ACE2 is a type 1 integral membrane protein that shares 42% homology with the metalloprotease catalytic domains of ACE. Whereas ACE promotes the formation of angiotensin II, ACE2 promotes the degradation of angiotensin (ANG) II to angiotensin-(1-7). Strategies geared at increasing ACE2 activity may provide a novel therapeutic target within the renin-angiotensin system by enhancing angiotensin II degradation that may complement the current approach of either inhibiting angiotensin II formation using ACE inhibitors or blocking its action using specific AT1 receptor antagonists. We hypothesize that decreased ANG II degradation coupled with decreased ANG-(1-7) formation owing to ACE2 downregulation may play an important role in diabetic kidney disease. This hypothesis is based on our recent findings of a distinctive pattern of ACE and ACE2 expression in kidneys from diabetic mice such that glomerular ACE2 expression is decreased and ACE is increased in the db/db mice. In keeping with this hypothesis, we have recently found that ACE2 inhibition using a specific pharmacologic agent, MLN-4760, worsens albuminuria and induces glomerular injury in two different models of nephropathy in diabetic mice. We propose that ACE2 upregulation will emerge as a target of new therapies aimed at reducing albuminuria and glomerular injury. We now have the tools to test this hypothesis directly by different approaches: the administration of murine recombinant ACE2, lentiviral ACE2 delivery and a novel ACE2 activator to diabetic mice. The postulated mechanism of local ACE2 protection will be further studied using a podocyte-specific ACE2 transgenic. The specific objectives of this proposal are:
Aim 1) To produce murine recombinant ACE2 and establish protocols for delivery to mice that achieve a sustained increase in serum ACE2 activity that effectively increases ANG II degradation and ANG-(1-7) formation.
Aim 2) To create a system for lentiviral murine ACE2 expression and establish protocols for delivery to mice that achieve a sustained increase in serum and tissue ACE2 activity that effectively increases ANG II degradation and ANG-(1-7) formation systemically and at the kidney level.
Aim 3) To examine the effect of the administration of murine recombinant (r)ACE2, lentiviral ACE2 delivery, and a novel ACE2 activator, XNT, on albuminuria and glomerular lesions in the db/db model of type 2 diabetes (C57BLK and FVB backgrounds). The relative contribution of ANG II and ANG-(1-7) following ACE2 amplification by these various approaches on these parameters will be examined in additional experiments using a specific blocker of the ANG-(1- 7)/Mas receptor.
Aim 4) To test the hypothesis that in diabetic (db/db) with glomerular ACE2 over-expression albuminuria and the glomerular lesions of diabetes can be prevented and that this protection can be accomplished with isolated glomerular ACE2 overexpression even in the face of systemic ACE2 deficiency.

Public Health Relevance

Kidney disease is a frequent complication of both type 1 and type 2 diabetes. The renin- angiotensin system (RAS) has been widely implicated in the development of diabetic kidney disease. It has been recently found that an enzyme called ACE2 plays a role in the disposal of angiotensin II, a hormone that may be responsible for the progression of diabetic kidney disease. This proposal will provide a better understanding of angiotensin II and, in particular, ACE2 in diabetic kidney disease and has the promise to offer novel insights into ways to treat patients afflicted with diabetes and kidney damage. We surmise that results from this proposal will be proof of concept for the development of therapies aimed at enhancing the activity of ACE2 to treat diabetic kidney disease much the same way that ACE inhibitors were developed to prevent the formation of angiotensin II and are now widely used in patients with diabetes and kidney disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG1-DKUS-G (51))
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Flessner, Michael Francis
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Haber, Philipp K; Ye, Minghao; Wysocki, Jan et al. (2014) Angiotensin-converting enzyme 2-independent action of presumed angiotensin-converting enzyme 2 activators: studies in vivo, ex vivo, and in vitro. Hypertension 63:774-82
Wysocki, Jan; Batlle, Daniel (2013) Reduced plasma ACE2 activity in dialysis patients: another piece in the conundrum of factors involved in hypertension and cardiovascular morbidity? Nephrol Dial Transplant 28:2200-2
Soler, Maria Jose; Wysocki, Jan; Batlle, Daniel (2013) ACE2 alterations in kidney disease. Nephrol Dial Transplant 28:2687-97
Wysocki, Jan; Garcia-Halpin, Laura; Ye, Minghao et al. (2013) Regulation of urinary ACE2 in diabetic mice. Am J Physiol Renal Physiol 305:F600-11
Soler, Maria Jose; Riera, Marta; Batlle, Daniel (2012) New experimental models of diabetic nephropathy in mice models of type 2 diabetes: efforts to replicate human nephropathy. Exp Diabetes Res 2012:616313
Nadarajah, Renisha; Milagres, Rosangela; Dilauro, Marc et al. (2012) Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice. Kidney Int 82:292-303
Batlle, Daniel; Wysocki, Jan; Soler, Maria J et al. (2012) Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy. Kidney Int 81:520-8
Batlle, Daniel; Wysocki, Jan; Khan, Mirza S (2010) Vascular angiotensin-converting enzyme 2: lord of the ring? Circ Res 107:822-4
Kalea, Anastasia Z; Batlle, Daniel (2010) Apelin and ACE2 in cardiovascular disease. Curr Opin Investig Drugs 11:273-82
Batlle, Daniel; Jose Soler, Maria; Ye, Minghao (2010) ACE2 and diabetes: ACE of ACEs? Diabetes 59:2994-6

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