Part Ⅰ Catalytic Antioxidants in The Kidney
Apr 19, 2023
Abstract
Reactive oxygen and reactive nitrogen are closely associated with kidney injury, including acute kidney injury, chronic kidney disease, hypertensive nephropathy, and diabetic nephropathy. Therefore, antioxidants are important in the treatment of kidney diseases. Catalytic antioxidants are defined as small molecule mimics of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase, some of which are potent detoxifiers of lipid peroxides and peroxynitrite. Several catalytic antioxidants have been shown to be effective in various in vitro and in vivo disease models associated with oxidative stress, including kidney disease. This article reviews the role of antioxidant enzymes in renal disease, the classification of catalytic antioxidants, and their current use in renal disease.
Keywords
catalase; glutathione peroxidase; superoxide dismutase; catalytic antioxidants; kidney; Cistanche benefits.
Click here to get Cistanche effects on Kidney
Introduction
Oxidative stress describes the imbalance between the formation of reactive substances and the defense of antioxidants when redox signaling or molecular damage is disturbed. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are toxic byproducts of essential oxygen metabolism in living organisms. These free radicals include superoxide (O2-), hydrogen peroxide (H2O2), nitric oxide (NO-), hydroxyl radicals (OH-), peroxynitrite (ONOO-), and lipid peroxyl radicals (LOO-). During respiration, intracellular O2 - is produced endogenously in mitochondria, and ROS are produced by complexes in the electron transport chain and by partially reduced metabolites of molecular oxygen formed in biological systems. Excessive ROS production occurs through the activation of specific oxidative enzymes, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), xanthine oxidase, uncoupled nitric oxide synthase (NOS), and arachidonic acid metabolizing enzymes.ROS induces damage to cellular proteins, lipids, carbohydrates, and DNA, ultimately leading to cellular dysfunction. Therefore, they have been considered important regulators in many cellular signaling pathways since early times (Figure 1). Antioxidant defense mechanisms are complex and compartmentalized and can independently regulate ROS levels in the cytoplasm, mitochondria, and nucleus. In living systems, ROS levels are regulated by a variety of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxiredoxin (Prx), thioredoxin (Trx), and cytochrome c oxidase.
Figure 1. Schematic overview of endogenous sources of oxidative stress and antioxidative reactions in renal damage. Exogenous (environmental factors such as air and water pollution, smoking, drugs, and radiation) and endogenous (normal metabolic processes in living organisms) sources of oxidative stress produce reactive oxygen species (ROS). Endogenously, ROS are generated as products of biochemical reactions in the mitochondria (electron-transport system; ETS), plasma membrane, cytoplasm (including peroxisomes and lysozymes), and the membrane of the endoplasmic reticulum. The mitochondrial ETS, adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, myeloperoxidase, and endothelial nitric oxide synthase (eNOS) are the main sources of cellular ROS formation. An important reaction in free radical formation is the Fenton and Fenton-like reactions to produce ROS in which Fe2+ and Cu+ react with H2O2 to form OH , respectively. To protect and repair the molecular injury caused by ROS, cells use a defense system composed of enzymatic antioxidants, including superoxide dismutase (SOD), catalase, peroxidase, and nonenzymatic antioxidants made by the glutathione system. The main site of O2•− generation is the inner mitochondrial membrane during ETS processes. The decomposition of H2O2 into water and oxygen is done by SOD, the glutathione system, and catalase, in that order. Excess ROS causes lipid peroxidation, nitro-oxidation, glycol-oxidation, and oxidative DNA damage, which can together cause protein alterations, DNA damage, cellular senescence, and apoptosis. All of those changes eventually lead to glomerulosclerosis and tubulointerstitial fibrosis.
Oxidative stress is involved in the pathogenesis of several renal diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), hypertensive nephropathy, and diabetic nephropathy. Therefore, antioxidants are effective tools for the treatment of kidney diseases. Catalytic antioxidants are small molecule mimics of antioxidant enzymes similar to SOD, CAT, and GPx, some of which can act as detoxifying agents for lipid peroxides and ONOO-. Since these compounds are catalytic and not just free radical scavengers, they show stronger antioxidant activity than other dietary supplements. This paper reviews the role of antioxidant enzymes in renal diseases, the classification of catalytic antioxidants, and the current status of their application in renal diseases.
Antioxidant Enzymes and Kidney Disease
Cells have important antioxidant defense mechanisms to protect themselves from the toxic damage of free radicals. Antioxidants can have endogenous or exogenous sources, with endogenous synthesis producing enzymes and small molecules or diet providing important exogenous defenses. Depending on their activity, antioxidants can be classified as enzymatic or non-enzymatic. The major enzymatic antioxidants are SOD, CAT, and GPx. Endogenous non-enzymatic antioxidants include l -arginine, lipoic acid, coenzyme Q10, melatonin, albumin, and uric acid. Exogenous non-enzymatic antioxidants include drugs such as ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), phenolic antioxidants, lecithin oil, and acetylcysteine. Several antioxidant systems are also present in the kidney to protect renal tissues and associated cells from oxidative stress.
Cistanche supplements
1. Superoxide Dismutase and Kidney Disease
Superoxide radical anion is a potentially harmful substance produced by the single-electron reduction of molecular oxygen during respiration.SOD is the key antioxidant enzyme system and most organisms living in the presence of oxygen express at least one SOD. The ligand metal of the active site allows the classification of SOD:copper-zinc SOD (Cu/Zn-SOD), manganese SOD (Mn-SOD), iron SOD ( Fe-SOD), and nickel SOD (NiSOD). SOD is a group of metalloenzymes that catalyze the cleavage reaction to detoxify ROS, which catalyzes the cleavage of two O2- to generate H2O2 and molecular O2, which are decomposed into water and oxygen by CAT.
