key: cord-0966995-8ogp89cx
authors: Diniz, Lúcio Ricardo Leite; Souza, Marilia Trindade de Santana; Duarte, Allana Brunna Sucupira; de Sousa, Damião Pergentino
title: Mechanistic Aspects and Therapeutic Potential of Quercetin against COVID-19-Associated Acute Kidney Injury
date: 2020-12-07
journal: Molecules
DOI: 10.3390/molecules25235772
sha: 576dc4c7befba6a6d5bd56c75ab722dcd1dc8514
doc_id: 966995
cord_uid: 8ogp89cx

The inflammatory mediator and oxidant agent storm caused by the SARS-CoV-2 infection has been strongly associated with the failure of vital organs observed in critically ill patients with coronavirus disease 2019 (COVID-19) and the death of thousands of infected people around the world. Acute kidney injury (AKI) is a common renal disorder characterized by a sudden and sustained decrease in renal function with a critical influence on poor prognosis and lethal clinical outcomes of various etiologies, including some viral infection diseases. It is known that oxidative stress and inflammation play key roles in the pathogenesis and development of AKI. Quercetin is a natural substance that has multiple pharmacological properties, such as anti-inflammatory action, and is used as a dietary supplement. There is evidence of the anti-coronavirus activities of this compound, including against the target SARS-CoV-2 3CLpro. The ability to inhibit coronavirus and its inflammatory processes is strongly desired in a new drug for the treatment of COVID-19. Therefore, in this review, the dual effect of quercetin is discussed from a mechanistic perspective in relation to AKI kidney injury and its nephroprotective potential to SARS-CoV-2 patients.

Coronavirus disease 2019 (COVID- 19) has killed more than one million people with SARS-CoV-2 worldwide, and it continues creating great concern for the world medical community due to the continually elevated number of deaths caused by COVID-19 [1] [2] [3] . Recent clinical reports have indicated that COVID-19 may lead to severe and fatal respiratory complications and even to other organ failures, such as renal failure [4] [5] [6] . The increasing number of studies that relate a substantial number of patients with SARS-CoV-2 with acute kidney injury (AKI) have suggested that the impairment of renal functions, such as the retention of waste products of cellular metabolism and the lack of maintaining fluids, electrolytes, and acid-base homeostasis, contributes to the worsening of clinical outcomes and consequently to the lethality of COVID-19 [7] [8] [9] [10] . AKI is a common renal disorder characterized by a sudden and sustained decrease in renal function with a critical influence on poor prognosis and lethal clinical outcomes of various etiologies, including cardiovascular diseases, diabetes, and sepsis [11, 12] .

The unavailability of specific treatment and the inability to accurately predict a timeline for an effective vaccine against COVID-19 [13] [14] [15] make it extremely necessary to test compounds with Moreover, sepsis appears to be the most frequent contributing factor for the development of AKI. Studies indicate that AKI is caused by about 50% of sepsis cases worldwide [33, 39] .

Preliminary findings have shown that the etiology and prevalence of AKI vary, mainly due to different aspects of the sample evaluated (i.e., animal species, sex, age, and comorbidity), differences in the income levels of countries (with low-to-middle income countries showing more severity and a higher incidence of AKI than high-income countries), and differences in AKI classification criteria [32, 38, 43, 44] . Throughout the last two decades, the AKI definition has been mainly based on the RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease), Acute Kidney Injury Network (AKIN), and Kidney Disease: Improving Global Outcomes (KDIGO) criteria and stages [43, 44] . Until 2004, the diagnosis of AKI was based on urine output as well as blood urea nitrogen (BUN) and serum creatinine (SCr) levels. The lack of a precise biochemical definition for AKI led the Acute Dialysis Quality Initiative group to create the RIFLE criteria in 2004, establishing a multidimensional staged definition. RIFLE uses glomerular filtration rate (GFR) criteria in addition to SCr and urine output criteria. The Risk, Injury, and Failure stages were determined by increases in SCr ≥ 1.5-, 2-, and 3-fold from a known baseline, respectively [43] [44] [45] . In 2007, the Acute Kidney Injury Network (AKIN) definitions were created with criteria driven by observations of minor increases in SCr over a shorter time period (48 h) . The Risk, Injury, and Failure categories of the RIFLE definition were replaced by stages 1, 2, and 3 and the GFR criteria were abandoned in the AKIN definitions. The diagnosis of AKI was assessed by a rise in SCr ≥ 0.3-mg/dl over 48h in AKIN stage 1 and an absolute rise in SCr > 26.4 µmol/l was added to the relative increase of 100% and 200% in SCr compared to baseline in AKIN stages 2 and 3, respectively. The current definition created by KDIGO is similar to the AKIN definition but the time frame is extended from 48 h to 7 days. The decrease in urinary output to less than 0.5 mL kg −1 h −1 for 6 h was also similar to the RIFLE and AKIN definitions [30, [43] [44] [45] [46] . The actual criteria used to define AKI and its stages are not entirely accepted by all researchers and clinicians, who consider SCr and urine output more accurate markers of kidney dysfunction than AKI; consequently, both parameters are not ideal markers of AKI [47] . Over the last few years, many urine or blood biomarkers of AKI have been proposed as adjunct diagnostics to SCr and urinary output to improve the early detection, differential diagnosis, and prognostic assessment of AKI [48, 49] . The following are among the novel biomarkers of AKI:

Neutrophil gelatinase-associated lipocalin (NGAL): lesions in the thick ascending loop of Henle and the intercalated cells of the collecting duct [49] [50] [51] .

