Mitochondria: a pathogenic paradigm in hypertensive renal disease.

Oxidative stress has been associated with cardiovascular disease and the development of hypertension in both humans and in animal models. Antioxidant therapy has been successful in ameliorating disease in animals, but the results from human studies have been largely disappointing. Despite these negative results, a wealth of evidence suggests that oxidative stress is involved in the development of cardiovascular disease both in humans and animal models. Because global attenuation of cellular reactive oxygen species (ROS) may not be advantageous, more recent therapeutic strategies target specific subcellular sources of oxidative stress. Most studies implicate plasmalemmal membrane-bound NADPH oxidase as a key mediator of ROS generation in cardiovascular disease. However, in the current issue of Circulation Research , Dikalova et al1 demonstrate that specific attenuation of mitochondrial derived oxidants prevents the development of angiotensin II–induced hypertension in the mouse. Perhaps more interesting is the mechanism: inhibition of a mitochondrial ROS-triggered activation of NADPH oxidase, interrupting a vicious cycle of ROS production. The novel approach of targeting the inciting source of ROS (mitochondria) to prevent accelerated oxidant production may hold more promise for humans by eliminating pathological but not homeostatic sources of ROS. Seminal observations by Harrison et al2 showed evidence of increased oxidative stress within the systemic vasculature in an Angiotensin II–induced rat model of hypertension, piquing interest in a possible etiologic role for ROS in this condition. In animal models, stimulating ROS production can induce hypertension,2,3 whereas treatment with a variety of antioxidants including vitamin C and E, or targeted inhibition of enzymatic oxidant production, can reduce blood pressure.3–6 Hypertensive patients demonstrate increased NAD(P)H oxidase activity7 with elevated levels of hydrogen peroxide in plasma.8 Antioxidant treatment leads to enhanced vasodilation in both forearm and coronary arteries of human hypertensive subjects,9,10 indicating a functional vasomotor …

Reactive oxygen species (ROS) produced in the neuronal, renal, and vascular systems not only influence cardiovascular physiology but are also strongly implicated in pathological signaling leading to hypertension. Different sources of ROS have been identified, ranging from xanthine-xanthine oxidase and mitochondria to NADPH oxidase (Nox) enzymes. Of 7 Nox family members, Nox1, Nox2, and Nox4 (and Nox5 in humans) influence the cardiovascular system. Their activation processes and cell and tissue distribution vary widely, adding complexity to understanding their functional roles. Whether these systems act collectively or independently in disease conditions is unclear, but recently feed forward mechanisms have been established between ROS sources. Studies published in Hypertension over the last few years are the focus of this review, and they provide a framework with which to consider the roles of Nox enzymes in neuronal, renal, and vascular hypertensive mechanisms, as well as cardiac remodeling, and their relationships with other ROS-generating systems. ### Neuronal ROS in Hypertension Redox signaling in the central nervous system is well recognized in neuronal control of blood pressure (BP), as well as in response to angiotensin II (Ang II) and aldosterone, which are linked to ROS-dependent hypertension. Recently, new roles for ROS have been described in the hypothalamus and brain stem, nucleus tractus solitarius (NTS), subfornical organ (SFO), rostral ventrolateral medulla, and area postrema (Figure 1). Figure 1. Neuronal NADPH oxidase–dependent ROS involved in central regulation of hypertension. NADPH oxidase homologues, mainly Nox2 and Nox4, are found in different regions of the neuronal system and are reported to have a role in the neuropathogenesis of hypertension by enhancing the sympathetic nerve activity. Nox-induced ROS initiate a forward loop in cross-activation of different receptors and between Nox and mitochondrial ROS. OVLT indicates organum vasculosum of the lamina terminalis; PVN, paraventricular nucleus; PP, posterior pituitary; AP, area postrema; RVLM, rostral ventrolateral medulla. Several …

Relative contributions of mitochondria and NADPH oxidase to deoxycorticosterone acetate-salt hypertension in mice

Which Way to Die: the Regulation of Acinar Cell Death in Pancreatitis by Mitochondria, Calcium, and Reactive Oxygen Species