SOD is also divided into three main isoforms according to its localization in subcellular compartments: SOD1 (Cu/Zn-SOD), SOD2 (Mn-SOD), and SOD3 (extracellular SOD, EC-SOD), which are usually found in the kidney.SOD1 is constitutively present in the cytoplasm and membrane gap of mitochondria, while SOD2 is present in the mitochondria of eukaryotic cells. SOD3 is a Cu/Zn-SOD that is secreted into the extracellular space. Of these three SODs, SOD1 is abundant in most tissues, accounting for 60-80% of SOD activity in the renal vasculature and approximately 30% of SOD activity in the renal vasculature.SOD2 is also expressed in most tissue cells, such as the stomach, lung, skeletal muscle, spleen, heart, liver, kidney, and brain.SOD3 is highly expressed in the vasculature, kidney, lung, and heart. Although SOD1 accounts for the highest percentage of renal SOD activity, the pathological changes associated with SOD2 deficiency and SOD1 deficiency are more severe because ROS and RNS are formed mainly in mitochondria.
All three SOD isoforms play a crucial role in the progression and remission of various renal diseases. Several experimental studies provide evidence that the removal or overexpression of sod by genetic manipulation or drugs can alter oxidative stress and disease severity in AKI or CKD. SOD1 depletion leads to a significant increase in nuclear factor light chain enhancer (NF-κB)-mediated renal signaling and oxidative DNA damage in activated B cells. Indeed, renal function was severely reduced after renal ischemia-reperfusion (I/R) injury in SOD1 knockout mice, and recombinant human SOD1 treatment significantly reduced ROS and improved renal function by decreasing tumor necrosis factor (TNF)-α and interleukin (IL)-1 levels in renal I/R-injured tissues. In unilateral ureteral obstruction (UUO) mice, SOD1 deficiency enhanced salt-sensitive hypertension and tubulointerstitial fibrosis, whereas, in unilateral ureteral obstruction mice b, SOD1 overexpression or chronic temporal lobe treatment abrogated these findings. sOD1 also modulates renal microvascular remodeling, small artery reactivity, and sensitivity to angiotensin II (Ang II). sOD1 knockout mice exhibited elevated blood pressure and reduced afferent small artery diameter during Ang II infusion, whereas these changes were attenuated in SOD1 transgenic mice. In diabetic nephropathy, advanced glycosylation end products (AGEs) enhance oxidative stress through NOX generation of ROS in mitochondria, and interactions between AGEs and receptors for AGEs (RAGE) enhance the initiation of related signaling. Antioxidant enzymes, such as SOD and CAT, inhibit age-mediated ROS production. Compared to control diabetic mice, SOD1 transgenic db/db mice and STZ streptozotocin-treated SOD1 transgenic mice exhibited reduced proteinuria, transforming growth factor (TGF)-β1 and collagen IV expressions, as well as thylakoid matrix expansion and reduced markers of oxidative stress.
SOD2 dysfunction has been reported to exacerbate renal dysfunction, tubulointerstitial fibrosis, inflammation, and renal apoptosis. Parajuli et al. found that kidney-specific SOD2-deficient mice had lighter and smaller kidneys than wild-type mice with enhanced oxidative stress and tubular injury, including distal tubular dilatation, protein cast formation, and distal tubular epithelial cell swelling. In renal I/R injury, SOD2 expression was reduced in the distal renal unit and renal function deteriorated in SOD2 knockout mice compared to control mice. In a rat model of radiocontrast-induced AKI, recombinant SOD2 pretreatment significantly increased SOD activity and ameliorated decreased renal function and tubular necrosis. In addition, a high salt diet in sod2-deficient mice led to a significant increase in arterial pressure and urinary albumin excretion through the upregulation of NOX and activation of NF-κB. Another study also showed that SOD2 deficiency exacerbates interstitial inflammation and accelerates glomerulosclerosis, tubulointerstitial injury, and salt-sensitive hypertension, especially in aged mice. The mechanism proposed by these authors for the impaired microvascular function is that SOD2 deficiency increases O2--levels and impairs flow and agonist-induced vasodilation in isolated mesenteric arteries.
Excessive mitochondrial O2 - production and associated mitochondrial dysfunction are associated with the pathogenesis of diabetic nephropathy. Several experiments have reported reduced SOD2 activity in animal models of type 1 and type 2 diabetic nephropathy. In contrast, other studies reported no significant difference in SOD2 expression between diabetic and control mice. Dugan et al. found increased renal ROS in SOD2-deficient diabetic mice, but they found no evidence of increased proteinuria or thylakoid stromal expansion. Thus, the role of SOD2 in diabetic nephropathy is controversial and further studies are needed to determine the mechanism of SOD2 activity in diabetic nephropathy.
As with SOD1 and SOD2, several studies have used SOD3 knockout animal models to demonstrate the role of SOD3 in protecting or accelerating renal injury in response to oxidative stress. after renal artery clipping in SOD3 knockout mice, Ang II treatment leads to increased blood pressure and induces endothelial dysfunction, and recombinant SOD3 treatment selectively reduces hypertensive SOD3 knockout mice [44 blood pressure. Another study reported that SOD3 is predominantly localized to the proximal tubule and co-localized with erythropoietin (EPO). Compared to control animals, hypoxia-exposed SOD3 knockout mice showed a smaller increase in EPO levels and less accumulation of nuclear translocation hypoxia-inducible factor (HIF)-1α. Consistent with this finding, SOD3 deletion retarded renal blood flow recovery after renal ischemia and significantly increased tubular necrosis and tubular cast formation after reperfusion.SOD3 knockout mice also showed increased proteinuria, renal fibrosis, and podocyte injury after adriamycin treatment, an experimental model of focal segmental glomerulosclerosis (FSGS), a finding associated with NOX2 and β-catenin signaling pathway was associated with upregulation of the NOX2 and β-catenin signaling pathways. Thus, SOD3 plays a crucial role in renal protection in a variety of renal diseases.