Kidney injury molecule-1 (KIM-1): lesions in proximal tubule cells [44, 49, 52] . Interleukin-18 (IL-18): lesions in collecting duct and tubular epithelial cells [48, 49] . Liver-type fatty acid-binding protein (L-FABP): lesions in proximal tubule cells [49] . Calprotectin (S100A8/9): lesions in collecting ducts and filtrating immune cells [48, 50] . In general, the mechanisms involved in the pathophysiology of AKI are attributed to renal damage caused by ischemic process, oxidative stress, and inflammation [30, 53] . Many pathophysiological mechanisms contribute to kidney tubular and endothelial cell injury and consecutive renal dysfunction observed in ischemic AKI, including reduced renal blood flow (RBF), renal tubular apoptosis, necrosis, and inflammation [54, 55] . In RBF-independent microcirculatory dysfunction, inflammatory mediators, immune cell infiltration, and the deregulation of nitric oxide synthase lead to the redistribution of blood flow from renal medulla to the cortex, the deterioration of microcirculatory oxygenation, tubular cell damages, and the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [35, 41, 54] .

Kidneys are high-risk organs for viral invasion, and the presence of AKI represents poor prognosis and potentially fatal outcome in several virus diseases [56] . Therefore, avoiding or even controlling the progression of AKI during viral infection have become challenges for the medical community. Various kidney diseases are associated with viral infections, including infection caused by the HIV virus [57] , Epstein-Barr virus [58] , parvovirus B19 [59] , hepatitis B virus (HBV) [60] , hepatitis C virus (HCV) [61] , Zika virus [62] , dengue virus [63] , and influenza A (H1N1) virus [64] . A large spectrum of prevalence and clinical manifestations are observed among viral diseases, ranging from mild and rare AKI caused by acute symptomatic Epstein-Barr virus infectious mononucleosis [58] to rapid deterioration of renal function, often resulting in the requirement of renal replacement therapy, as observed in hantavirus-type infection [51, 58, 65, 66] .

Virus-associated glomerular disease, such as membranous glomerulopathy, glomerulosclerosis, and membranoproliferative glomerulonephritis associated with HCV infection [67] [68] [69] , as well as interstitial nephritis and necrotizing tubulointerstitial nephritis are common clinical manifestations caused by BK virus, cytomegalovirus, and adenovirus infections [56, 59] . AKI-associated nephritis is also a common renal disorder observed in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) and adenovirus infections [60, 70, 71] . In the last decade, high incidences of AKI have been found in critically ill patients with severe acute respiratory syndrome (SARS) and influenza A (H1N1), while in turn a strong relation between AKI and mortality rate was also observed [72, 73] .

The pathological mechanisms behind virus-associated kidney injury manifestations are either immune complex deposition or immune reactions resulting in glomerular membrane proliferation, based on severe coagulopathy, endothelial damage, and increased vascular permeability [70, 74, 75] . Massive releases of myoglobin-, cytokine-, and humoral factor-mediated acute interstitial nephritis play an important role in many viral infections [67, 76] . Histological investigation shows the presence of acute distal tubular necrosis and viral particles in epithelial cells as well as the Bowman's capsule found in many viral diseases, which differ significantly from those reported in bacterial infection characterized by increased rates of apoptosis in renal tubular epithelia as well as leucocytic infiltration in glomeruli and capillaries [56, 68, 70] .

One relevant aspect in the incidence and outcome of AKI in viral infection is the presence of comorbidities and coinfection, particularly in those patients with a longer ICU stay and/or immunodeficiency [77, 78] . In this context, HIV-infected patients may be predisposed to acquiring new viral coinfections added to HIV-associated nephropathy (HIVAN), immune complex kidney disease, thrombotic microangiopathy, and drug-related injury [75] . Thus, the kidney diseases found in HIV patients, such as immunotactoid glomerulopathy and fibrillary glomerulonephritis, are usually more severe and complex than other virus-associated kidney injuries [79] .

An important feature of virus-associated kidney injury is the presence of virus in the urine for long periods after initial infection [80] . Considering that neither CD4+ nor CD8+ T cells are detected in the kidney, even after a long period of viral infection, increasing evidence that virus can infect renal tubules without the recruitment of immune cells as a viral strategy for persistent survival has been reported [54, 75, 79] . Ou et al. [80] investigated the replication strategies and immune responses of kidney caused by the duck hepatitis A virus (DHAV) up to 280 days after virus infection. In accordance with preliminary findings that cytokines, interferons, and interleukins are vital for both antiviral responses and the pathogenesis of viral infection, the results showed a strong cytokine storm, including type I (IFN-α/β) and type II (IFN-γ) IFNs, Th1-related ILs (IL-1β/2/6), and Th2-related ILs (IL-4), followed by a sudden decrease in virus loads in the mesangial cells and vascular endothelial cells for early infection [80] . The cytokine storm was consistent with both viral decrease and kidney injury, which combined with the histopathological changes indicated a double-edged sword for the host defense, since it not only enhanced viral clearance but also had a pathogenic effect [54, 56] .

