Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy

Batlle, Daniel; Wysocki, Jan; Soler, María José; Ranganath, Keerthi

doi:10.1038/ki.2011.381

Cited by 115 publications

(120 citation statements)

References 56 publications

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“…3A). As previously shown by other researchers (3,20,45), the lack of increase in ace2 gene expression in nontreated diabetic animals was not translated to the protein level (Fig. 3).…”

Section: Resultssupporting

confidence: 65%

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Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Riera

Anguiano

Clotet

et al. 2016

American Journal of Physiology-Renal Physiology

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-Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 g/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H 2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies. diabetic nephropathy; renin-angiotensin system; angiotensin-converting enzyme 2; animal model DIABETIC NEPHROPATHY IS THE leading cause of end-stage renal disease in the developed world (34). Previous studies have suggested that the renin-angiotensin system (RAS) is a major mediator of progressive renal injury in diabetic nephropathy. Drugs that target the RAS, including angiotensin-converting enzyme inhibitors and ANG II type 1 receptor blockers, have been shown to reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria (1, 4, 6, 21, 31). The systemic components of the RAS are altered in diabetes mellitus (32) and the intrarenal RAS is thought to play the major damaging role (25). The angiotensin-converting enzyme 2 (ACE2) has been identified in humans and differs from angiotensin-converting enzyme (ACE) in that it preferentially removes carboxy-terminal hydrophobic or basic amino acids (5, 12). Whereas ACE forms ANG II from ANG I, ACE2 is a major route of ANG II metabolism to ANG 1-7 (5, 39). ...

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“…3A). As previously shown by other researchers (3,20,45), the lack of increase in ace2 gene expression in nontreated diabetic animals was not translated to the protein level (Fig. 3).…”

Section: Resultssupporting

confidence: 65%

“…ACE2 activity has been shown to be altered in diabetic kidney disease, hypertensive renal disease, and various models of kidney injury (3,40,49,50). Our group has recently demonstrated that circulating and renal ACE2 is increased in NOD mice, and that enzyme expression was lowered by insulin treatment (33).…”

Section: Discussionmentioning

confidence: 99%

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Riera

Anguiano

Clotet

et al. 2016

American Journal of Physiology-Renal Physiology

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“…For instance, Giani et al [8] reported Ang-(1-7) attenuation of SBP (systolic blood pressure) and reduction in renal oxidative stress and inflammatory markers in Zucker rats. Benter's group [9,10] reported decreased SBP by Ang- (1)(2)(3)(4)(5)(6)(7) in SHRs (spontaneously hypertensive rats), but not in streptozotocin-induced diabetic SHRs, despite amelioration of albuminuria and renal vascular dysfunction. In contrast, Tan et al [11] found no significant reductions in SBP in response to Ang- (1)(2)(3)(4)(5)(6)(7) in SHR and Wistar-Kyoto rats.…”

mentioning

confidence: 96%

“…However, the catalytic efficiency of ACE2 on AngII is 400-fold greater than on AngI, resulting in direct Ang-(1-7) formation [3,4]. Evidence now supports a counter-regulatory role for Ang-(1-7) via its own receptor, the Ang-(1-7) receptor or MasR, which oppose many AT 1 -R (AngII subtype 1 receptor)-mediated outcomes (for reviews, see [5][6][7]). Earlier studies on the effects of Ang-(1-7) on hypertension, and cardiovascular and renal function in hypertensive rats with or without diabetes yielded contradictory results.…”

mentioning

confidence: 96%

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

Padda

et al. 2015

Clinical Science

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We investigated the relationship between Ang-(1-7) [angiotensin-(1-7)] action, sHTN (systolic hypertension), oxidative stress, kidney injury, ACE2 (angiotensin-converting enzyme-2) and MasR [Ang-(1-7) receptor] expression in Type 1 diabetic Akita mice. Ang-(1-7) was administered daily [500 μg/kg of BW (body weight) per day, subcutaneously] to male Akita mice from 14 weeks of age with or without co-administration of an antagonist of the MasR, A779 (10 mg/kg of BW per day). The animals were killed at 20 weeks of age. Age-matched WT (wild-type) mice served as controls. Ang-(1-7) administration prevented sHTN and attenuated kidney injury (reduced urinary albumin/creatinine ratio, glomerular hyperfiltration, renal hypertrophy and fibrosis, and tubular apoptosis) without affecting blood glucose levels in Akita mice. Ang-(1-7) also attenuated renal oxidative stress and the expression of oxidative stress-inducible proteins (NADPH oxidase 4, nuclear factor erythroid 2-related factor 2, haem oxygenase 1), pro-hypertensive proteins (angiotensinogen, angiotensin-converting enzyme, sodium/hydrogen exchanger 3) and profibrotic proteins (transforming growth factor-β1 and collagen IV), and increased the expression of anti-hypertensive proteins (ACE2 and MasR) in Akita mouse kidneys. These effects were reversed by A779. Our data suggest that Ang-(1-7) plays a protective role in sHTN and RPTC (renal proximal tubular cell) injury in diabetes, at least in part, through decreasing renal oxidative stress-mediated signalling and normalizing ACE2 and MasR expression.