Herba Cistanche
To assess the role of SOD isoforms in diabetic nephropathy, Fijuta et al. evaluated SOD activity and SOD isoform expression in the kidney of a diabetic mouse model and found that SOD1 and SOD3 were downregulated in diabetic kidneys, but SOD2 was not. The same group reported using SOD1- and sod3-knockout diabetic mice to confirm the unique role of SOD isoforms in diabetic nephropathy. They concluded that in C57BL/6-Akita diabetic mice, SOD1 deficiency but not SOD3 deficiency increases renal O2 - and causes significant renal injury - and that SOD1 plays a more prominent role than SOD3 in the pathogenesis of diabetic nephropathy. However, recent studies have reported an independent role for SOD3 in the protection against diabetic nephropathy. Our study showed that SOD3 expression in the glomerular and tubular regions of db/db mice was significantly increased after recombinant human SOD3 supplementation. In animal models of type 1 and type 2 diabetic nephropathy, recombinant human SOD3 supplementation improved the expression of SOD3 by inhibiting phosphorylation of ROS and extracellular signal-regulated kinase (ERK)1/2 or intrarenal 5 ' - amp activated protein kinase-peroxisome proliferator-activated receptor γ coactivator (PGC)-1α -nuclear factor erythroid 2-related factor (Nrf)2 activation of signaling pathways to improve diabetic nephropathy. Therefore, further experiments are needed to elucidate the independent role of SOD3 in diabetic nephropathy protection.
2. Catalase and Kidney Disease
CAT is a 240 kDa heme-containing homotetrameric protein located mainly in the peroxisome and abundantly present in the liver, lung, and kidney. In the kidney, CAT is mainly distributed in the cytoplasm of the proximal tubules of the paramedian cortex and is less expressed in the proximal tubules of the superficial cortex. On the other hand, CAT is not present in the glomeruli, distal tubules, collaterals of Hench, or collecting ducts.CAT deficiency leads to mitochondrial ROS overexpression and functional mitochondrial damage.CAT reduces H2O2 produced by SOD to oxygen and water. Although CAT is efficient in reducing H2O2, its role in regulating H2O2 may not be central, as it is mainly located in the peroxisome.
CAT deficiency has been reported to increase tubulointerstitial fibrosis and lipid peroxidation products of tubulointerstitial lesions in UUO mice. Kobayashi et al. demonstrated that CAT reduces renal function and accelerates progressive renal fibrosis by upregulating the epithelial-to-mesenchymal transition of remnant kidneys in 5/6 nephrectomized mice. Furthermore, compared with wild-type mice, adriamycin-treated mice with blood loss produced severe proteinuria, accelerated glomerulosclerosis and tubulointerstitial fibrosis, and increased lipid peroxidation accumulation.
In diabetic nephropathy, proximal tubule-specific CAT overexpression in STZ-treated diabetic mice and db/db mice inhibited renal ROS generation and tubular interstitial fibrosis and attenuated angiotensinogen, p53, and pro-apoptotic Bcl-2-associated x protein (BAX) gene expression. Consistent with these studies, CAT overexpression in Akita mice significantly reduced systolic blood pressure by regulating the intrarenal renin-angiotensin system (RAS), enhancing angiotensin-converting enzyme (ACE) 2, inhibiting ACE and angiotensinogen expression, or by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase (HO)-1 signaling pathway. Godin et al. used proximal tubule-specific CAT and/or angiotensinogen transgenic mice to confirm the association of CAT and intrarenal RAS action in the development of hypertension and renal injury. Another researcher also reported that CAT deficiency accelerates diabetic nephropathy by impairing peroxisome/mitochondrial biogenesis and fatty acid oxidation. Thus, endogenous CAT has an important protective role in diabetic nephropathy by regulating intrarenal RAS and peroxisome metabolism and reducing oxidative stress.
3. Glutathione Peroxidase and Kidney Diseases
Another H2O2 scavenger, GPx, converts peroxides and OH- to non-toxic substances by oxidizing reduced glutathione (GSH) to glutathione disulfide (GSSG), which is then reduced to glutathione by glutathione reductase via NADPH.GPx synergizes with CAT to break down H2O2 to H2O and oxidizes glutathione, which is then reduced by glutathione reductase. GPx requires GSH as a hydrogen donor to catabolize H2O2 to water and oxygen and requires selenium (Se) as a cofactor to participate in the reaction with peroxides.
The GPx is a tetrameric protein in which each monomer contains a Se atom at the catalytic site. Each monomer contains selenocysteine, where the sulfur in the cysteine has been replaced by selenium (R-SeH). Throughout the catalytic cycle, selenol (protein Se-) reacts with hydrogen peroxide (H2O2 or lipid hydrogen peroxide, LOOH) to produce selenite (protein- SeOH). Selenious acid regenerates selenol via two GSHs, which are eventually oxidized to GSSG and LOOH. LOOH is reduced to the corresponding lipid alcohol (LOH).
To date, eight different GPx have been identified in mammals; however, only five isoforms contain selenocysteine and require the use of glutathione as a reducing cofactor to catalyze the reduction of H2O2 and LOOH (GPx 1-4 and 6). In the kidney, large amounts of GPx are found in the proximal and distal tubules and smooth muscle cells of the renal arteries. among the GPx isoforms, GPx1 and GPx4 are mainly expressed in podocytes and thylakoid cells; GPx3 is produced in the basement membrane of the proximal and distal tubules of the renal cortex; GPx2 and GPx5 are not detected in the kidney. GPx1, the earliest identified gene, is the high expression, and its role in reducing oxidative stress has been widely demonstrated. GPx1 is predominantly found in normal kidneys and accounts for 96% of renal GPx activity. Esposito et al. demonstrated that GPx1 is abundantly expressed in the mitochondria of the renal cortex and that GPx1 deficiency reduces body weight and exacerbates an endogenous, age-dependent decline in overall cellular function. Thus, the regulation of renal GPx1 is thought to play a major role in protecting the kidney from oxidative stress.