Even though a better understanding of the pathophysiologic mechanisms of COVID-19-associated AKI is needed, there is increasing evidence that AKI is prevalent in critically ill patients with SARS-CoV-2 infection and it is closely associated with the severity of COVID-19 [11, 12, 81, 82] . Moreover, clinical data have suggested that AKI represents poor prognosis and is associated with high mortality of patients with SARS-CoV-2 in ICU settings, especially in those with underlying comorbidities and requiring renal replacement therapy [3, 9] . For example, a study that analyzed the clinical characteristics and complications in fatal cases with coronavirus disease 2019 (COVID- 19) in Renmin Hospital of Wuhan University in China reported that 14 patients suffered from renal injury after the infection of SARS-CoV-2 in 92 deceased patients with COVID-19. AKI was determined based on levels of SCr, BUN, and GFR found in these 14 patients and compared with the cases without renal injury. The median levels of SCr, BUN, and GFR in cases with renal insufficiency were 262 µmol/L, 30 mmol/L, and 18 mL/min, respectively [83] . In a study performed with 138 patients with SARS-CoV-2 hospitalized in the ICU of Mount Sinai Hospital (New York, NY, USA), 49 cases of AKI, characterized by an increase in the SCr level from approximately 1.0 to 8.0 mg/dL, a rise in the BUN level from about 20 to 100 mg/dL, and an increase in the serum phosphorus level > 8 mg/dL, over three days, were diagnosed among patients with COVID-19 by the Nephrology Department of the hospital. The magnitude of the variance of renal function parameters depends on certain factors, such as age and pre-existing comorbidities. Based on the serum phosphorus level > 10 mg/dL and a parameter arbitrarily chosen, 9 of 49 patients were found with AKI, with a mean AKI duration before phosphorus levels reaching 10 mg/dL after six days. Among the 9 patients, 6 died, 2 recovered, and 1 experienced no change [16] .

In an attempt to obtain a definite conclusion on the association between AKI and the risk of mortality in patients with COVID-19, Yang et al. [83] performed a systematic review and meta-analysis study, in which a total of 24 studies published up to 26 April 2020 were evaluated, by searching the PubMed, Web of Science, and China National Knowledge Infrastructure databases, involving 4963 confirmed COVID-19 patients. The results showed that the incidence of AKI was 1.3%, 2.8%, and 36.4% in mild or moderate cases, severe cases, and critical cases, respectively. Meanwhile, the incidence of AKI was 52.9% and 0.7% in non-survivors and survivors, respectively [84] .

In a recent study based on the analysis of several clinical reports, Gagliardi et al. [85] related that up to 15% of the hospitalized COVID-19 patients had at least one kidney abnormality represented by increased BUN and reduced GFR, as well as 26-63% of patients presented proteinuria at admission or developed proteinuria during their stay in hospital. Moreover, the incidence of AKI in COVID-19 patients varied from 0.5% to 23%, with an interval from baseline visit to the onset of AKI of 7-15 days in median, and that mortality from the COVID-19 patients who developed AKI could be up to 13 times higher than those infected patients without clinical signs of AKI. In addition, the authors suggested that the high prevalence of kidney involvement at hospital admission of some COVID-19 patients may be associated with some factors, including report of previous renal impairments, patients' age, severity of illness, and presence of diabetes and/or heart failure, which are all risk factors for AKI that contribute to a pro-inflammatory state with functional defects in their immune system, worsening the clinical conditions of COVID-19 patients [85] .

It should be noted that, in spite of strong evidence of increasing kidney dysfunction caused by COVID-19 and of AKI being closely associated with the severity and prognosis of COVID-19 patients, the actual AKI incidence, in particular in ICUs, remains uncertain and may have been underestimated due to different causes, including the design of the studies, the lack of clear operational AKI definitions, the reported AKI stages, and the timeline of AKI onset incidences [4, 5, 8, 81, 82] .

Quercetin is a widespread flavonoid, more specifically a flavonol (3,5,7,3 ,4 -pentahydroxyflavone), with a broad range of pharmacological properties and is found in a large variety of medicinal plants and dietary supplements [17, 18] . Very diverse foods containing quercetin are present in oriental and occidental diets. Among food-based sources of quercetin are black and green teas, nuts, apples, grapes, berries, oranges, lettuces, potatoes, onions, and tomatoes. Quercetin is also available at the market and can be used in the isolated form [17, 18, 86, 87] .

Preliminary investigations on the pharmacokinetic properties of oral and intravenous quercetin, at dose levels varying from 8 to 2000 mg/m 2 , in humans have indicated that quercetin has a very poor oral bioavailability (~2%), with low oral absorption, ranging from 3% to 17%, distribution and volume of distribution of 0.7-7.8 min and 3.7 L/m 2 , respectively, and extensive metabolism and/or rapid elimination, as indicated by clearance of 0.23-0.84 L/min/m 2 and elimination half-life of 3.8-86 min [86] [87] [88] [89] [90] . In addition, the reported Cmax and Tmax of quercetin are 2.3 ± 1.5 µg/mL and 0.7 ± 0.3 h, respectively [89] . The low bioavailability of quercetin has limited its oral use in experimental and pharmaceutical studies. Consequently, parenteral routes of administration have been commonly used to investigate the biological properties of quercetin [86, 87] . However, conjugated forms of quercetin's glycosides (with different sugar types and sugar group conjugation sites or pharmaceutical formulations in which it is associated with materials that enhance the solubility and/or dissolution rate of lipophilic drugs in aqueous media such as cyclodextrin) have shown improved bioavailability and are frequently used to evaluate pharmacological activities of oral quercetin [88, 89] . Previous studies have indicated that quercetin's safety dose is about 1000 mg/m 2 and its main toxicological effects are emesis, hypertension, and hypokalemia [90] .

