Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease

Abstract

The pathways implicated in diabetic kidney disease (DKD) are largely derived from animal models. To examine if alterations in renin-angiotensin system (RAS) in humans are concordant with those in rodent models, we measured concentration of angiotensinogen (AOG), cathepsin D (CTSD), angiotensin-converting enzyme (ACE), and ACE2 and enzymatic activities of ACE, ACE2, and aminopeptidase-A in FVB mice 13-20 wk after treatment with streptozotocin ( = 9) or vehicle ( = 15) and people with long-standing type 1 diabetes, with ( = 37) or without ( = 81) DKD. In streptozotocin-treated mice, urine AOG and CTSD were 10.4- and 3.0-fold higher than in controls, respectively ( < 0.001). Enzymatic activities of ACE, ACE2, and APA were 6.2-, 3.2-, and 18.8-fold higher, respectively, in diabetic animals ( < 0.001). Angiotensin II was 2.4-fold higher in diabetic animals ( 0.017). Compared with people without DKD, those with DKD had higher urine AOG (170 vs. 15 μg/g) and CTSD (147 vs. 31 μg/g). In people with DKD, urine ACE concentration was 1.8-fold higher (1.4 vs. 0.8 μg/g in those without DKD), while its enzymatic activity was 0.6-fold lower (1.0 vs. 1.6 × 10 RFU/g in those without DKD). Lower ACE activity, but not ACE protein concentration, was associated with ACE inhibitor (ACEI) treatment. After adjustment for clinical covariates, AOG, CTSD, ACE concentration, and ACE activity remained associated with DKD. In conclusion, in mice with streptozotocin-induced diabetes and in humans with DKD, urine concentrations and enzymatic activities of several RAS components are concordantly increased, consistent with enhanced RAS activity and greater angiotensin II formation. ACEI use was associated with a specific reduction in urine ACE activity, not ACE protein concentration, suggesting that it may be a marker of exposure to this widely-used therapy.

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

“…Several studies using diabetic models show activation of the RAS locally within the kidney by glucose, including an increase in Ang II production [33][34][35][36]. Additional evidence comes from findings of increased RAS components in the kidney and urines from rodent models of diabetic kidney disease (DKD) and in patients with DKD [16,37] and non-diabetic CKD [38,39]. There is a need for new approaches to counteract RAS overactivity that expand and improve on the existing ones which are based on blockade of Ang II formation or action.…”

“…For instance, in a diabetic model with local kidney but not systemic RAS over-activity [13], long-term augmentation of circulating ACE2 activity was not sufficient to alter glomerular pathology, GFR or albuminuria [13]. These observations provide the rationale for the development of shorter forms of ACE2 with a molecular size that render them filtrable by the kidney and, therefore, potentially useful therapeutically to amplify ACE2 activity in forms of kidney disease with an overactive local RAS in the kidney [13,16].…”

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

“…Yet, there is a gap, and limited research focus was on the risk predictors for kidney disease. Some of the proposed candidates are neutrophil gelatinase-associated lipocalin, angiotensinogen, renin, and NEP (20,29,33,42,49,56). In addition, other RAS enzymes, such as urinary ACE and ACE2, have also been investigated as potential new markers for hypertension (6) and diabetes (28).…”

Riligustilide Attenuated Renal Injury by the Blockade of Renin

“…Previous studies have shown that SHR had high serum levels of renin in vivo, which usually cause renal damage and other symptoms, such as hyperdipsia, polyuria, proteinuria, and so on [35]. The volume of drinking water (Fig.…”