High levels of oxygen (hyperoxia) are often used to treat individuals with respiratory distress, yet prolonged hyperoxia causes mitochondrial dysfunction and excessive reactive oxygen species (ROS) that can damage molecules such as DNA. Ataxia telangiectasia mutated (ATM) kinase is activated by nuclear DNA double strand breaks and delays hyperoxia-induced cell death through downstream targets p53 and p21. Evidence for its role in regulating mitochondrial function is emerging, yet it has not been determined if mitochondrial dysfunction or ROS activates ATM. Because ATM maintains mitochondrial homeostasis, we hypothesized that hyperoxia induces both mitochondrial dysfunction and ROS that activate ATM. In A549 lung epithelial cells, hyperoxia decreased mitochondrial respiratory reserve capacity at 12h and basal respiration by 48h. ROS were significantly increased at 24h, yet mitochondrial DNA double strand breaks were not detected. ATM was not required for activating p53 when mitochondrial respiration was inhibited by chronic exposure to antimycin A. Also, ATM was not further activated by mitochondrial ROS, which were enhanced by depleting manganese superoxide dismutase (SOD2). In contrast, ATM dampened the accumulation of mitochondrial ROS during exposure to hyperoxia. Our findings suggest that hyperoxia-induced mitochondrial dysfunction and ROS do not activate ATM. ATM more likely carries out its canonical response to nuclear DNA damage and may function to attenuate mitochondrial ROS that contribute to oxygen toxicity.

Over the past 10 to 15 years, a vast collection of studies have provided evidence indicating that reactive oxygen species (ROS), particularly superoxide (O2·−) and hydrogen peroxide (H2O2), contribute to the pathogenesis of cardiovascular diseases, such as heart failure and hypertension. Griendling et al1 first demonstrated that NADPH oxidase present in the vasculature is a primary source of the elevated ROS levels. Since these initial studies, NADPH oxidase-derived ROS in the kidney,2 heart,3 and brain4 have been linked to the development and progression of numerous cardiovascular-related diseases. More recently, however, mitochondria have also been identified as important sources of ROS in controlling cardiovascular function. Considering that mitochondria are the primary source of ROS in most cells during normal respiration because of the leaking of electrons from the electron transport chain (ETC), perhaps it should not be all that surprising that mitochondrial-produced ROS are involved in pathophysiological conditions of the cardiovascular system. To date, most of the evidence linking mitochondrial dysfunction and mitochondrial-produced ROS to the pathogenesis of cardiovascular diseases comes from studies on the peripheral renin-angiotensin system.5 For example, using a model of cardiac ischemic reperfusion injury, Kimura et al6 reported that angiotensin II (Ang II)-induced preconditioning is mediated by mitochondrial-produced ROS. The authors further demonstrated that Ang II-induced NADPH oxidase-derived ROS lie upstream of mitochondrial-produced ROS, thus, implicating a ROS-induced ROS mechanism. Similarly, it was demonstrated recently that, in aortic endothelial cells, Ang II-induced NADPH oxidase activation leads to an increase in mitochondrial ROS production, as well as mitochondrial dysfunction, as determined by a decrease in mitochondrial membrane potential and mitochondrial respiration.7 Together, these studies and others (detailed elsewhere5) clearly illustrate a role for mitochondrial-produced ROS and mitochondrial dysfunction in peripheral tissues in the pathogenesis of …

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Role of caveolin and heat shock protein 70 interaction in the antioxidative effects of an angiotensin II type 1 receptor blocker in spontaneously hypertensive rats proximal tubules