In recent years, diverse pharmacological properties have been attributed to quercetin, such as cardioprotection in spontaneous and experimentally induced hypertension, inhibition of secondary biliary cirrhosis, prevention of platelet aggregation, as well as antiangiogenic, anticancer, antiallergic, antiulcer and anti-inflammatory properties [17, 18, 86, [91] [92] [93] [94] . In general, the majority of the beneficial effect of quercetin is associated with antioxidant effects mainly through free radical scavenging and metal chelation and anti-inflammatory properties through NF-κB inhibition [27, [95] [96] [97] .

In this context, quercetin has been extensively studied for essential pharmacological properties requested in the treatment of Covid-19 and coronavirus-induced organ injury, such as antiviral, anti-oxidative and anti-inflammatory activities [13, 15, 94] . Previous studies have reported that quercetin and quercetin-derived compounds, such as quercetin-3-β-galactoside, display potent inhibitory effect on 3C-like protease (3CL(pro)) of SARS-CoV and MERS-CoV, a vital enzyme for viral replication, leading to inhibition of both coronavirus replications [98, 99] .

Multiple studies in different cell types and in both animal and human models have supported the long-lasting anti-inflammatory properties of quercetin [17, 18, 94] . Briefly, in vitro studies have shown that quercetin inhibited both cyclooxygenase and lipoxygenase activities in guinea pig epithelial cells [100] , reduced mRNA levels and TNFα, IL-1α, and apoptotic neuronal cell death induced by microglial activation [100] as well as inhibiting TNF-α and IL-8 production induced by lipopolysaccharide (LPS) in macrophages and lung A549 cells, respectively [101] . In rat liver epithelial cells, quercetin promoted the inhibition of arsenite-induced COX-2 expression mainly by blocking the activation of the PI3K signaling pathway [102] . It also inhibited Src-and Syk-mediated PI3K-(p85) tyrosine phosphorylation and subsequent TLR4/MyD88/PI3K complex formation that limits the activation of downstream signaling pathways in RAW 264.7 cells [103] . Quercetin inhibited the IL-1-induced IL-6 secretion in mast cells [104] . Other anti-inflammatory mechanisms, such as downregulation of MMP-1, VCAM-1, and CD80 expression produced by quercetin, were observed in human umbilical skin and vein endothelial cells [101] . Various animal experiments have supported the in vitro anti-inflammatory properties of quercetin. Studies using rodents showed a modulation of prostanoid synthesis and cytokine production promoted by quercetin. Stewart et al. [104] showed that quercetin caused a decrease in interferon-γ, interleukin-1α, and interleukin-4 from C57BL/6J mice, corroborating with the inhibition of macrophage-derived cytokines and nitric oxide produced by quercetin in Lewis rats previously reported [95] . In humans, the anti-inflammatory effect of quercetin remains not fully consistent with results from cell (in vitro) and animal (in vivo) studies [87] . According to data of studies with humans, the anti-inflammatory properties of quercetin appear to be dependent on the type of subject and their level of health. For example, it was observed that there was no significant anti-inflammatory effect promoted by quercetin in cyclists after intense exercise [105] , whereas quercetin treatment promoted anti-inflammatory effects, evidenced by a decrease in nitric oxide, C-reactive protein, and γ-glutamyl transferase activity in elderly human subjects [106] . Thus, the outcomes in humans need to be carefully evaluated and further investigation must be done in order to support the results of tests in cells and animals aiming at a broad application in the future.

Polyphenolic compounds, such as the flavonoids, commonly show antioxidant properties due to the presence of phenolic rings that promote the electron donation and hydrogen atom transfer to free radicals, acting as free-radical scavengers, reducing agents, and quenchers of single oxygen formation [93, 107] . The antioxidant properties of quercetin have been strongly evidenced in studies using cells and animals. Quercetin (10 µmol/L) inhibited oxidative stress promoted by H 2 O 2 in HepG2 cells [108, 109] . Chen et al. [109] reported that quercetin decreased apoptosis and ROS production and increased SOD levels in intestinal porcine enterocyte cells [109] . In addition, Meng et al. [110] showed that quercetin produced an increase in SOD, CAT, and glutathione peroxidase (GSH-Px) levels accompanied by a decrease in lipid peroxidation in rats subjected to experimental sepsis and chronic prostatitis/chronic pelvic pain syndrome [111] .

In addition to the antiviral, anti-inflammatory and antioxidant actions of quercetin, some mechanisms of quercetin's action on the regulation of ion transporters and channels are important for understanding vasodilation and the increase in blood flow involved in protective properties of quercetin against organ injury [112] . It has been demonstrated that quercetin activates Na + -K + -2Cl − cotransporter 1 (NKCC1) that leads to elevation of the cytosolic Cl − concentration ([Cl − ]c), which in turn downregulates gene expression of ENaC and decreases Na + , K + -ATPase activity [113, 114] . These actions contribute to the reduction in vascular contraction and the renal Na+ reabsorption that explain, at least in part, the effects of quercetin on the regulation of blood pressure and renal function [17, 115] .

