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Published on: September 28, 2015
Angiotensin-converting enzyme 2 amplification limited to the circulation does not protect mice from development of
Jan Wysocki1, Minghao Ye1, Ahmed M Khattab1
1Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
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.
Insights
Augmenting circulating angiotensin-converting enzyme 2 (ACE2) did not improve diabetic nephropathy in mice. Targeting the kidney directly is crucial for treating this condition.
Area of Science:
- Nephrology
- Endocrinology
- Biochemistry
Background:
- Diabetic nephropathy is a common complication of diabetes, characterized by kidney damage.
- Blockade of the renin-angiotensin system is a current treatment strategy.
- Enhancing the degradation of angiotensin II via angiotensin-converting enzyme 2 (ACE2) presents an alternative therapeutic approach.
Purpose of the Study:
- To investigate the renal effects of increasing circulating angiotensin-converting enzyme 2 (ACE2) activity in a mouse model of diabetic nephropathy.
- To evaluate the efficacy of recombinant ACE2 and minicircle DNA-mediated ACE2 amplification in ameliorating kidney damage.
Main Methods:
- Streptozotocin-induced diabetic nephropathy model in mice.
- Administration of murine recombinant ACE2 via daily intraperitoneal injections.
- Amplification of circulating ACE2 using minicircle DNA delivery prior to diabetes induction.
- Assessment of renal function (glomerular filtration rate, albuminuria) and kidney pathology (glomerular mesangial expansion, cellularity, size).
Main Results:
- Minicircle ACE2 delivery significantly increased serum ACE2 activity but did not alter urinary ACE2 activity.
- Both minicircle ACE2-treated and untreated diabetic mice exhibited increased glomerular filtration rate, albuminuria, and pathological kidney changes compared to controls.
- Recombinant ACE2 treatment also failed to improve albuminuria or kidney pathology in diabetic mice.
Conclusions:
- Profound augmentation of circulating ACE2 is ineffective in ameliorating the glomerular lesions and hyperfiltration in early diabetic nephropathy.
- These findings highlight the importance of targeting the kidney directly, rather than the circulatory renin-angiotensin system, for combating diabetic nephropathy.