Paricalcitol attenuates cyclosporine-induced kidney injury in rats

Background and Aims Chronic kidney disease (CKD) is a common kidney disease with high mortality and disability, which has caused serious health burden worldwide. Renal fibrosis plays a critical role in the progression of CKD to end-stage renal disease, with tubulointerstitial fibrosis (TIF) exerting a decisive influence on CKD prognosis. Tubular epithelial cells (TECs), being the most abundant resident cell type in the kidney, are particularly vulnerable to metabolic damage due to their elevated metabolic activity. Cyclin dependent kinase 12 (CDK12) is a kinase that regulates RNA transcription. CDK12 normally promotes transcriptional elongation by phosphorylating ser2 and Ser5 in the C-terminal domain of RNA polymerase II. In addition, CDK12 is involved in the regulation of intronic polyadenylation (IPA). The loss of CDK12 leads to an increase in IPA for some genes, resulting in shortened RNA transcripts and subsequent dysfunction of target genes. CDK12 is a newly discovered CKD-associated locus negatively associated with eGFR. CDK12 inhibitor, as a new anti-tumor drug, has made a breakthrough in the treatment of a variety of solid tumors, but the incidence of kidney injury is high during the treatment. Nevertheless, its role in CKD is unclear. Method In this study, we conducted a detection of CDK12 on renal biopsy specimens. Furthermor, we constructed mouse models with renal tubular cell-specific CDK12 knockdown (CDK12PT+/−) and overexpression (CDK12PTki) , and induced CKD mouse models through unilateral ureteral obstruction (UUO) and adenine administration. Blood, urine, and kidney tissue samples were collected from mice in each group. Western blot, quantitative polymerase chain reaction (q-PCR), immunofluorescence, transcriptome sequencing, electron microscopy, and oil red staining were employed to detect the expression of CDK12 and its impact on CKD-related renal injury and TIF. For in vitro experiments, mouse renal tubular cells were used to establish a tubular injury model induced by TGF-β. By downregulating or overexpressing CDK12, we investigated the association between CDK12 and renal tubular injury using Western blot, q-PCR, immunofluorescence, and 3' rapid amplification of cDNA ends (3' RACE). Additionally, the downstream targets of CDK12 were explored. Results Our research found that the expression of CDK12 was significantly downregulated in renal biopsy tissues from patients with CKD. Subsequently, by constructing mouse models with renal tubular-specific CDK12 knockdown, we discovered that CDK12PT+/- mice exhibited more severe renal injury and renal interstitial fibrosis. Furthermore, we found that under injury conditions, renal tubular-specific CDK12 knockdown also led to increased lipid deposition and mitochondrial dysfunction in TECs. Through transcriptome sequencing combined with 3' RACE, we confirmed that CDK12 directly regulates the IPA of PPARγ, a key molecule in regulating lipid metabolism in renal tubular cells. Increased IPA of PPARγ and subsequent downregulation of its expression resulted in an increase in truncated transcripts of PPARγ. Results from mouse models with renal tubular-specific CDK12 overexpression indicated that renal tubular-specific CDK12 overexpression ameliorated renal injury and fibrosis induced by UUO and adenine administration, as well as the associated abnormalities in lipid deposition and mitochondrial dysfunction. Conclusion This study found that in the context of CKD, the expression of CDK12 in renal tubular cells is downregulated, which can lead to an increase in the IPA of PPARγ, subsequently reducing the expression of its functional protein. As a result, this exacerbates lipid metabolic disorders within renal tubular cells, contributing to renal injury and interstitial fibrosis associated with CKD. Our research explored the pathogenesis of renal tubular injury in CKD and provided a new therapeutic target for intervening in renal injury and renal interstitial fibrosis in CKD.

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Objectives: Study of complex ROS dynamics and ROS mito-flashes in various living cells using fluorescent confocal imaging. Simultaneous analysis of the mitochondrial and extra-mitochondrial ROS dynamics. Analysis of the mitochondrial membrane potential and depolarization. Simultaneous analysis of mitochondrial calcium and ROS kinetics. It is well documented that mitochondria can produce a major amount of reactive oxygen species (ROS) which are involved in many physiological and pathological processes. The complex interrelationships, however, between ROS, mitochondrial inner membrane potential (\(\Delta\Psi\)m) and mitochondrial Ca2+ were not entirely investigated. In this work, we further underline biphasic ROS dynamics, demonstrating initial and continuing ROS expansion, followed by mitochondrial ROS flashes. Additionally, a huge heterogeneity in the rates of mitochondrial ROS production and ROS flashes start times has been shown. Comparing mitochondrial and extra mitochondrial fluorescence signals, we demonstrated that the mechanisms of ROS flashes may be a triggering of flashes by certain amounts of external ROS. These mechanisms involve mitochondrial permeability transition pore opening (collapse of mitochondrial membrane potential, \(\Delta\Psi\)m) and mitochondrial calcium sparks. Furthermore, mitochondria to mitochondria interactions can be seen as a wave propagation of mitochondrial ROS flashes and \(\Delta\Psi\)m collapses similar to the phenomenon of ROS-induced ROS release first demonstrated for cardiomyocytes. Our data show that mechanisms of mitochondrial ROS flashes activation and simultaneous depolarization can entail involvement of extra mitochondrial ROS produced either by individual mitochondrion or by adjacent mitochondria. This could represent common processes in ROS-ROS and mitochondria-mitochondria signaling, playing thus an important role in the cellular and mitochondrial physiology.

Effects of andrographolide on renal tubulointersticial injury and fibrosis. Evidence of its mechanism of action

Sustained Activation of EGFR Triggers Renal Fibrogenesis after Acute Kidney Injury

Mitochondrial ROS Fire Up T Cell Activation