Over the last few years, the renoprotective effect of quercetin has been tested in a wide range of experimental models of AKI [20, 46, 53, 116] . In general, the studies have shown that quercetin treatment, at doses varying from 1 to 100 mg/kg, promotes significant nephroprotective activity, evidenced by inhibition or attenuation of the increase in classical biomarkers of AKI in renal injuries of toxic, obstructive, and inflammatory origins [20, 94, 115, 116] . As shown in Table 1 , several studies using AKI models created for several nephrotoxic compounds, including cisplatin [24, 117] , methotrexate [118, 119] , contrast [120] , NaF [121] , HgCl2 [122] , manganese [123] , cadmium [124] , and ciprofloxacin [29] , showed that pretreatment with quercetin orally avoided an increase in BUN and SCr and a lower decrease in the GFR of animals that received a high dose of a nephrotoxic agent. Similarly, quercetin treatment improved renal function, evidenced by lessened renal pathologies, and lowered BUN and SCr levels, and histological integrity has been reported in an experimental model of renal ischemia and reperfusion (I/R) injury and sepsis-induced AKI, the most common causes of AKI in ICUs worldwide [21, 53, 115] . Gholampour and Sadidi [125] related that oral treatment with quercetin inhibited kidney dysfunction, characterized by a significant decrease in creatinine clearance and histological damages in the I/R-induced AKI, by clamping renal arteries for 45 min followed by 24 h reperfusion [125] . Previously, Shoskes [21] had reported the renoprotective properties of quercetin on ischemia/reperfusion in rats who underwent 30 min of left renal pedicle occlusion with simultaneous right nephrectomy [21] .

The nephroprotective effects of quercetin appear to be directly associated with the reduction of oxidative stress [53, 94] . The improvement of renal function promoted by quercetin treatment is accompanied by control of the oxidant-antioxidant balance [26, 94] . Data from various studies with different nephrotoxic origins have shown that quercetin inhibits a decrease in glutathione peroxidase, superoxide dismutase, and catalase activities and an increase in malondialdehyde levels (lipid peroxidation) in AKI caused by toxins or drugs, ischemia/reperfusion, and sepsis [25, 26, [125] [126] [127] .

Another very important feature of the mechanism underlying the renoprotective property of quercetin has been attributed to its actions on different targets of inflammatory response involved in the genesis and progression of renal injuries [53, 87, 92] . Pretreatment with quercetin significantly inhibited TNF-α, IL-1β, and IL-6 production in mice with LPS-induced AKI [128, 129] . In addition, quercetin also significantly inhibited TLR4, MyD88, and TRAF-6 expressions and NF-κBp65 activation in the kidneys of rats with LPS challenge [23, 128] . Shu et al. [130] showed that quercetin blocked CD38, possessing ADP-ribosyl cyclase (ADPR-cyclase) and cyclic ADP-ribose hydrolase (cADPR-hydrolase), in a mouse model with LPS-induced AKI [130] . In addition, quercetin treatment promoted a decrease in the renal levels of iNOS and IL-12 and the excessive accumulation of extracellular matrix and interstitial fibrosis by antagonizing NF-κB signaling activation and TGF-β1/Smad2/3 signaling [29] . It was also observed that quercetin increased AMPK phosphorylation, inhibited mTOR phosphorylation, and activated autophagy observed in the kidneys of I/R mice, suggesting that quercetin might protect the kidney against the ischemic process by activating the AMPK-regulated autophagy signaling pathway [131] .

Data from animal models of AKI and human biopsies have shown that macrophage is a major contributor to the inflammatory response to AKI. There are growing sources of evidence that quercetin ameliorates kidney injury via modulating macrophage polarization, which appears to be associated with downregulated activities of NF-κB p65 and IRF5, as well as by inhibiting ASK1/JNK3/caspase-3 by enhancing the Akt signaling pathway [28, 132, 133] . Quercetin also inhibited the infiltration of CD68+ macrophages, the proportion of F4/80+/CD11b+/CD86+ macrophages, and the polarization of F4/80+/CD11b+/CD206+ M2 macrophages in cultured macrophages from kidneys and spleens in mice after LPS injection, indicating a quercetin-induced inhibitory effect on inflammatory macrophage polarization [100, 134, 135] . Recently, Tan et al. [24] showed that quercetin reduced inflammatory mediators in LPS-induced bone marrow-derived macrophages (BMDMs) and in a cisplatin-induced AKI model, which were accompanied by downregulation of protein levels of Mincle, phosphorylation of Syk and NF-κB in kidney macrophage I, and upregulation of M2 macrophage activity [24, 28] . 

Unilateral ureteral obstruction-induced renal fibrosis Anti-inflammatory Inhibited tubulointerstitial injury; Reduced the synthesis and release of inflammatory factors; Inhibited the infiltration of CD68+ macrophages in renal interstitium; Decreased levels of iNOS and IL-12, as well as the proportion of F4/80+/CD11b+/CD86+ macrophages; Inhibitory effects associated with downregulated activities of NF-κB p65 and IRF5, and thus led to the inactivation of upstream signaling TLR4/Myd88; Inhibited the polarization of F4/80+/CD11b+/CD206+ M2 macrophages; Reduced excessive accumulation of extracellular matrix and interstitial fibrosis by antagonizing the TGF-β1/Smad2/3 signaling.

