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Diminazene aceturate prevents type 1 diabetic nephropathy through increasing glomerular ACE2 and AT2 receptor expression.

Diminazene aceturate prevents type 1 diabetic nephropathy through increasing glomerular ACE2 and AT2 receptor expression.
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Goru SK, Kadakol A, Malek V, Pandey A, Sharma N, Gaikwad AB,


Goru SK, Kadakol A, Malek V, Pandey A, Sharma N, Gaikwad AB, (click to view)

Goru SK, Kadakol A, Malek V, Pandey A, Sharma N, Gaikwad AB,

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British journal of pharmacology 2017 07 08() doi 10.1111/bph.13946
Abstract
BACKGROUND AND PURPOSE
Angiotensin converting enzyme 2 (ACE2) shows its protective actions through degrading Ang II. ACE2 activity and its expression was found to be reduced in glomeruli of diabetic patients as well as in animal models of diabetes. Several recent studies have also showed the potential role of recombinant ACE2 administration in preventing diabetic nephropathy (DN). Hence, we hypothesized that ACE2 activator, diminazene aceturate (DIZE) may be beneficial in preventing DN.

EXPERIMENTAL APPROACH
Male Wistar rats were rendered diabetic using a single dose of Streptozotocin (55mg kg(-1) , i.p.). After 4 weeks, diabetic animals were grouped in to respective groups and the drug, DIZE, low dose (5mg kg(-1) day(-1) ), high dose (15mg kg(-1) day(-1) ) and high dose in presence of AT2 blocker (PD123319, 10mg kg(-1) day(-1) ) was administered. At the end, kidneys from all the groups were collected and processed separately for glomerular isolation, protein isolation, mRNA extraction and for immunohistochemical studies.

KEY RESULTS
DIZE administration restored the ACE2 expression in glomeruli and increased the AT2 expression in whole kidney and isolated glomeruli of diabetic animals. DIZE administration, reduced the Ang II levels and increased Ang 1-7 levels in diabetic kidney. However, AT2 blockade, reversed all these actions of DIZE.

CONCLUSION AND IMPLICATIONS
DIZE treatment reduced the diabetes induced renal damage through inhibiting fibrosis and apotosis. Moreover, DIZE failed to show its protective actions in presence of AT2 blocker. Taken together, these results suggest the protective role of DIZE in preventing DN through ACE2/Ang 1-7/AT2 axis.

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