Cistanche extract
Several previous studies have evaluated the nephroprotective effects of GPx1 in renal disease.GPx1 gene inhibition exacerbates cocaine-induced AKI by inhibiting the phosphoinositide kinase (PI3K)-Akt signaling pathway to activate the angiotensin II type 1 receptor (AT1R).In addition, GPx1 overexpression ameliorates oxidative stress and mitochondrial ROS in aged mice by attenuating glomerulosclerosis [74]. In diabetic nephropathy, Chiu et al. reported that plasma and urinary GPx levels were significantly lower in diabetic glomerulosclerosis patients than in non-glomerulosclerosis patients and that glomerular GPx expression was lower in diabetic rats than in normal control rats. However, GPx1-deficient diabetic mice exhibited similar levels of oxidative damage, glomerular damage, and renal fibrosis as control diabetic mice, and GPx1 deficiency was not endogenously compensated by increases in CAT or other GPx isoforms during the early stages of diabetic nephropathy. enhanced GPx activity and GPx carboxylation were not accompanied by increased GPx expression in the kidneys of young diabetic mice. The expression and activity of GPx1 and GPx4 did not differ in the kidneys of aged diabetic and non-diabetic mice either. In contrast, Chew et al. demonstrated that GPx1 deficiency increased proteinuria in diabetic ApoE/GPx1 double knockout mice, which was associated with increased glomerular thylakoid matrix expansion and upregulation of mediators of inflammation and fibrosis. Therefore, the nephroprotective effect of GPx1 in diabetic nephropathy remains uncertain.
GPx3 is an extracellular antioxidant selenoprotein, also known as plasma GPx. GPx3 is synthesized primarily in the outer lumen of the renal base and binds to the basement membrane of renal cortical epithelial cells. GPx3 also binds to the basement membrane of extrarenal epithelial cells in the gastrointestinal tract, lung, and epididymis via the bloodstream. These findings suggest that GPx3 deficiency caused by renal injury may affect distal organs. In a surgically induced CKD model, GPx3 deficiency significantly reduces survival and promotes left ventricular dysfunction, as ROS accumulation exacerbates inflammatory signaling and platelet activation. Thus, GPx3 may play an important role in the crosstalk between the kidney and other organs.
Recently, ferroptosis, an iron-dependent programmed cell death characterized by the accumulation of lipid hydroperoxides to lethal levels, has been reported to be involved in the pathophysiology of several renal diseases.GPx4 is the main enzyme that blocks ferroptosis, and GPx4 inhibitors induce ferroptosis cell death by binding and inactivating GPx4.GPx4 deficiency also exacerbates AKI by increasing intracellular LOOH and promoting iron-causing cell death exacerbates AKI; lipo statin-1 prevents GPx4 depletion-induced kidney injury. A recent study showed significantly elevated levels of acyl-coenzyme A synthase long-chain family member 4 (ACSL4) and significantly reduced levels of GPx4 in diabetic mice, and these findings suggest that iron sagging is involved in the pathogenesis of diabetic nephropathy [85]. To date, there has been no association between GPx2 and GPx5 and renal disease.
References
1. Sies, H. Oxidative Stress: A Concept in Redox Biology and Medicine. Redox Biol. 2015, 4, 180–183.
2. Murphy, M.P. How Mitochondria Produce Reactive Oxygen Species. Biochem. J. 2009, 417, 1–13.
3. Xu, N.; Jiang, S.; Persson, P.B.; Persson, E.A.G.; Lai, E.Y.; Patzak, A. Reactive Oxygen Species in Renal Vascular Function. Acta Physiol. 2020, 229, e13477.
4. Wang, Y.; Branicky, R.; Noë, A.; Hekimi, S. Superoxide Dismutases: Dual Roles in Controlling ROS Damage and Regulating ROS Signaling. J. Cell Biol. 2018, 217, 1915–1928.
5. Go, Y.M.; Jones, D.P. Redox Compartmentalization in Eukaryotic Cells. Biochim. Biophys. Acta 2008, 1780, 1273–1290.
6. Matés, J.M.; Pérez-Gómez, C.; Núñez de Castro, I. Antioxidant Enzymes and Human Diseases. Clin. Biochem. 1999, 32, 595–603.
7. Espinosa-Diez, C.; Miguel, V.; Mennerich, D.; Kietzmann, T.; Sanchez-Perez, P.; Cadenas, S.; Lamas, S. Antioxidant Responses and Cellular Adjustments to Oxidative Stress. Redox Biol. 2015, 6, 183–197.
8. Sharma, K. Obesity and Diabetic Kidney Disease: Role of Oxidant Stress and Redox Balance. Antioxid. Redox Signal. 2016, 25, 208–216.
9. Dennis, J.M.; Witting, P.K. Protective Role for Antioxidants in Acute Kidney Disease. Nutrients 2017, 9, 718.
10. Irazabal, M.V.; Torres, V.E. Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease. Cells 2020, 9, 1342.
11. Ratliff, B.B.; Abdulmahdi, W.; Pawar, R.; Wolin, M.S. Oxidant Mechanisms in Renal Injury and Disease. Antioxid. Redox Signal. 2016, 25, 119–146.
12. Day, B.J. Catalytic Antioxidants: A Radical Approach to New Therapeutics. Drug Discov. Today 2004, 9, 557–566.
13. Mirończuk-Chodakowska, I.; Witkowska, A.M.; Zujko, M.E. Endogenous Non-Enzymatic Antioxidants in the Human Body. Adv. Med. Sci. 2018, 63, 68–78.
14. Pisoschi, A.M.; Pop, A. The Role of Antioxidants in the Chemistry of Oxidative Stress: A Review. Eur. J. Med. Chem. 2015, 97, 55–74.
15. Rouco, L.; González-Noya, A.M.; Pedrido, R.; Maneiro, M. Pursuing the Elixir of Life: In Vivo Antioxidative Effects of Manganosalen Complexes. Antioxidants 2020, 9, 727.
16. Zelko, I.N.; Mariani, T.J.; Folz, R.J. Superoxide Dismutase Multigene Family: A Comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) Gene Structures, Evolution, and Expression. Free Radic. Biol. Med. 2002, 33, 337–349.