[28]

Fe-NTA-Induced AKI Renoprotective Decreased the BUN and SCr; Preserved the normal renal morphology; [126] Antioxidant Reduced the lipid peroxidation; Restored the depleted renal antioxidant enzymes, such as glutathione reductase, catalase, superoxide dismutase, and glutathione.

Reduced of BUN, SCr and uric acid levels; Protected against the Cd-induced pathological condition, as tubular necrosis, degeneration, desquamation, thickening of basement membrane and luminal cast formation; [124] Antioxidant Decreased the renal lipid peroxidation; Increased total sulfhydryl group, glutathione, vitamin C and vitamin E, and antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, and glucose 6-phosphate dehydrogenase.

Reduced the elevated levels of serum uric acid, BUN, and SCr; [20] Antioxidant Increased the superoxide dismutase activity.

Increased superoxide dismutase, glutathione, and catalase levels. [121] Methotrexate-induced AKI Renoprotective Reduced the renal tubular degeneration and dilation; [118, 119] Antioxidant Decreased the number of apoptotic cells and caspase-3 expression; Decreased the malondialdehyde levels; Increased superoxide dismutase, glutathione peroxidase, and catalase levels; Lowered apoptotic index.

Decreased the renal accumulation of Hg in the kidney; Reduced urinary excretion of protein-based biomarkers, including clusterin, KIM-1, NGAL, MCP-1, TIMP-1, and VEGF; Protected against renal proximal tubular damage; Reduced apoptotic cell death in the kidney.

[122]

Valproic acid-induced AKI Antioxidant

Decreased the lipid peroxidation and protein carbonyl; Reduced glutathione and nonprotein thiol levels.

[25]

Ciprofloxacin-induced AKI Renoprotective

Reduced the tubular infiltration, dilatation, and atrophy as well as the Bowman's space, congestion, hemorrhage, and necrosis; [29] Antioxidant Decreased the malondialdehyde levels; Increased the superoxide dismutase and catalase activities.

Counteracted Mn-induced morphological glomerular damage; Decreased the expression of GRP78, CHOP, and caspase-3 proteins.

[123] 

Inhibited the increase in SCr and albuminuria accompanied by a lower decrease in the GFR.

[120]

Relieved kidney dysfunction; Decreased the histopathological damage; Lowered the BUN and SCr levels.

Reduced the inflammatory cell accumulation; [24, 130] Anti-inflammatory

Inhibited the Toll-like receptor-4, MyD88, and TRAF-6 expressions and NF-κBp65 activation in the kidneys; Inhibited the TNF-α, IL-1β, and IL-6 levels;

Blockaded the CD38 expression of the macrophages possessing ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase; Inhibited the LPS-induced macrophage M1 polarization accompanied by diminished NF-κB signaling activation.

Quercetin is a safe widespread flavonoid, found in many medicinal plants and dietary supplements, that presents a broad range of biological effects in cells and animals [100] . Over the last few years, numerous studies have shown a significant renoprotective effect of quercetin against kidney injury induced by different nephrotoxic agents (see Table 1 ). As outlined above, quercetin showed nephroprotective effects against kidney injury directly associated with oxidative stress and inflammatory response, which lead, respectively, to the rise in renal levels of ROS/RNS and the massive release of inflammatory mediators, in very diverse animal models of AKI [17, 56, 87] . Quercetin was effective in blocking or attenuating kidney lesions and dysfunctions caused by sepsis, diabetic nephropathy, ischemia/reperfusion as well as renal damage induced by varied nephrotoxic substances [26, 27, 29, 115] . In general, the renoprotective effect of quercetin is associated with antioxidant effects mainly through free radical scavenging and metal chelation [93] , and anti-inflammatory properties by modulating macrophage polarization, via downregulated activities of NF-κB p65 and IRF5 [23, 24] .

We can take into account the following facts: the frequent onset of AKI in patients with SARS-CoV-2 represents a life-threatening complication and increased risk of death [4] [5] [6] [7] [8] [9] ; the unavailability of a specific treatment for COVID-19 and its clinical complications [1] [2] [3] ; and experimental evidence of the renoprotective properties of quercetin [23] [24] [25] [26] [27] [28] . The underlying mechanisms by which quercetin promotes renoprotection act directly on important mediators of the pathophysiology of coronavirus-induced AKI [117, 118, 126, 128, 129] (see . Taken all together, it is plausible to consider quercetin as a promising drug to be tested against COVID-19-induced AKI in clinical trials.

Even though the results suggest that quercetin exhibited renoprotection, anti-inflammation, and antioxidant in vitro (cells) and in vivo (animals) activities, it often happens that studies in humans do not totally support the results from tests in cells and animals [100] . Thus, some relevant factors related to both clinical trials and quercetin need to be further verified for a future broad application in humans. For example, the type of subject, their level of health, illness severity, and presence of comorbidities are some of factors that might affect the results and should be considered by physicians and researchers [85] . Moreover, route of administration, formulation, and toxicity are parameters linked to pharmacological properties of quercetin that must also be evaluated beforehand [86] [87] [88] [89] . Many features of quercetin that may alter the extrapolation of experimental results to clinical trials have already been minimized, such as the association of quercetin with cyclodextrins to the formulation of the inclusion complexes that improve its aqueous solubility and dissolution rate, increasing the bioavailability and the oral use of quercetin [89] . The choice of therapeutic dose could be based on preliminary findings of quercetin's safety dose of 945 mg/m 2 and the effective dose of quercetin used in previous studies in humans [87, 88] .

