The angiotensin-converting enzyme 2 (ACE2) and its role in diabetic nephropathy Diabetic nephropathy (DN) is the main cause of terminal chronic kidney disease in developing countries. Blocking the renin-angiotensin system (RAS) with the angiotensin-converting enzyme (ACE) and the angiotensin II receptor type 1 antagonist (ARA2) reduces the progression of kidney damage. The complexity of the renin-angiotensin system has been increasing in recent years, with new pathway components appearing such as angiotensin-converting enzyme 2 (ACE2). This makes the RAS pathway very complex. ACE2 is found in organs and abundantly expressed in the kidneys. Its main function is to degrade the angiotensin I and II peptides. Previous studies have shown that in the glomeruli, ACE2 is mainly found in the glomerular epithelial cells (podocytes) and mesangial cells, while ACE is located in endothelial cells. In the experimental model of type 2 diabetes in db/db mice, there is an imbalance in the expression of glomerular ACE2/ACE with a reduction in the expression of ACE2 and increased ACE. Our group has shown that the activity level of ACE2 can be measured at the renal and cardiac levels, as well as circulating in NOD mice (non-obese diabetic, type 1 diabetes). This murine model develops a diabetes very similar to that in humans. In addition, the administration of insulin, as well as normalising glycaemia and albuminuria in diabetic NOD mice, decreases the renal and circulating activity of ACE2. However, administrating calcidiol decreases oxidative stress and modifies ACE2 activity in the same murine model of diabetes. We are currently studying the effect of ACE2 selection in diabetic NOD mice on the appearance of "new" diabetes and the progression of diabetic nephropathy.
ACE2 has been shown to be present in the glomerular epidthelial cells (podocytes) and mesangial cells in the kidneys of diabetic db/db mice. With the aim of expanding the findings mentioned in relation to the importance of ACE2 in the intrarenal renin-angiotensin-aldosterone system (RAAS) in diabetic nephropathy, we have demonstrated that ACE2 is present in podocytes, and that its expression is modulated in the presence or absence of insulin depending on the albuminuria.
At the translational level we have shown that, in humans, the activity of circulating ACE2 can be measured in serum and plasma. However, ACE2 increases with acute myocardial infarction and in patients with chronic renal disease (data from the NEFRONA study), as well as with classic cardiovascular risk factors such as age, diabetes and the fact of being male. At the 2-year follow-up it was found that basal circulating ACE2 was increased in patients with a higher risk of silent atherosclerosis.
Growing evidences suggest that males are more prone to develop diabetic kidney disease than premenopausal women. Thus, exploring new treatments for diabetic renal disease should be carried out in relation to the sex hormones, which have a role in renal pathophysiology. In experimental type 1 diabetes, our group demonstrated that diabetic males presented worse renal pathology and function than diabetic females. The severity of these renal alterations differed between sexes.
Diabetic males presented albuminuria, hyperfiltration, glomerular hypertrophy, and mesangial matrix expansion. Male sex hormones played a direct role in this glomerular injury, as gonadectomy (GDX) prevented all these alterations. Furthermore, studies in Ace2 knockout mice revealed that the role of ACE2 in diabetic nephropathy was sex-specific. In females, loss of ACE2 aggravated DN progression by worsening albuminuria, renal hypertrophy and cortical fibrosis. In males, loss of ACE2 increased blood pressure and accentuated glomerular injury and renal fibrosis, and GDX prevented these alterations by modulating the expression of renal and circulating RAS and decreasing cortical Akt phosphorylation.
In a further step our group will explore sex differences in the inflammatory and fibrotic renal profile in experimental models of diabetic nephropathy. Circulating and renal protein detection by immunohistochemistry and proteomics analyses will help us to elucidate differential renal pathogenesis to identify new personalized therapeutic strategies.
Despite the efforts in early diagnosis and therapeutic interventions in diabetes control, the rate of end stage renal disease caused by diabetic kidney disease (DKD) decreases less than the rates of all other diabetes complications. Biomarkers, such as serum creatinine or albuminuria, are currently used to assess the renal function but despite the use of different formulas to estimate the glomerular filtration rate and renal damage, these parameters have several well-known limitations, including lack of sensitivity in early stage of CKD. Therefore, more sensitive and specific biomarkers are needed for early diagnosis and the assessment of the nature, severity and rate of progression of renal disease.
The usual approach in the assessment of DKD pathophysiology has been the analysis of single pathways. However, numerous pathways are simultaneous and synergistically involved in this kidney damage. Thus, holistic multifaceted approach with replication in external cohorts, using high performance technologies in the detection of metabolites and protein glycosylation may identify diagnostic and prognostic biomarkers in DKD.
We have performed the GenodiabMar study which is a type 2 diabetes (T2D) adult registry, recruited between 2012 and 2015 from the healthcare area Litoral-Mar of Barcelona, Spain, to investigate macro and microvascular complications of diabetes. Patients older than 45 with a medical history of T2D for more than 10 years and under anti-diabetic drug therapy were included. Renal ultrasound, fundoscopy and 40 clinical and analytical parameters were registered. The cohort includes 700 participants between the ages 44-94 years at their baseline visit. A subsequent follow-up visit is conducted 4.5 years (average) after the baseline visit.
Clinical and analytical data are available during the follow up period and both, baseline and second-visit include biological samples for biobank. After the baseline visit, we have currently performed different omics analysis as 1HNMR metabolomics (Nightingale Health Ltd), total IgG-Glycosylation (Ultra performance Liquid Chromatography) and circulating Galectine-3 (ELISA). To date the biobank count with 100 urine samples and serum-bank and total blood for genotyping from all the participants.
We welcome data analysis proposals from interested scientific investigators.
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