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“…angiotensin; kidney; neprilysin; hypertension; proteinuria ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2), a homolog of ACE, is recognized as an important enzymatic component of the renin-angiotensin system (RAS) that may regulate functional output of this hormonal system (5,7,8,14,28,30,51,50). Although ACE2 was originally characterized for its ability to hydrolyze ANG I to Ang-(1-9), subsequent studies revealed a very high catalytic activity to convert ANG II to Ang-(1-7) (41,44,45,56,58).…”

mentioning

confidence: 99%

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

Yamaleyeva¹,

Gilliam-Davis

Almeida³

et al. 2012

American Journal of Physiology-Renal Physiology

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Yamaleyeva LM, Gilliam-Davis S, Almeida I, Brosnihan KB, Lindsey SH, Chappell MC. Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes. Am J Physiol Renal Physiol 302: F1374 -F1384, 2012. First published February 29, 2012 doi:10.1152/ajprenal.00656.2011We examined the impact of early diabetes on the circulating and kidney renin-angiotensin system (RAS) in male and female mRen2.Lewis (mRen2) hypertensive rats. Diabetes (DB) was induced by streptozotocin (STZ; 65 mg/kg) at 11 wk of age for 4 wk without insulin replacement. Systolic blood pressures were not increased in DB males or females compared with controls (CON). Circulating angiotensinconverting enzyme 2 (ACE2) increased ninefold (P Ͻ 0.05) in DB females and threefold (P Ͻ 0.05) in DB males, but circulating ACE and ANG II were higher in the DB groups. Serum C-reactive protein was elevated in DB females but not DB males, and the vascular responses to acetylcholine and estradiol were attenuated in the DB females. Proteinuria, albuminuria, and angiotensinogen excretion increased to a similar extent in both DB females and males. Glomerular VEGF expression also increased to a similar extent in both DB groups. Renal inflammation (CD68 ϩ cells) increased only in DB females although males exhibited greater inflammation that was not different with DB. Cortical ACE2 did not change in DB females but was reduced (30%) in DB males. Renal neprilysin activity (Ͼ75%, P Ͻ 0.05) was markedly reduced in the DB females to that in the DB and CON males. ACE activity was significantly lower in both female (75%, P Ͻ 0.05) and male (50%; P Ͻ 0.05) DB groups, while cortical ANG II and Ang-(1-7) levels were unchanged. In conclusion, female mRen2 rats are not protected from vascular damage, renal inflammation, and kidney injury in early STZ-induced diabetes despite a marked increase in circulating ACE2 and significantly reduced ACE within the kidney.angiotensin; kidney; neprilysin; hypertension; proteinuria ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2), a homolog of ACE, is recognized as an important enzymatic component of the renin-angiotensin system (RAS) that may regulate functional output of this hormonal system (5,7,8,14,28,30,51,50). Although ACE2 was originally characterized for its ability to hydrolyze ANG I to Ang-(1-9), subsequent studies revealed a very high catalytic activity to convert ANG II to Ang-(1-7) (41,44,45,56,58). Indeed, ACE2 inhibition or genetic knockout studies reveal a heightened sensitivity to ANG II-induced increases in blood pressure, as well as an exacerbation of end-organ damage in these experimental models (31,32,46,48,52,60). In contrast to ACE, circulating ACE2 is low to nondetectable in rodents and humans, and tissue sources of the enzyme are more likely to influence the local RAS (12, 40). Diabetic renal injury is generally associated with a reduction in the activity and/or expression of renal tissue ACE2, which may contribute to a deleterious imbalance in the relative expression of ANG I...

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Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy

Cited by 115 publications

References 56 publications

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

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

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

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