Universitas Indonesia Conferences, Asian Federation for Pharmaceutical Sciences (AFPS) 2019

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Inactivation of Cysteine 674 at SERCA2 Increases Blood Pressure by Induction of Endoplasmic Reticulum Stress and Soluble Epoxide Hydrolase
Xiaoyong Tong

Last modified: 2019-06-16


Background and Purpose

The kidney is crucial in the regulation of sodium homeostasis and blood pressure (BP). Enhancement of Na+/K+-ATPase (NKA) activity in the kidney reduces urine Na+ excretion and causes Na+ retention followed by hypertension. The irreversible oxidation of cysteine 674 (C674) at sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is increased in the renal cortex of hypertensive mice. We investigated whether inactivation of SERCA2 C674 affects blood pressure and how kidney participates in its regulation.

Experimental Approach

We used heterozygous SERCA2 C674S knock-in (SKI) mice that half of C674 was substituted by S674 to represent the partial irreversible oxidation of C674. The BP of male SKI mice and their littermate wild type (WT) mice was measured by tail-cuff plethysmography, and tissue samples were collected for cell culture, NKA activity, protein expression and immunohistological analysis.

Key Results

Compared with WT mice, SKI mice had elevated BP accompanied with reduced urine Na+ excretion. In renal cortex and cells from renal proximal tubule (RPT), both endoplasmic reticulum (ER) stress markers and soluble epoxide hydrolase (sEH) were upregulated, while dopamine D1 receptor (D1R) was downregulated in SKI mice compared with WT mice. ER stress and sEH could mutually regulate each other, and both were upstream of D1R. Inhibition of ER stress or sEH activity reversed downregulated D1R expression, enhanced NKA and elevated BP in SKI mice.

Conclusions and Implications

SERCA2 C674 inactivation under pathophysiological conditions, via inducing ER stress and upregulating sEH, decreases D1R and increases NKA activity in RPT cells and causes elevated BP; pharmacological inhibition of sEH activity or ER stress may exert therapeutic benefits in hypertension under these conditions.