Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

Abstract

Angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) are metalloproteases that are highly expressed in the renal proximal tubules. ACE2 and NEP generate renoprotective angiotensin (1-7) from angiotensin II and angiotensin I, respectively, and therefore could have a major role in chronic kidney disease (CKD). Recent data demonstrated increased urinary ACE2 in patients with diabetes with CKD and kidney transplants. We tested the hypothesis that urinary ACE2, NEP, and a disintegrin and metalloproteinase 17 (ADAM17) are increased and could be risk predictors of CKD in patients with diabetes. ACE2, NEP, and ADAM17 were investigated in 20 nondiabetics (ND) and 40 patients with diabetes with normoalbuminuria (Dnormo), microalbuminuria (Dmicro), and macroalbuminuria (Dmacro) using ELISA, Western blot, and fluorogenic and mass spectrometric-based enzyme assays. Logistic regression model was applied to predict the risk prediction. Receiver operating characteristic curves were drawn, and prediction accuracies were calculated to explore the effectiveness of ACE2 and NEP in predicting diabetes and CKD. Results demonstrated that there is no evidence of urinary ACE2 and ADAM17 in ND subjects, but both enzymes were increased in patients with diabetes, including Dnormo. Although there was no detectable plasma ACE2 activity, there was evidence of urinary and plasma NEP in all the subjects, and urinary NEP was significantly increased in Dmicro patients. NEP and ACE2 showed significant correlations with metabolic and renal characteristics. In summary, urinary ACE2, NEP, and ADAM17 are increased in patients with diabetes and could be used as early biomarkers to predict the incidence or progression of CKD at early stages among individuals with type 2 diabetes.

Effect of hyperglycemia and rosiglitazone on renal and urinary neprilysin indb/dbdiabetic mice

“…Our previous studies have shown increased shedding of enzymatically active renal ACE2 and NEP in the urine of type 2 diabetic mice (Chodavarapu et al, ; Somineni et al, ) and in type 2 diabetic patients (Gutta et al, ). We have also shown colocalization of ACE2 and ADAM 17 in the brush border of renal proximal tubules in Akita and db / db diabetic mice (Chodavarapu et al, ; Salem, Grobe, & Elased, ).…”

“…It is important to mention that both NEP and ACE2 can counteract the effects of ACE and Ang II via the formation of Ang-(1-7). Our recent studies demonstrated increased urinary NEP in patients with type 2 diabetes compared with nondiabetic volunteers (Gutta et al, 2018). This cohort of diabetic patients were treated with different classes of antidiabetic medications including PPAR-γ agonists.…”

Obesity, Diabetes and COVID-19: An Infectious Disease Spreading From the East Collides With the Consequences of an Unhealthy Western Lifestyle

“…However, other reports indicate increased levels of ACE2 in the heart, liver, and lungs of mice with diabetes (85) and it has been suggested that this could make these tissues more vulnerable to SARS-CoV-2 infection and contribute to an increased risk of MOF in patients with diabetes. Evidence from humans indicate that levels of ACE2 in urine are increased in patients with type I diabetes (86) and type II diabetes (87) and positively related to blood glucose and HbA1c levels (88). It is not yet clear however, whether increased ACE2 in the urine is due to increased shedding of ACE2 in the kidney or whether it reflects increased circulating or systemic tissue levels.…”

Renal ADAM10 and 17: Their Physiological and Medical Meanings

“…This shedding is stimulated by high glucose and Ang II, can increase Ang II-degrading products in the urine of DN patients, and could serve as a biomarker of early kidney injury ( Xiao et al, 2014 ). Furthermore, urinary ADAM17 and its substrate, ACE2, are increased in diabetic patients and its model mice ( Chodavarapu et al, 2013 ; Gutta et al, 2018 ), and the shedding fragments could also be an early biomarker to predict DN-induced CKD.…”

“…ADAM10 and 17 are closely correlated with renal injuries including excess inflammation and tubular cell destruction. In addition to their substrates, ADAM10 and 17 per se are also important biomarkers of renal dysfunctions, such as early DN ( Petrica et al, 2017 ; Gutta et al, 2018 ). Furthermore, many efforts have been made to develop strategies to block ADAM10 and 17 activities involving small molecules and monoclonal antibodies (Figure 2 ).…”