IMR Press / FBL / Volume 10 / Issue 3 / DOI: 10.2741/1695

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
Endogenous digitalis-like ligands and Na/K-ATPase inhibition in experimental diabetes mellitus
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1 I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Science, 44 Torez Prospect, 194223, St. Petersburg, Russia

Academic Editor: Joseph Shapiro

Front. Biosci. (Landmark Ed) 2005, 10(3), 2257–2262; https://doi.org/10.2741/1695
Published: 1 September 2005
(This article belongs to the Special Issue Regulation and function of NaK-ATPase in health and disease)
Abstract

Dysregulation of the Na/K-ATPase (NKA) in the kidney, cardiovascular system, and peripheral nervous system is believed to contribute to pathogenesis of diabetes mellitus (DM) and its complications. Recently we demonstrated that, in addition to endogenous ouabain (EO), mammalian tissues contain another NKA inhibitor, a bufadienolide marinobufagenin (MBG). In vitro MBG, a natriuretic and a vasoconstrictor, acts as a selective inhibitor of alpha-1 NKA, the main isoform of the sodium pump in renal tubules and vascular smooth muscle. To determine whether digitalis-like NKA inhibitors are linked to NKA dysregulation in DM, we studied changes in renal excretion and plasma levels of MBG and EO and the activity of erythrocyte NKA in male Wistar rats with type 1 DM and type 2 DM. Rats with type 1 DM were studied four weeks following a single intraperitoneal injection of 65 mg/kg streptozotocin (STZ)(n = 12), and rats with type 2 DM were studied 10 weeks after intraperitoneal injection of STZ during the neonatal period (n = 12). Renal excretion and plasma levels of EO did not change in rats with both types of DM as compared to that in the control groups. Renal excretion (57.5 ± 9.4 pmol/kg/ 3 hours vs. 12.6 ± 2.1 pmol/kg/ 3 hours; P < 0.01) and plasma levels (2.23 ± 0.82 nmol/L vs. 0.29 ± 0.07 nmol/L; P < 0.01) of MBG increased, and NKA activity in erythrocytes was inhibited by 50% in rats with type 1 DM as compared to controls. In rats with type 2 DM, plasma levels (1.48 ± 0.09 nmol/L vs. 0.46 ± 0.02 nmol/L; P < 0.01) and renal excretion (21.3 ± 3.2 pmol/kg/ 3 hours vs. 13.1 ± 2.1 pmol/kg/ 3 hours) of MBG also became elevated, but less than in the animals with type 1 DM. Accordingly, activity of NKA in erythrocytes from rats with type 2 DM was inhibited by 35%. In vitro treatment of erythrocytes from rats with type 1 and type 2 DM with anti-MBG antibody reversed the DM induced inhibition of the NKA. These results suggest that digitalis-like factors are involved in the pathogenesis of DM and that MBG, rather than EO, is responsible for DM-induced NKA inhibition.

Keywords
Na+
K+ Exchanging ATPase
Antagonists
Inhibitors
Diabetes mellitus
Bufadienolides
Marinobufagenin
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