Abstract
Podocyte mitochondrial dysfunction plays a critical role in the pathogenesis of chronic kidney disease (CKD). Previous studies demonstrated that excessive mitochondrial fission could lead to the overproduction of reactive oxygen species (ROS) and promote podocyte apoptosis. Therefore, the maintenance of stable mitochondrial function is a newly identified way to protect podocytes and prevent the progression of CKD. As a mitochondria-targeted antioxidant, mitoquinone (MitoQ) has been proven to be a promising agent for the prevention of mitochondrial injury in cardiovascular disease and Parkinson's disease. The present study examined the effects of MitoQ on angiotensin II- (Ang II-) induced podocyte injury both in vivo and in vitro. Podocyte mitochondria in Ang II-infused mice exhibited morphological and functional alterations. The observed mitochondrial fragmentation and ROS production were alleviated with MitoQ treatment. In vitro, alterations in mitochondrial morphology and function in Ang II-stimulated podocytes, including mitochondrial membrane potential reduction, ROS overproduction, and adenosine triphosphate (ATP) deficiency, were significantly reversed by MitoQ. Moreover, MitoQ rescued the expression and translocation of Nrf2 (nuclear factor E2-related factor 2) and decreased the expression of Keap1 (Kelch-like ECH-associated protein 1) in Ang II-stimulated podocytes. Nrf2 knockdown partially blocked the protective effects of MitoQ on Ang II-induced mitochondrial fission and oxidative stress in podocytes. These results demonstrate that MitoQ exerts a protective effect in Ang II-induced mitochondrial injury in podocytes via the Keap1-Nrf2 signaling pathway.
Highlights
Podocytes are an important component of the glomerular filtration barrier, which is responsible for extremely complex filtration functions, and podocyte damage causes proteinuria and initiates the progression of chronic kidney disease (CKD) [1]
To explore whether MitoQ is able to improve the outcome of podocyte injury induced by Angiotensin II (Ang II), podocyte apoptosis was assayed by flow cytometry, and we observed that MitoQ pretreatment significantly reduced apoptotic podocytes induced by Ang II (Figures 4(f ) and 4(g))
Knockdown of Nuclear factor E2-related factor 2 (Nrf2) significantly but incompletely abolished the protective effects of MitoQ on angiotensin II- (Ang II-)induced podocyte apoptosis (Figures 7(f) and 7(g)). These results suggest that the protective effects of MitoQ on podocytes are in part dependent on Nrf2
Summary
Podocytes are an important component of the glomerular filtration barrier, which is responsible for extremely complex filtration functions, and podocyte damage causes proteinuria and initiates the progression of chronic kidney disease (CKD) [1]. Angiotensin II (Ang II), a major component of the RAS, has been shown to directly induce podocyte injury [3, 4]. The precise mechanism of Ang II-induced podocyte injury remains elusive. Ang II stimulates intracellular reactive oxygen species (ROS) formation and participates in the pathogenesis and development of CKD [7]. It has been demonstrated that ROS are mainly produced by the mitochondria [8], but the molecular mechanism by which Ang II stimulates mitochondria to produce a large amount of ROS is not completely clear [9]. Mitochondria undergo continuous fission and fusion to meet energy needs and to remove damaged mitochondria; collectively, these behaviors are referred to as mitochondrial dynamics [10].
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