17. Marklund, S.L. Extracellular Superoxide Dismutase and Other Superoxide Dismutase Isoenzymes in Tissues from Nine Mammalian Species. Biochem. J. 1984, 222, 649–655.
18. Van Remmen, H.; Salvador, C.; Yang, H.; Huang, T.T.; Epstein, C.J.; Richardson, A. Characterization of the Antioxidant Status of the Heterozygous Manganese Superoxide Dismutase Knockout Mouse. Arch. Biochem. Biophys. 1999, 363, 91–97.
19. Schieber, M.; Chandel, N.S. ROS Function in Redox Signaling and Oxidative Stress. Curr. Biol. 2014, 24, R453–R462.
20. Brzoska, K.; Sochanowicz, B.; Siomek, A.; Olinski, R.; Kruszewski, M. Alterations in the Expression of Genes Related to NFkappaB Signaling in Liver and Kidney of CuZnSOD-Deficient Mice. Mol. Cell. Biochem. 2011, 353, 151–157.
21. Siomek, A.; Brzoska, K.; Sochanowicz, B.; Gackowski, D.; Rozalski, R.; Foksinski, M.; Zarakowska, E.; Szpila, A.; Guz, J.; Bartlomiejczyk, T.; et al. Cu, Zn-superoxide Dismutase Deficiency in Mice Leads to Organ-Specific Increase in Oxidatively Damaged DNA and NF-kappaB1 Protein Activity. Acta Biochim. Pol. 2010, 57, 577–583.
22. Yamanobe, T.; Okada, F.; Iuchi, Y.; Onuma, K.; Tomita, Y.; Fujii, J. Deterioration of Ischemia/Reperfusion-Induced Acute Renal Failure in SOD1-Deficient Mice. Free Radic. Res. 2007, 41, 200–207.
23. Yin, M.; Wheeler, M.D.; Connor, H.D.; Zhong, Z.; Bunzendahl, H.; Dikalova, A.; Samulski, R.J.; Schoonhoven, R.; Mason, R.P.; Swenberg, J.A.; et al. Cu/Zn-Superoxide Dismutase Gene Attenuates Ischemia-Reperfusion Injury in the Rat Kidney. J. Am. Soc. Nephrol. 2001, 12, 2691–2700.
24. Carlström, M.; Brown, R.D.; Sällström, J.; Larsson, E.; Zilmer, M.; Zabihi, S.; Eriksson, U.J.; Persson, A.E. SOD1 Deficiency Causes Salt Sensitivity and Aggravates Hypertension in Hydronephrosis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009, 297, R82–R92.
25. Carlström, M.; Lai, E.Y.; Ma, Z.; Steege, A.; Patzak, A.; Eriksson, U.J.; Lundberg, J.O.; Wilcox, C.S.; Persson, A.E. Superoxide Dismutase 1 Limits Renal Microvascular Remodeling and Attenuates Arteriole and Blood Pressure Responses to Angiotensin II via Modulation of Nitric Oxide Bioavailability. Hypertension 2010, 56, 907–913.
26. Cepas, V.; Collino, M.; Mayo, J.C.; Sainz, R.M. Redox Signaling and Advanced Glycation Endproducts (AGEs) in Diet-Related Diseases. Antioxidants 2020, 9, 142.
27. DeRubertis, F.R.; Craven, P.A.; Melhem, M.F.; Salah, E.M. Attenuation of Renal Injury in db/db Mice Overexpressing Superoxide Dismutase: Evidence for Reduced Superoxide-Nitric Oxide Interaction. Diabetes 2004, 53, 762–768.
28. Craven, P.A.; Melhem, M.F.; Phillips, S.L.; DeRubertis, F.R. Overexpression of Cu2+/Zn2+ Superoxide Dismutase Protects against Early Diabetic Glomerular Injury in Transgenic Mice. Diabetes 2001, 50, 2114–2125.
29. Kitada, M.; Xu, J.; Ogura, Y.; Monno, I.; Koya, D. Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease. Front. Physiol. 2020, 11, 755.
30. Parajuli, N.; Marine, A.; Simmons, S.; Saba, H.; Mitchell, T.; Shimizu, T.; Shirasawa, T.; Macmillan-Crow, L.A. Generation and Characterization of a Novel Kidney-Specific Manganese Superoxide Dismutase Knockout Mouse. Free Radic. Biol. Med. 2011, 51, 406–416.
31. Parajuli, N.; MacMillan-Crow, L.A. Role of Reduced Manganese Superoxide Dismutase in Ischemia-Reperfusion Injury: A Possible Trigger for Autophagy and Mitochondrial Biogenesis? Am. J. Physiol. Renal Physiol. 2013, 304, F257–F267.
32. Pisani, A.; Sabbatini, M.; Riccio, E.; Rossano, R.; Andreucci, M.; Capasso, C.; De Luca, V.; Carginale, V.; Bizzarri, M.; Borrelli, A.; et al. Effect of a Recombinant Manganese Superoxide Dismutase on Prevention of Contrast-Induced Acute Kidney Injury. Clin. Exp. Nephrol. 2014, 18, 424–431.
33. Jin, K.; Vaziri, N.D. Salt-Sensitive Hypertension in Mitochondrial Superoxide Dismutase Deficiency Is Associated with IntraRenal Oxidative Stress and Inflammation. Clin. Exp. Nephrol. 2014, 18, 445–452.
34. Rodriguez-Iturbe, B.; Sepassi, L.; Quiroz, Y.; Ni, Z.; Wallace, D.C.; Vaziri, N.D. Association of Mitochondrial SOD Deficiency with Salt-Sensitive Hypertension and Accelerated Renal Senescence. J. Appl. Physiol. 2007, 102, 255–260.
35. Yan, C.; Huang, A.; Wu, Z.; Kaminski, P.M.; Wolin, M.S.; Hintze, T.H.; Kaley, G.; Sun, D. Increased Superoxide Leads to Decreased Flow-Induced Dilation in Resistance Arteries of Mn-SOD-Deficient Mice. Am. J. Physiol. Heart Circ. Physiol. 2005, 288, H2225–H2231.
