Of diabetic mice and ACE2: a new biomarker of renal disease?

DIABETIC NEPHROPATHY is a leading cause of progressive renal failure and mortality in an increasing number of patients, as well as a key risk factor in cardiovascular disease, and constitutes an accelerating burden on the healthcare system. Blockade of the renin-angiotensin systems (RAS) continues to be an effective therapeutic strategy to attenuate diabetic renal injury and the decline in renal function. The current RAS therapies target either the angiotensin-converting enzyme (ACE) to block the conversion of ANG I to ANG II, or the AT1 subtype receptor antagonists (ARB) to prevent ANG II-AT1 receptor (AT1R) signaling. Both of these approaches impact other intrinsic pathways of the RAS, including the activation of the ACE2-ANG-(1–7)-AT7/Mas receptor (AT7R) axis that antagonizes the actions of ANG II (3). The carboxypeptidase ACE2 is now recognized as a key component of this system that efficiently converts ANG II to ANG-(1–7) in a single hydrolytic step and may alter the functional output of the RAS (3). Indeed, knockdown of ACE2 or administration of an ACE2 inhibitor exacerbated the degree of renal injury in several diabetic models and reduced the therapeutic benefit of ACE inhibition that likely reflects increased ANG II and lower levels of ANG-(1–7) within the kidney (10, 12). The current study by Wysocki et al. (13) in the American Journal of Physiology-Renal Physiology established the enhanced excretion of ACE2 in both type 1 (streptozotocin-induced) and type 2 (db/db strain) diabetic models and reveals the potential role of the enzyme as a urinary biomarker of diabetic injury and/or activation of the intrarenal RAS. The authors report that the proximal tubules of the kidney are the primary source for increased excretion of ACE2 and that the urinary enzyme comprises both 110and 75-kDa molecular forms. Although circulating ACE2 is normally low or nondetectable, serum levels are increased in both experimental and human diabetes (11–14). The present study clearly demonstrates that infusion of a recombinant soluble form of ACE2 does not influence urinary levels of the enzyme, suggesting the distinct compartmentalization of circulating and renal/urinary ACE2. Importantly, the present results add to the emerging view that renal pathologies may not be due to a deficit in ACE2 per se but that increased expression of the enzyme may reflect a compensatory tubular response to alter the ANG II/ANG-(1–7) balance within the kidney. Exacerbation of renal injury by ACE2 blockade in diabetic or hypertensive conditions may be particularly evident as the tubular epithelium attempts to buffer the ANG II-AT1R axis and the stimulation of fibrotic and inflammatory pathways. The study also suggests that the increase in urinary ACE2 reflects the enhanced release or shedding of the peptidase into the tubular fluid and its potential use as a biomarker of diabetic injury. However, it is not known whether the shedding of ACE2 from the apical face of the proximal tubule is ultimately beneficial or deleterious to the kidney. This report and others find that the soluble form of ACE2 (110to 120-kDa species) is catalytically active and hydrolyzes ANG II to ANG-(1–7) similar to the membranebound form (4, 9). Given the high catalytic efficiency of ACE2 Address for reprint requests and other correspondence: M. C. Chappell, Hypertension and Vascular Research Center, Wake Forest Univ. School of Medicine, One Medical Center Blvd., Winston-Salem, NC 27157 (e-mail: [email protected]).