Abstract
The renin-angiotensin-aldosterone system (RAAS) is overactivated in patients with chronic kidney disease. Oxidative stress and endoplasmic reticulum stress (ERS) are two major mechanisms responsible for aldosterone-induced kidney injury. Cyclophilin (CYP) B is a chaperone protein that accelerates the rate of protein folding through its peptidyl-prolyl cis-trans isomerase (PPIase) activity. We report that overexpression of wild-type CYPB attenuated aldosterone-induced oxidative stress (evidenced by reduced production of reactive oxygen species and improved mitochondrial dysfunction), ERS (indicated by reduced expression of the ERS markers glucose-regulated protein 78 [GRP78] and C/-EBP homologous protein [CHOP]), and tubular cell apoptosis in comparison with aldosterone-induced human kidney-2 (HK-2) cells. The in vivo study also yielded similar results. Hence, CYPB performs a crucial function in protecting cells against aldosterone-induced oxidative stress, ERS, and tubular cell injury via its PPIase activity.
Highlights
Activation of the renin-angiotensin-aldosterone system (RAAS) is a major hallmark in the development and progression of organ damage in chronic kidney disease (CKD) [1, 2]
The condition caused by ER dysfunctions, where there is aberrant protein folding in the ER lumen, is termed endoplasmic reticulum stress (ERS), and we have previously indicated an important role for reactive oxygen species (ROS)-mediated ERS in aldosterone-induced human kidney-2 (HK-2) cell apoptosis [8]
Further examination of renal tissues by terminal deoxyribonucleotidyl transferasemediated dUTP-digoxigenin nick end labeling (TUNEL) assay indicated that aldosterone significantly induced tubular cell apoptosis, which was reduced in Cypboverexpressing mice (Figure 2B and 2D)
Summary
Activation of the renin-angiotensin-aldosterone system (RAAS) is a major hallmark in the development and progression of organ damage in chronic kidney disease (CKD) [1, 2]. In this regard, plasma aldosterone levels and renal expression of the mineralocorticoid receptor (MR) are elevated in patients with CKD and in CKD animal experimental models [3]. The condition caused by ER dysfunctions, where there is aberrant protein folding in the ER lumen, is termed ERS, and we have previously indicated an important role for ROS-mediated ERS in aldosterone-induced human kidney-2 (HK-2) cell apoptosis [8]. ERS-induced apoptosis is mainly mediated by C/-EBP homologous protein (CHOP), referred to as GADD153 (growth arrest and DNA damage 153) [11]
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