36. Forbes, J.M.; Thorburn, D.R. Mitochondrial Dysfunction in Diabetic Kidney Disease. Nat. Rev. Nephrol. 2018, 14, 291–312.
37. Sharma, K. Mitochondrial Dysfunction in the Diabetic Kidney. Adv. Exp. Med. Biol. 2017, 982, 553–562.
38. Li, C.; Matavelli, L.C.; Akhtar, S.; Siragy, H.M. (Pro)renin Receptor Contributes to Renal Mitochondria Dysfunction, Apoptosis and Fibrosis in Diabetic Mice. Sci. Rep. 2019, 9, 11667.
39. Kim, M.Y.; Lim, J.H.; Youn, H.H.; Hong, Y.A.; Yang, K.S.; Park, H.S.; Chung, S.; Ko, S.H.; Shin, S.J.; Choi, B.S.; et al. Resveratrol Prevents Renal Lipotoxicity and Inhibits Mesangial Cell Glucotoxicity in a Manner Dependent on the AMPK-SIRT1-PGC1alpha Axis in db/db Mice. Diabetologia 2013, 56, 204–217.
40. De Cavanagh, E.M.; Ferder, L.; Toblli, J.E.; Piotrkowski, B.; Stella, I.; Fraga, C.G.; Inserra, F. Renal Mitochondrial Impairment Is Attenuated by AT1 Blockade in Experimental Type I Diabetes. Am. J. Physiol. Heart Circ. Physiol. 2008, 294, H456–H465.
41. Hong, Y.A.; Lim, J.H.; Kim, M.Y.; Kim, T.W.; Kim, Y.; Yang, K.S.; Park, H.S.; Choi, S.R.; Chung, S.; Kim, H.W.; et al. Fenofibrate Improves Renal Lipotoxicity Through Activation of AMPK-PGC-1alpha in db/db Mice. PLoS ONE 2014, 9, e96147.
42. Fujita, H.; Fujishima, H.; Chida, S.; Takahashi, K.; Qi, Z.; Kanetsuna, Y.; Breyer, M.D.; Harris, R.C.; Yamada, Y.; Takahashi, T. Reduction of Renal Superoxide Dismutase in Progressive Diabetic Nephropathy. J. Am. Soc. Nephrol. 2009, 20, 1303–1313.
43. Dugan, L.L.; You, Y.H.; Ali, S.S.; Diamond-Stanic, M.; Miyamoto, S.; DeCleves, A.E.; Andreyev, A.; Quach, T.; Ly, S.; Shekhtman, G.; et al. AMPK Dysregulation Promotes Diabetes-Related Reduction of Superoxide and Mitochondrial Function. J. Clin. Invest. 2013, 123, 4888–4899.
44. Jung, O.; Marklund, S.L.; Geiger, H.; Pedrazzini, T.; Busse, R.; Brandes, R.P. Extracellular Superoxide Dismutase Is a Major Determinant of Nitric Oxide Bioavailability: In Vivo and Ex Vivo Evidence from ecSOD-Deficient Mice. Circ. Res. 2003, 93, 622–629.
45. Suliman, H.B.; Ali, M.; Piantadosi, C.A. Superoxide Dismutase-3 Promotes Full Expression of the EPO Response to Hypoxia. Blood 2004, 104, 43–50.
46. Schneider, M.P.; Sullivan, J.C.; Wach, P.F.; Boesen, E.I.; Yamamoto, T.; Fukai, T.; Harrison, D.G.; Pollock, D.M.; Pollock, J.S. Protective Role of Extracellular Superoxide Dismutase in Renal Ischemia/Reperfusion Injury. Kidney Int. 2010, 78, 374–381.
47. Tan, R.J.; Zhou, D.; Xiao, L.; Zhou, L.; Li, Y.; Bastacky, S.I.; Oury, T.D.; Liu, Y. Extracellular Superoxide Dismutase Protects against Proteinuric Kidney Disease. J. Am. Soc. Nephrol. 2015, 26, 2447–2459.
48. Fujita, H.; Fujishima, H.; Takahashi, K.; Sato, T.; Shimizu, T.; Morii, T.; Shimizu, T.; Shirasawa, T.; Qi, Z.; Breyer, M.D.; et al. SOD1, but Not SOD3, Deficiency Accelerates Diabetic Renal Injury in C57BL/6-Ins2(Akita) Diabetic Mice. Metabolism 2012, 61, 1714–1724.
49. Kuo, C.W.; Shen, C.J.; Tung, Y.T.; Chen, H.L.; Chen, Y.H.; Chang, W.H.; Cheng, K.C.; Yang, S.H.; Chen, C.M. Extracellular Superoxide Dismutase Ameliorates Streptozotocin-Induced Rat Diabetic Nephropathy via Inhibiting the ROS/ERK1/2 Signaling. Life Sci. 2015, 135, 77–86.
50. Hong, Y.A.; Lim, J.H.; Kim, M.Y.; Kim, Y.; Park, H.S.; Kim, H.W.; Choi, B.S.; Chang, Y.S.; Kim, H.W.; Kim, T.Y.; et al. Extracellular Superoxide Dismutase Attenuates Renal Oxidative Stress Through the Activation of Adenosine Monophosphate-Activated Protein Kinase in Diabetic Nephropathy. Antioxid. Redox Signal. 2018, 28, 1543–1561.
51. Ho, Y.S.; Xiong, Y.; Ma, W.; Spector, A.; Ho, D.S. Mice Lacking Catalase Develop Normally but Show Differential Sensitivity to Oxidant Tissue Injury. J. Biol. Chem. 2004, 279, 32804–32812.
52. Zhou, Z.; Kang, Y.J. Cellular and Subcellular Localization of Catalase in the Heart of Transgenic Mice. J. Histochem. Cytochem. 2000, 48, 585–594.
53. Hwang, I.; Lee, J.; Huh, J.Y.; Park, J.; Lee, H.B.; Ho, Y.S.; Ha, H. Catalase Deficiency Accelerates Diabetic Renal Injury Through Peroxisomal Dysfunction. Diabetes 2012, 61, 728–738.
