises the expression of antioxidant enzymes catalase and HO-1, and oxidative stress inducible proteins Nrf2 and HO-1 in diabetic RPTs (7,15). The normalisation of oxidative stress with Ang 1-7 treatment can be visualised as a reduction in dihydroethidium (DHE) and 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) staining of kidney cells (7). Although Nrf2 is a critical factor for the activation of antioxidant pathways, however, overactivation of Nrf2 itself by chronic hyperglycemia can trigger the expression of the renal Agt gene in diabetes (45).…”

Section: Ang 1-7 Limits Ros Generation and Normalises Antioxidant Patmentioning

confidence: 99%

“…Our lab found that administration of Ang 1-7 limits the activation of NADPH oxidase by attenuating the mRNA and protein expressions of NOX4, a crucial component of the NADPH oxidase complex in diabetic RPTs (7). Furthermore, Ang 1-7 also normalises the expression of antioxidant enzymes catalase and HO-1, and oxidative stress inducible proteins Nrf2 and HO-1 in diabetic RPTs (7,15). The normalisation of oxidative stress with Ang 1-7 treatment can be visualised as a reduction in dihydroethidium (DHE) and 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) staining of kidney cells (7).…”

Section: Ang 1-7 Limits Ros Generation and Normalises Antioxidant Patmentioning

confidence: 99%

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

Padda

Shi

et al. 2015

J Diabetes Metab

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The renin-angiotensin system (RAS) plays a pivotal role in mammalian homeostasis physiology. The RAS can be delineated into a classical RAS (the pressor arm) including angiotensinogen (Agt), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang II) and angiotensin type 1 receptor (AT1R), and a counterbalancing novel RAS (the depressor arm) including Agt, renin, angiotensin-converting enzyme-2 (ACE-2), angiotensin-(1-7) (Ang 1-7) and Ang 1-7 receptor (or Mas receptor (MasR)). Hyperglycemia (diabetes) induces severe tissue oxidative stress, which stimulates the pressor arm of the renal RAS axis and leads to an increase in ACE/ACE-2 ratio, with excessive formation of Ang II. There is a growing body of evidence for beneficial effects of the depressor arm of RAS (ACE-2/Ang 1-7/MasR) axis in diabetes, hypertension and several other diseased conditions. Evidence from in vitro, in vivo and clinical studies reflects anti-oxidant, antifibrotic, and anti-inflammatory properties of Ang 1-7. Most of the currently available therapies only target suppression of the pressor arm of RAS with angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEi). However, it is time to consider simultaneous activation of the depressor arm for more effective outcomes. This review summarizes the recent updates on the protective role of Ang 1-7 in hypertension and kidney injury in diabetes, as well as the possible underlying mechanism(s) of Ang 1-7 action, suggesting that the ACE-2/Ang 1-7/MasR axis can be developed as a therapeutic target for the treatment of diabetes-induced hypertension and renal damage.

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Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice

Okita

Nemoto

Yamagata

et al. 2018

European Journal of Pain

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Background We have recently reported that the spinal angiotensin (Ang) converting enzyme (ACE)/Ang II/AT1 receptor axis and downstream p38 MAPK phosphorylation are activated in streptozotocin (STZ)‐induced diabetic mice and lead to tactile hypersensitivity. Moreover, our previous results suggested that the intrathecal (i.t.) administration of Ang (1‐7), an N‐terminal fragment of Ang II, may attenuate the Ang II‐induced nociceptive behaviour through the inhibition of p38 MAPK phosphorylation via Mas receptors. Here, we investigated whether the i.t. administration of Ang (1‐7) can attenuate STZ‐induced diabetic neuropathic pain. Methods Tactile and thermal hypersensitivities were determined using the von Frey filament and Hargreaves tests, respectively. The protein expression of ACE2, Mas receptors and phospho‐p38 MAPK was measured by western blotting. Spinal ACE2 activity was determined using ACE2 activity assay kit. Results The i.t. administration of Ang (1‐7) significantly reduced the tactile and thermal hypersensitivities on day 14 after STZ injection, and these effects were significantly prevented by the Mas receptor antagonist A779. The expression of ACE2 and Mas receptors in the plasma membrane fraction of the lumbar dorsal spinal cord was both significantly decreased in STZ mice. Spinal ACE2 activity was also decreased while p38 MAPK phosphorylation was increased in the lumbar dorsal region of these mice. This phosphorylation was attenuated by the injection of Ang (1‐7), whose effect was reversed by A779. Conclusions Our data demonstrate that Ang (1‐7) attenuates STZ‐induced diabetic neuropathic pain and that this occurs through a mechanism involving spinal Mas receptors and he inhibition of p38 MAPK phosphorylation. Significance The ACE2/Ang (1‐7)/Mas receptor axis was down‐regulated in the spinal cord of STZ mice and the i.t. administration of Ang (1‐7) attenuated the STZ‐induced diabetic neuropathic pain via Mas receptors. Therefore, the activation of this axis could be an effective therapeutic target to alleviate the neuropathic pain in diabetic patients.

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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

Cited by 79 publications

References 47 publications

Rodent models of diabetic nephropathy: their utility and limitations

Rodent models of diabetic nephropathy: their utility and limitations

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

Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice

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