Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system

Sergi Clotet, María José Soler, Marta Rebull, Javier Gimeno, Susan Gurley, Julio Pascual, Marta Riera

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Angiotensin-converting enzyme 2 (ACE2) deletion worsens kidney injury, and its amplification ameliorates diabetic nephropathy. Male sex increases the incidence, prevalence, and progression of chronic kidney disease in our environment. Method: Here, we studied the effect of ACE2 deficiency and gonadectomy (GDX) on diabetic nephropathy and its relationship with fibrosis, protein kinase B (Akt) activation, and the expression of several components of the renin-angiotensin system (RAS). Mice were injected with streptozotocin to induce diabetes and followed for 19 weeks. Physiological and renal parameters were studied in wild-type and ACE2 knockout (ACE2KO) male mice with and without GDX. Results: Diabetic ACE2KO showed increased blood pressure (BP), glomerular injury, and renal fibrosis compared with diabetic wild-type. Gonadectomized diabetic ACE2KO presented a decrease in BP. In the absence of ACE2, GDX attenuated albuminuria and renal lesions, such as mesangial matrix expansion and podocyte loss. Both, α-smooth muscle actin accumulation and collagen deposition were significantly decreased in renal cortex of gonadectomized diabetic ACE2KO but not diabetic wild-type mice. GDX also reduced circulating ACE activity in ACE2KO mice. Loss of ACE2 modified the effect of GDX on cortical gene expression of RAS in diabetic mice. Akt phosphorylation in renal cortex was increased by diabetes and loss of ACE2 and decreased by GDX in control and diabetic ACE2KO but not in wild-type mice. Conclusions: Our results suggest that GDX may exert a protective effect within the kidney under pathological conditions of diabetes and ACE2 deficiency. This renoprotection may be ascribed to different mechanisms such as decrease in BP, modulation of RAS, and downregulation of Akt-related pathways.

Original languageEnglish (US)
Pages (from-to)1752-1765
Number of pages14
JournalJournal of Hypertension
Volume34
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Fingerprint

Renin-Angiotensin System
Blood Pressure
Kidney
Wounds and Injuries
Diabetic Nephropathies
Knockout Mice
Fibrosis
Podocytes
Proto-Oncogene Proteins c-akt
Albuminuria
Streptozocin
angiotensin converting enzyme 2
Chronic Renal Insufficiency
Smooth Muscle
Actins
Collagen
Down-Regulation
Phosphorylation
Gene Expression
Incidence

Keywords

  • blood pressure
  • diabetic nephropathy
  • gonadectomy
  • renin-angiotensin system
  • streptozotocin

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system. / Clotet, Sergi; Soler, María José; Rebull, Marta; Gimeno, Javier; Gurley, Susan; Pascual, Julio; Riera, Marta.

In: Journal of Hypertension, Vol. 34, No. 9, 01.09.2016, p. 1752-1765.

Research output: Contribution to journalArticle

Clotet, Sergi ; Soler, María José ; Rebull, Marta ; Gimeno, Javier ; Gurley, Susan ; Pascual, Julio ; Riera, Marta. / Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system. In: Journal of Hypertension. 2016 ; Vol. 34, No. 9. pp. 1752-1765.
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T1 - Gonadectomy prevents the increase in blood pressure and glomerular injury in angiotensin-converting enzyme 2 knockout diabetic male mice. Effects on renin-angiotensin system

AU - Clotet, Sergi

AU - Soler, María José

AU - Rebull, Marta

AU - Gimeno, Javier

AU - Gurley, Susan

AU - Pascual, Julio

AU - Riera, Marta

PY - 2016/9/1

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N2 - Background: Angiotensin-converting enzyme 2 (ACE2) deletion worsens kidney injury, and its amplification ameliorates diabetic nephropathy. Male sex increases the incidence, prevalence, and progression of chronic kidney disease in our environment. Method: Here, we studied the effect of ACE2 deficiency and gonadectomy (GDX) on diabetic nephropathy and its relationship with fibrosis, protein kinase B (Akt) activation, and the expression of several components of the renin-angiotensin system (RAS). Mice were injected with streptozotocin to induce diabetes and followed for 19 weeks. Physiological and renal parameters were studied in wild-type and ACE2 knockout (ACE2KO) male mice with and without GDX. Results: Diabetic ACE2KO showed increased blood pressure (BP), glomerular injury, and renal fibrosis compared with diabetic wild-type. Gonadectomized diabetic ACE2KO presented a decrease in BP. In the absence of ACE2, GDX attenuated albuminuria and renal lesions, such as mesangial matrix expansion and podocyte loss. Both, α-smooth muscle actin accumulation and collagen deposition were significantly decreased in renal cortex of gonadectomized diabetic ACE2KO but not diabetic wild-type mice. GDX also reduced circulating ACE activity in ACE2KO mice. Loss of ACE2 modified the effect of GDX on cortical gene expression of RAS in diabetic mice. Akt phosphorylation in renal cortex was increased by diabetes and loss of ACE2 and decreased by GDX in control and diabetic ACE2KO but not in wild-type mice. Conclusions: Our results suggest that GDX may exert a protective effect within the kidney under pathological conditions of diabetes and ACE2 deficiency. This renoprotection may be ascribed to different mechanisms such as decrease in BP, modulation of RAS, and downregulation of Akt-related pathways.

AB - Background: Angiotensin-converting enzyme 2 (ACE2) deletion worsens kidney injury, and its amplification ameliorates diabetic nephropathy. Male sex increases the incidence, prevalence, and progression of chronic kidney disease in our environment. Method: Here, we studied the effect of ACE2 deficiency and gonadectomy (GDX) on diabetic nephropathy and its relationship with fibrosis, protein kinase B (Akt) activation, and the expression of several components of the renin-angiotensin system (RAS). Mice were injected with streptozotocin to induce diabetes and followed for 19 weeks. Physiological and renal parameters were studied in wild-type and ACE2 knockout (ACE2KO) male mice with and without GDX. Results: Diabetic ACE2KO showed increased blood pressure (BP), glomerular injury, and renal fibrosis compared with diabetic wild-type. Gonadectomized diabetic ACE2KO presented a decrease in BP. In the absence of ACE2, GDX attenuated albuminuria and renal lesions, such as mesangial matrix expansion and podocyte loss. Both, α-smooth muscle actin accumulation and collagen deposition were significantly decreased in renal cortex of gonadectomized diabetic ACE2KO but not diabetic wild-type mice. GDX also reduced circulating ACE activity in ACE2KO mice. Loss of ACE2 modified the effect of GDX on cortical gene expression of RAS in diabetic mice. Akt phosphorylation in renal cortex was increased by diabetes and loss of ACE2 and decreased by GDX in control and diabetic ACE2KO but not in wild-type mice. Conclusions: Our results suggest that GDX may exert a protective effect within the kidney under pathological conditions of diabetes and ACE2 deficiency. This renoprotection may be ascribed to different mechanisms such as decrease in BP, modulation of RAS, and downregulation of Akt-related pathways.

KW - blood pressure

KW - diabetic nephropathy

KW - gonadectomy

KW - renin-angiotensin system

KW - streptozotocin

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