54. Sunami, R.; Sugiyama, H.; Wang, D.H.; Kobayashi, M.; Maeshima, Y.; Yamasaki, Y.; Matsuoka, N.; Ogawa, N.; Kira, S.; Makino, H. Acatalasemia Sensitizes Renal Tubular Epithelial Cells to Apoptosis and Exacerbates Renal Fibrosis after Unilateral Ureteral Obstruction. Am. J. Physiol. Renal Physiol. 2004, 286, F1030–F1038.
55. Kobayashi, M.; Sugiyama, H.; Wang, D.H.; Toda, N.; Maeshima, Y.; Yamasaki, Y.; Matsuoka, N.; Yamada, M.; Kira, S.; Makino, H. Catalase Deficiency Renders Remnant Kidneys More Susceptible to Oxidant Tissue Injury and Renal Fibrosis in Mice. Kidney Int. 2005, 68, 1018–1031.
56. Takiue, K.; Sugiyama, H.; Inoue, T.; Morinaga, H.; Kikumoto, Y.; Kitagawa, M.; Kitamura, S.; Maeshima, Y.; Wang, D.H.; Masuoka, N.; et al. Acatalasemic Mice Are Mildly Susceptible to Adriamycin Nephropathy and Exhibit Increased Albuminuria and Glomerulosclerosis. BMC Nephrol. 2012, 13, 14.
57. Brezniceanu, M.L.; Liu, F.; Wei, C.C.; Tran, S.; Sachetelli, S.; Zhang, S.L.; Guo, D.F.; Filep, J.G.; Ingelfinger, J.R.; Chan, J.S. Catalase Overexpression Attenuates Angiotensinogen Expression and Apoptosis in Diabetic Mice. Kidney Int. 2007, 71, 912–923.
58. Brezniceanu, M.L.; Liu, F.; Wei, C.C.; Chénier, I.; Godin, N.; Zhang, S.L.; Filep, J.G.; Ingelfinger, J.R.; Chan, J.S. Attenuation of Interstitial Fibrosis and Tubular Apoptosis in db/db Transgenic Mice Overexpressing Catalase in Renal Proximal Tubular Cells. Diabetes 2008, 57, 451–459.
59. Shi, Y.; Lo, C.S.; Chenier, I.; Maachi, H.; Filep, J.G.; Ingelfinger, J.R.; Zhang, S.L.; Chan, J.S. Overexpression of Catalase Prevents Hypertension and Tubulointerstitial Fibrosis and Normalization of Renal Angiotensin-Converting Enzyme-2 Expression in Akita Mice. Am. J. Physiol. Renal Physiol. 2013, 304, F1335–F1346.
60. Abdo, S.; Shi, Y.; Otoukesh, A.; Ghosh, A.; Lo, C.S.; Chenier, I.; Filep, J.G.; Ingelfinger, J.R.; Zhang, S.L.; Chan, J.S. Catalase Overexpression Prevents Nuclear Factor Erythroid 2-Related Factor 2 Stimulation of Renal Angiotensinogen Gene Expression, Hypertension, and Kidney Injury in Diabetic Mice. Diabetes 2014, 63, 3483–3496.
61. Godin, N.; Liu, F.; Lau, G.J.; Brezniceanu, M.L.; Chénier, I.; Filep, J.G.; Ingelfinger, J.R.; Zhang, S.L.; Chan, J.S. Catalase Overexpression Prevents Hypertension and Tubular Apoptosis in Angiotensinogen Transgenic Mice. Kidney Int. 2010, 77, 1086–1097.
62. Flohe, L.; Günzler, W.A.; Schock, H.H. Glutathione Peroxidase: A Selenoenzyme. FEBS Lett. 1973, 32, 132–134.
63. Schafer, F.Q.; Buettner, G.R. Redox Environment of the Cell as Viewed Through the Redox State of the Glutathione Disulfide/Glutathione Couple. Free Radic. Biol. Med. 2001, 30, 1191–1212.
64. Lei, X.G.; Cheng, W.H. New Roles for an Old Selenoenzyme: Evidence from Glutathione Peroxidase-1 Null and Overexpressing Mice. J. Nutr. 2005, 135, 2295–2298.
65. Day, B.J. Catalase and Glutathione Peroxidase Mimics. Biochem. Pharmacol. 2009, 77, 285–296.
66. Behne, D.; Kyriakopoulos, A. Mammalian Selenium-Containing Proteins. Annu. Rev. Nutr. 2001, 21, 453–473.
67. Muse, K.E.; Oberley, T.D.; Sempf, J.M.; Oberley, L.W. Immunolocalization of Antioxidant Enzymes in Adult Hamster Kidney. Histochem. J. 1994, 26, 734–753.
68. Wiedenmann, T.; Dietrich, N.; Fleming, T.; Altamura, S.; Deelman, L.E.; Henning, R.H.; Muckenthaler, M.U.; Nawroth, P.P.; Hammes, H.P.; Wagner, A.H.; et al. Modulation of Glutathione Peroxidase Activity by Age-Dependent Carbonylation in Glomeruli of Diabetic Mice. J. Diabetes Complicat. 2018, 32, 130–138.
69. Olson, G.E.; Whitin, J.C.; Hill, K.E.; Winfrey, V.P.; Motley, A.K.; Austin, L.M.; Deal, J.; Cohen, H.J.; Burk, R.F. Extracellular Glutathione Peroxidase (Gpx3) Binds Specifically to Basement Membranes of Mouse Renal Cortex Tubule Cells. Am. J. Physiol. Renal Physiol. 2010, 298, F1244–F1253.
70. De Haan, J.B.; Bladier, C.; Griffiths, P.; Kelner, M.; O’Shea, R.D.; Cheung, N.S.; Bronson, R.T.; Silvestro, M.J.; Wild, S.; Zheng, S.S.; et al. Mice with a Homozygous Null Mutation for the Most Abundant Glutathione Peroxidase, Gpx1, Show Increased Susceptibility to the Oxidative Stress-Inducing Agents Paraquat and Hydrogen Peroxide. J. Biol. Chem. 1998, 273, 22528–22536.
