Back to Search
Start Over
Angiotensin-converting enzyme 2 amplification limited to the circulation does not protect mice from development of diabetic nephropathy
- Source :
- Kidney International
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Blockers of the renin-angiotensin system are effective in the treatment of experimental and clinical diabetic nephropathy. An approach different from blocking the formation or action of angiotensin II (1-8) that could also be effective involves fostering its degradation. Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that cleaves angiotensin II (1-8) to form angiotensin (1-7). Therefore, we examined the renal effects of murine recombinant ACE2 in mice with streptozotocin-induced diabetic nephropathy as well as that of amplification of circulating ACE2 using minicircle DNA delivery prior to induction of experimental diabetes. This delivery resulted in a long-term sustained and profound increase in serum ACE2 activity and enhanced ability to metabolize an acute angiotensin II (1-8) load. In mice with streptozotocin-induced diabetes pretreated with minicircle ACE2, ACE2 protein in plasma increased markedly and this was associated with a more than 100-fold increase in serum ACE2 activity. However, minicircle ACE2 did not result in changes in urinary ACE2 activity as compared to untreated diabetic mice. In both diabetic groups, glomerular filtration rate increased significantly and to the same extent as compared to non-diabetic controls. Albuminuria, glomerular mesangial expansion, glomerular cellularity, and glomerular size were all increased to a similar extent in minicircle ACE2-treated and untreated diabetic mice, as compared to non-diabetic controls. Recombinant mouse ACE2 given for 4 weeks by intraperitoneal daily injections in mice with streptozotocin-induced diabetic nephropathy also failed to improve albuminuria or kidney pathology. Thus, a profound augmentation of ACE2 confined to the circulation failed to ameliorate the glomerular lesions and hyperfiltration characteristic of early diabetic nephropathy. These findings emphasize the importance of targeting the kidney rather than the circulatory renin angiotensin system to combat diabetic nephropathy.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Angiotensin II receptor type 1
Renal function
030204 cardiovascular system & hematology
Biology
medicine.disease
Angiotensin II
Article
Diabetic nephropathy
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Endocrinology
Nephrology
Internal medicine
Diabetes mellitus
Angiotensin-converting enzyme 2
Renin–angiotensin system
medicine
Albuminuria
medicine.symptom
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 00852538
- Volume :
- 91
- Database :
- OpenAIRE
- Journal :
- Kidney International
- Accession number :
- edsair.doi.dedup.....a52d243478fcee9a407e152c4fe597fc