Changes associated with Na,K-ATPase in brain, kidney, heart and liver of the spontaneously diabetic Goto-Kakizaki rat

Abstract

Alterations in Na,K-ATPase activity, in isoenzyme expression and/or number of units of the pump present in the plasma membrane have been associated with diabetes. These changes were described in different organs and tissues such as brain, heart, kidney, among others, and may result from altered insulin levels. However, the vast majority of studies were conducted in animal models of chemically induced diabetes, which are not consensual models for type 2 diabetes (T2D). The major goal of this work was to investigate putative modifications in Na,K-ATPase enzymatic activity or expression in brain, kidney, heart and liver in T2D. The Goto-Kakizaky rat (GK) strain was used as a model of spontaneously developed T2D, and Wistar rats as controls. Na,K-ATPase activity was assessed by the hydrolysis of ATP (Pi formed in the presence/absence of ouabain was measured using a colorimetric assay) and the isoenzymatic expression by Westernblot. A decrease in Na,K-ATPase activity in renal and cardiac tissues from GK comparatively to controls (55.7% and 77.5%, respectively) was observed. The pump activity was similar in liver and brain tissues. In renal tissue, expression of α1-Na,K-ATPase was similar between GK and controls but α2- was 2.3x higher and α3- was detected only in GK. Contrastingly a decreased expression of α1- (49.5%) and α2-isoforms (67.6%) was found in cardiac tissue. Despite similar Na,K-ATPase activity in liver and brain tissues, α1-isoform expression was decreased (33.9%) in the liver from GK while in the brain an increase of α1-isoform (~2x) together with a decrease of α2-isoform (14.0%) expressions were observed. It is unclear, except maybe for cardiac tissue where lower expression is potentially underlying the diminished pump activity in GK, whether the changes in isoenzyme expression is a key factor for differential Na,K-ATPase activity. Being responsive to complex regulation, other regulatory mechanisms may contribute to the impaired activity observed in kidney and heart. These results have uncover changes in Na,K-ATPase activity and/or enzymatic expression in GK brain, kidney, heart and liver that may contribute to the undesirable conditions associated with T2D. This work highlight the relevance of further investigation about Na,K-ATPase regulation and role in physiopathology of T2D.