71. De Haan, J.B.; Stefanovic, N.; Nikolic-Paterson, D.; Scurr, L.L.; Croft, K.D.; Mori, T.A.; Hertzog, P.; Kola, I.; Atkins, R.C.; Tesch, G.H. Kidney Expression of Glutathione Peroxidase-1 Is Not Protective against Streptozotocin-Induced Diabetic Nephropathy. Am. J. Physiol. Renal Physiol. 2005, 289, F544–F551.
72. Esposito, L.A.; Kokoszka, J.E.; Waymire, K.G.; Cottrell, B.; MacGregor, G.R.; Wallace, D.C. Mitochondrial Oxidative Stress in Mice Lacking the Glutathione Peroxidase-1 Gene. Free Radic. Biol. Med. 2000, 28, 754–766.
73. Mai, H.N.; Chung, Y.H.; Shin, E.J.; Kim, D.J.; Jeong, J.H.; Nguyen, T.T.; Nam, Y.; Lee, Y.J.; Nah, S.Y.; Yu, D.Y.; et al. Genetic Depletion of Glutathione Peroxidase-1 Potentiates Nephrotoxicity Induced by Multiple Doses of Cocaine via Activation of Angiotensin II AT1 Receptor. Free Radic. Res. 2016, 50, 467–483.
74. Chu, Y.; Lan, R.S.; Huang, R.; Feng, H.; Kumar, R.; Dayal, S.; Chan, K.S.; Dai, D.F. Glutathione Peroxidase-1 Overexpression Reduces Oxidative Stress, and Improves Pathology and Proteome Remodeling in the Kidneys of Old Mice. Aging Cell 2020, 19, e13154.
75. Chiu, Y.W.; Kuo, M.C.; Kuo, H.T.; Chang, J.M.; Guh, J.Y.; Lai, Y.H.; Chen, H.C. Alterations of Glomerular and Extracellular Levels of Glutathione Peroxidase in Patients and Experimental Rats with Diabetic Nephropathy. J. Lab. Clin. Med. 2005, 145, 181–186.
76. Chew, P.; Yuen, D.Y.; Stefanovic, N.; Pete, J.; Coughlan, M.T.; Jandeleit-Dahm, K.A.; Thomas, M.C.; Rosenfeldt, F.; Cooper, M.E.; de Haan, J.B. Antiatherosclerotic and Renoprotective Effects of Ebselen in the Diabetic Apolipoprotein E/GPx1-Double Knockout Mouse. Diabetes 2010, 59, 3198–3207.
77. Ottaviano, F.G.; Tang, S.S.; Handy, D.E.; Loscalzo, J. Regulation of the Extracellular Antioxidant Selenoprotein Plasma Glutathione Peroxidase (GPx-3) in Mammalian Cells. Mol. Cell. Biochem. 2009, 327, 111–126.
78. Burk, R.F.; Olson, G.E.; Winfrey, V.P.; Hill, K.E.; Yin, D. Glutathione Peroxidase-3 Produced by the Kidney Binds to a Population of Basement Membranes in the Gastrointestinal Tract and in Other Tissues. Am. J. Physiol. Gastrointest. Liver Physiol. 2011, 301, G32–G38.
79. Pang, P.; Abbott, M.; Abdi, M.; Fucci, Q.A.; Chauhan, N.; Mistri, M.; Proctor, B.; Chin, M.; Wang, B.; Yin, W.; et al. Pre-Clinical Model of Severe Glutathione Peroxidase-3 Deficiency and Chronic Kidney Disease Results in Coronary Artery Thrombosis and Depressed Left Ventricular Function. Nephrol. Dial. Transplant. 2018, 33, 923–934.
80. Martin-Sanchez, D.; Fontecha-Barriuso, M.; Martinez-Moreno, J.M.; Ramos, A.M.; Sanchez-Niño, M.D.; Guerrero-Hue, M.; Moreno, J.A.; Ortiz, A.; Sanz, A.B. Ferroptosis and Kidney Disease. Nefrologia 2020, 40, 384–394.
81. Hu, Z.; Zhang, H.; Yang, S.K.; Wu, X.; He, D.; Cao, K.; Zhang, W. Emerging Role of Ferroptosis in Acute Kidney Injury. Oxid. Med. Cell. Longev. 2019, 2019, 8010614.
82. Belavgeni, A.; Meyer, C.; Stumpf, J.; Hugo, C.; Linkermann, A. Ferroptosis and Necroptosis in the Kidney. Cell Chem. Biol. 2020, 27, 448–462.
83. Yang, W.S.; SriRamaratnam, R.; Welsch, M.E.; Shimada, K.; Skouta, R.; Viswanathan, V.S.; Cheah, J.H.; Clemons, P.A.; Shamji, A.F.; Clish, C.B.; et al. Regulation of Ferroptotic Cancer Cell Death by GPX4. Cell 2014, 156, 317–331.
84. Friedmann Angeli, J.P.; Schneider, M.; Proneth, B.; Tyurina, Y.Y.; Tyurin, V.A.; Hammond, V.J.; Herbach, N.; Aichler, M.; Walch, A.; Eggenhofer, E.; et al. Inactivation of the Ferroptosis Regulator Gpx4 Triggers Acute Renal Failure in Mice. Nat. Cell Biol. 2014, 16, 1180–1191.
85. Wang, Y.; Bi, R.; Quan, F.; Cao, Q.; Lin, Y.; Yue, C.; Cui, X.; Yang, H.; Gao, X.; Zhang, D. Ferroptosis Involves in Renal Tubular Cell Death in Diabetic Nephropathy. Eur. J. Pharmacol. 2020, 888, 173574.
Yu Ah Hong 1 and Cheol Whee Park 1,2,
1 Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; amorfati@catholic.ac.kr
2 Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
