Circulating ACE2 and kidney disease: modulation of expresion and value as a biomarker of a atheromatosis progession

Abstract

Angiotensin-converting enzyme (ACE) 2 is a carboxypeptidase that degrades angiotensin (Ang) II to Ang 1-7, thus counteracting the vasoconstrictor and deleterious effects of Ang II. Circulating ACE2 activity is increased in patients with cardiovascular (CV) disease and in experimental models of diabetic nephropathy (DN). Renin-angiotensin system (RAS) blockade by ACE inhibitors and angiotensin II type 1 receptor blockers (ARBs) have been considered the gold standard treatment in patients with kidney disease. However, there is a need for new therapeutic strategies to slow-down the progression of kidney disease. In this regard, the vitamin D analog paricalcitol has been suggested as a novel therapeutic agent to protect against DN. Given these premises, two studies have been proposed in this thesis: a) to evaluate the role of circulating ACE2 as a biomarker of CV disease in chronic kidney disease (CKD) patients, and b) to study the role of paricalcitol in modulating ACE2 in a mouse model of DN. For the human study, baseline circulating ACE2 activity was measured in human plasma samples from the NEFRONA Study, which includes CKD patients without previous history of CV disease. Baseline and prospective studies were performed to evaluate the association of circulating ACE2 with baseline clinical and analytical variables, and with silent atherosclerosis and CV outcomes during the 2-year and 4-year follow-up. For the experimental study, female non-obese diabetic (NOD) mice were studied after diabetes onset and divided into different treatment groups: low-dose and high-dose paricalcitol, aliskiren and a combination of paricalcitol and aliskiren. The effect of paricalcitol was also studied in proximal tubular epithelial cells. The human study showed: 1) CV risk factors, such as male gender, older age and diabetes were found as independent predictors of ACE2 activity in CKD patients; 2) higher number of territories with plaques at 2 years of follow-up was independently associated with higher levels of baseline circulating ACE2 activity in CKD patients; and 3) cox regression analysis confirmed an association between baseline circulating ACE2 activity and CV and non-CV outcomes at 4 years of follow-up in CKD patients. Within the experimental study: 1) paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice, beyond the glycemic profile; 2) there were no significant changes in urinary albumin excretion; 3) renal content of ADAM17 was significantly decreased by treatment with high-dose paricalcitol; 4) renal and circulating oxidative stress were reduced in high-dose paricalcitol-treated mice; and 5) in culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with untreated cells. In summary, ACE2 activity can be modulated by administration of paricalcitol, counterbalancing the effect of diabetes on circulating ACE2 activity. Paricalcitol may modulate circulating ACE2 by reducing renal ADAM17 content, thus blocking ACE2 shedding from the membrane. In CKD patients without previous history of CV disease, circulating ACE2 activity can also serve as a biomarker of silent atherosclerosis and CV outcomes. Therefore, clinical assessment of circulating ACE2 levels and ACE2 modulators may be beneficial in treating patients with kidney disease.

Date of Award	12 Jul 2016
Original language	English
Supervisor	María José Soler Romeo (Director), Marta Marta Riera Oliva (Director) & Julio Pascual Santos (Director)