Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria

Abstract

-Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 g/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H 2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies. diabetic nephropathy; renin-angiotensin system; angiotensin-converting enzyme 2; animal model DIABETIC NEPHROPATHY IS THE leading cause of end-stage renal disease in the developed world (34). Previous studies have suggested that the renin-angiotensin system (RAS) is a major mediator of progressive renal injury in diabetic nephropathy. Drugs that target the RAS, including angiotensin-converting enzyme inhibitors and ANG II type 1 receptor blockers, have been shown to reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria (1, 4, 6, 21, 31). The systemic components of the RAS are altered in diabetes mellitus (32) and the intrarenal RAS is thought to play the major damaging role (25). The angiotensin-converting enzyme 2 (ACE2) has been identified in humans and differs from angiotensin-converting enzyme (ACE) in that it preferentially removes carboxy-terminal hydrophobic or basic amino acids (5, 12). Whereas ACE forms ANG II from ANG I, ACE2 is a major route of ANG II metabolism to ANG 1-7 (5, 39). ...

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

“…ADAM17 is abundant in different organs and cleaves several cell surface enzymes, including ACE2 and NEP (8,16,23,36,38,41,54). We detected increased urinary ADAM17 in all patients with diabetes, including Dnormo.…”

Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT2 receptor expression in a rat model of type1 diabetes

“…In addition, DIZE treatment reduced the mRNA expression of ACE in whole kidney and increased the mRNA expression of ACE2 in glomeruli of diabetic animals, whereas adding PD123319 had no effect on these actions of DIZE (Figure A, B, F, G). Recent studies have demonstrated that the increased urinary levels of ACE2 and activity in animal models of DN were due to increased activity of ADAM17 and that inhibition of ADAM17 reduced urinary ACE2 levels and activity (Salem et al ., ; Riera et al ., ). In our study, DIZE significantly reduced levels of urinary ACE2, whereas DIZE combined with PD123319 lost this effect to some extent and resulted in increased urinary ACE2 levels (Figure A).…”

Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse

“…With regard to protein expression, ACE2 expression levels were increased in lungs and heart at early stage of diabetes and in pancreas at late stage of diabetes. Previous studies postulated that the differences observed in ACE2 activities are related to ADAM17 sheddase activity [41]. However, no differences were found when studying ACE2 and ADAM17 activities and gene expression in pancreas islet from db / db mice as compared to the respective db / m controls [42].…”