In conclusion, the present review provides scientific evidence that supports the use of quercetin as a useful tool for the treatment of renal function impairment, to avoid the worsening of the clinical condition and, consequently, the short-and long-term morbidity and deaths of patients infected with SARS-COV-2 (see Figure 1 ). not totally support the results from tests in cells and animals [100] . Thus, some relevant factors related to both clinical trials and quercetin need to be further verified for a future broad application in humans. For example, the type of subject, their level of health, illness severity, and presence of comorbidities are some of factors that might affect the results and should be considered by physicians and researchers [85] . Moreover, route of administration, formulation, and toxicity are parameters linked to pharmacological properties of quercetin that must also be evaluated beforehand [86] [87] [88] [89] .

Many features of quercetin that may alter the extrapolation of experimental results to clinical trials have already been minimized, such as the association of quercetin with cyclodextrins to the formulation of the inclusion complexes that improve its aqueous solubility and dissolution rate, increasing the bioavailability and the oral use of quercetin [89] . The choice of therapeutic dose could be based on preliminary findings of quercetin's safety dose of 945 mg/m 2 and the effective dose of quercetin used in previous studies in humans [87, 88] .

In conclusion, the present review provides scientific evidence that supports the use of quercetin as a useful tool for the treatment of renal function impairment, to avoid the worsening of the clinical condition and, consequently, the short-and long-term morbidity and deaths of patients infected with SARS-COV-2 (see Figure 1 ). Funding: This research was supported by the National Council for Scientific and Technological Development (CNPq) and the Coordination for the Improvement of Higher Education Personnel (CAPES).

The authors declare no conflict of interest. 

Excess mortality: The gold standard in measuring the impact of COVID-19 worldwide?

Mortality in COVID-19 is not merely a question of resource availability

COVID-19 mortality and health-care resources: Organization

Disease progression patterns and risk factors associated with mortality in deceased patients with COVID-19 in Hubei Province

Risk Factors Associated with Mortality Among Patients With COVID-19 in Intensive Care Units in

Multiorgan Failure with Emphasis on Acute Kidney Injury and Severity of COVID-19: Systematic Review and Meta-Analysis

Kidney disease and electrolytes in COVID-19: More than meets the eye

Mortality rate of acute kidney injury in SARS, MERS, and COVID-19 infection: A systematic review and meta-analysis

Acute Kidney Injury is Associated with Worse Prognosis in COVID-19 Patients: A systematic Review and Meta-analysis

COVID-19 and Kidney Failure in the Acute Care Setting: Our Experience from Seattle

Kidney Injury in COVID-19: An Emerging Concern to the Clinician. SN Compr

COVID-19 and the kidney: A matter of concern

Recent progress and challenges in drug development against COVID-19 coronavirus (SARS-CoV-2)-an update on the status

Recent Insight into SARS-CoV2 Immunopathology and Rationale for Potential Treatment and Preventive Strategies in COVID-19. Vaccines 2020, 8, 224

Recent Advancements in the Diagnosis, Prevention, and Prospective Drug Therapy of COVID-19

COVID-19-Associated Acute Kidney Injury: A Case Series

The Pharmacological Activity, Biochemical Properties, and Pharmacokinetics of the Major Natural Polyphenolic Flavonoid: Quercetin. Foods 2020

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Natural Antioxidants: A Review of Studies on Human and Animal Coronavirus

Preventive and therapeutic effects of quercetin on hyperuricemia and renal injury in rats

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Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation

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Beneficial effects of quercetin on renal injury and oxidative stress caused by ciprofloxacin in rats: A histological and biochemical study

Acute kidney injury: Current concepts and new insights

AKI patients have worse long-term outcomes, especially in the immediate post-ICU period

AKI in the ICU: Definition, epidemiology, risk stratification, and outcomes

Epidemiology of acute kidney injury in critically ill patients: The multinational AKI-EPI study

Impact of acute kidney injury on distant organ function: Recent findings and potential therapeutic targets

Acute Kidney Injury and Progression of Diabetic Kidney Disease

ICU survival and need of renal replacement therapy with respect to AKI duration in critically ill patients

Preventing acute kidney injury and improving outcome in critically ill patients utilizing risk prediction score (PRAIOC-RISKS) study. A prospective controlled trial of AKI prevention

Incidence, timing and outcome of AKI in critically ill patients varies with the definition used and the addition of urine output criteria

Risk Factors for Recurrent Acute Kidney Injury in a Large Population-Based Cohort

Hypertension in patients with acute kidney injury

Acute kidney injury from sepsis: Current concepts, epidemiology, pathophysiology, prevention and treatment

Acute kidney injury in patients with severe sepsis or septic shock: A comparison between the 'Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease' (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease: Improving Global Outcomes (KDIGO) classifications. Clin. Kidney

Evaluation of acute kidney injury (AKI) with RIFLE, AKIN, CK, and KDIGO in critically ill trauma patients

Biomarkers in acute kidney injury (AKI)

Comparison of RIFLE, AKIN, and KDIGO classifications for assessing prognosis of patients on extracorporeal membrane oxygenation

Acute kidney injury prediction models: Current concepts and future strategies

AKI biomarkers are poor discriminants for subsequent need for renal replacement therapy, but do not disqualify them yet

Biomarkers and predicting acute kidney injury

New biomarkers in the diagnostics of acute kidney injury (AKI) following invasive cardiology procedures

Biomarkers of acute kidney injury: Mixed results and huge heterogeneity of reporting

Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) and proteinuria predict severity of acute kidney injury in Puumala virus infection

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

Mechanisms and therapeutic targets of ischemic acute kidney injury

Cellular and Molecular Mechanisms of AKI

Ischemic Duration and Frequency Determines AKI-to-CKD Progression Monitored by Dynamic Changes of Tubular Biomarkers in IRI Mice

Infection-Induced Kidney Diseases

Acute kidney injury in patients with human immunodeficiency virus infection

Acute kidney injury in symptomatic primary Epstein-Barr virus infectious mononucleosis: Systematic review

Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy

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Acute Kidney Injury in Patients Undergoing Chronic Hepatitis C Virus Treatment With Ledipasvir/Sofosbuvir

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Acute kidney injury in patients with hemorrhagic fever with renal syndrome caused by Hantaan virus: Comparative evaluation by RIFLE and AKIN criteria. Vector Borne Zoonotic Dis

The degree of leukocytosis and urine GATA-3 mRNA levels are risk factors for severe acute kidney injury in Puumala virus nephropathia epidemica

Dialysis-requiring acute kidney injury among hospitalized adults with documented hepatitis C Virus infection: A nationwide inpatient sample analysis

Glomerular Diseases Associated With Hepatitis B and C. Adv. Chronic Kidney Dis

Hepatitis C virus-related glomerulonephritis with acute kidney injury requiring hemodialysis that improved with virus removal and eradication using double-filtration plasmapheresis without interferon

Infection-related glomerulonephritis: Understanding mechanisms

Membranoproliferative glomerulonephritis and interstitial nephritis in the setting of Epstein-Barr virus-related hemophagocytic syndrome

Characteristics of acute kidney injury in patients infected with the 2009 influenza A (H1N1) virus

Influenza A (H1N1) Virus Infection Associated Acute Kidney Injury-A Study from a Tertiary Care Center in South India

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Acute kidney injury and inflammatory immune reconstitution syndrome in mixed genotype (A/E) hepatitis B virus co-infection in HIV-associated lymphoma

Incidence and predictors of acute kidney injury in an urban cohort of subjects with HIV and hepatitis C virus coinfection

Acute kidney injury in patients with human immunodeficiency virus infection

Incidence of Acute Kidney Injury in Patients Coinfected with HIV and Hepatitis C Virus Receiving Tenofovir Disoproxil Fumarate and Ledipasvir

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Severe Acute Kidney Injury in COVID-19 Patients with Acute Respiratory Distress Syndrome

Acute kidney injury in critically ill patients with COVID-19

Analysis of 92 deceased patients with COVID-19

Prevalence and impact of acute renal impairment on COVID-19: A systematic review and meta-analysis

COVID-19 and the Kidney: From Epidemiology to Clinical Practice

Quercetin and its derivatives: Synthesis, pharmacological uses with special emphasis on anti-tumor properties and prodrug with enhanced bio-availability

Toxicity and carcinogenicity studies of quercetin, a natural component of foods

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Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man

The antioxidative and antihistaminic properties of quercetin in ethanol-induced gastric lesions

Molecular targets of quercetin with anti-inflammatory properties in atopic dermatitis

The Bioactive Potential of Functional Products and Bioavailability of Phenolic Compounds

Antioxidant properties of quercetin

Therapeutic and preventive properties of quercetin in experimental arthritis correlate with decreased macrophage inflammatory mediators

Lipid antioxidant properties of quercetin in vitro

Synthesis and antiviral evaluation of 7-O-arylmethylquercetin derivatives against SARS-associated coronavirus (SCV) and hepatitis C virus (HCV)

Antiviral activity of quercetin 7-rhamnoside against porcine epidemic diarrhea virus

Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs

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Protective effect of quercetin against arsenite-induced COX-2 expression by targeting PI3K in rat liver epithelial cells

Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-kappaB-induced inflammatory mediators production in RAW 264.7 cells

Regulation of IL-1-induced selective IL-6 release from human mast cells and inhibition by quercetin

Quercetin transiently increases energy expenditure but persistently decreases circulating markers of inflammation in C57BL/6J mice fed a high-fat diet

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Suppression of Nitric Oxide Production and Cardiovascular Risk Factors in Healthy Seniors and Hypercholesterolemic Subjects by a Combination of Polyphenols and Vitamins

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Effects of Quercetin on Proliferation and H 2 O 2 -Induced Apoptosis of Intestinal Porcine Enterocyte Cells

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The effect of quercetin on renal ischemia and reperfusion injury in the rat

Differential effect of quercetin on cisplatin-induced toxicity in kidney and tumor tissues

Effects of quercetin on methotrexate-induced nephrotoxicity in rats

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Protective Effects of Quercetin Against HgCl(2)-Induced Nephrotoxicity in Sprague-Dawley Rats

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Effects of quercetin on apoptosis, NF-kappaB and NOS gene expression in renal ischemia/reperfusion injury

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The Risk of Acute Kidney Injury in Hepatitis B Virus-Related Acute on Chronic Liver Failure with Tenofovir Treatment

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