key: cord-283366-xwxg9991
authors: He, Tian; Qu, Rendong; Qin, Caimeng; WANG, Zheyi; Zhang, Yue; Shao, Xiangming; Lu, Tao
title: Potential mechanisms of Chinese Herbal Medicine that implicated in the treatment of COVID-19 related renal injury
date: 2020-08-10
journal: Saudi Pharm J
DOI: 10.1016/j.jsps.2020.08.002
sha: 
doc_id: 283366
cord_uid: xwxg9991

Clinical studies have shown that renal injury in Corona Virus Disease 2019 (COVID-19) patients has been a real concern, which is associated with high mortality and an inflammation/apoptosis-related causality. Effective target therapy for renal injury has yet been developed. Besides, potential anti-COVID-19 medicines have also been reported to cause adverse side effects to kidney. Chinese Herbal Medicine (CHM), however, has rich experience in treating renal injury and has successfully applied in China in the battle of COVID-19. Nevertheless, the molecular mechanisms of CHM treatment are still unclear. In this study, we searched prescriptions in the treatment of renal injury extensively and the potential mechanisms to treat COVID-19 related renal injury were investigated. The association rules analysis showed that the core herbs includes Huang Qi, Fu Ling, Bai Zhu, Di Huang, Shan Yao. TCM herbs regulate core pathways, such as AGE-RAGE, PI3K-AKT, TNF and apoptosis pathway, etc. The ingredients (quercetin, formononetin, kaempferol, etc.,) from core herbs could modulate targets (PTGS2 (COX2), PTGS1 (COX1), IL6, CASP3, NOS2, and TNF, etc.), and thereby prevent the pharmacological and non-pharmacological renal injury comparable to that from COVID-19 infection. This study provides therapeutic potentials of CHM to combat COVID-19 related renal injury to reduce complications and mortality.

The outbreak of COVID-19 has quickly developed to a pandemic, bringing a severe challenge to global health. It has been confirmed that the angiotensinconverting enzyme II (ACE2) is the receptor for new coronavirus to enter cells , same as SARS-CoV . Several studies showed that ACE2 was highly expressed in the kidney, suggesting that the kidney may be one of the potential targets of COVID-19 . Recently, the "Novel Coronavirus Pneumonia Diagnosis and Treatment Scheme (Trial Edition 7)" issued by the National Health Commission (NHC) of China (National Health Commission) suggested that the COVID-19 patients were found generally to have protein exudates in the glomerular balloon lumen. Pathological anatomy characteristics, such as tubular epithelial cells degeneration and shedding, hyaline casts, renal interstitial congestion, microthrombi and focal fibrosis, were also observed in autopsy. In addition, we reviewed the current clinical reports of COVID-19 and revealed that a remarkable fraction of patients had signs of kidney dysfunctions, including 59% with proteinuria, 44% with hematuria, 14% with increased levels of blood urea nitrogen, and 10% with increased levels of serum creatinine, although mild but worse than that in cases with other pneumonia . For patients with mild condition, 3-10.8% had elevated blood urea nitrogen and creatinine . For patients at critically stage, acute renal injury accounted for 29%, which was higher than cardiac injury (23%) . Moreover, in a study of 82 deaths, renal injury accounted for up to 31.7% .

Renal injury after coronavirus infection was common. A review of clinical studies of SARS found that although the overall proportion of patients with acute renal injury was 6.7%, the mortality rate of patients with acute renal injury was as high as 92% (Chu et al., 2005) . In addition, renal injury was also common during MERS infection, and the mortality rate accompanied with renal injury was 67% (Zumla et al., 2015) . In an in vitro experiment, it was shown that renal epithelial cells were more susceptible to MERS virus invasion than bronchial epithelial cells (Eckerle et al., 2013) , while in pathological examination, high viral loads were detected in the renal tissue of SARS patients (Gu and Korteweg, 2007) . There is evidence that the pathology and pathogenesis of COVID-19 coincides with MERS and SARS . These results indicate that development of acute kidney injury in patients with COVID-19 might be a crucial negative prognostic factor for survival . COVID-19 related renal injury includes the renal injuries during disease progression or from clinical treatments. There are three possible mechanisms of renal injury after COVID-19 infection: direct viral mediated, prolonged cytokine storm mediated, and drug-induced renal injury. ACE2, the receptor of COVID-19, is highly expressed in tubular cells; and the acute tubular necrosis was predominant in renal injury in SARS and MERS patients )Zumla et al., 2015 . In addition, several clinical reports Xu et al., 2020) have documented that patients with renal injury from COVID-19 infection have a higher systemic immune-inflammatory index. The release of a large number of proinflammatory cytokines can cause damage to kidney. Conventional treatment for COVID-19 pneumonia included antivirals and antimicrobials. Notably, the potential anti-COVID-19 drugs, ribavirin and ritonavir, have been shown to cause adverse effects of renal impairment in the treatment of COVID-19 Cao et al., 2020) .

For the treatment of renal injury, Western medicine routinely uses CRRT for supportive measure, and there is no targeted drug therapy (Bellomo and Kellum; 2012Zuk and Bonventre, 2016) . However, the relevant reviews or medical records of Chinese Herbal Medicine (CHM) for the treatment of renal injury dated back to 2000 before, and many valuable experiences have been accumulated in this area. Therefore, CHM has certain advantages in the treatment of renal injury, and it is of particular importance to clarify its mechanisms of action in both traditional medicine and modern medicine. As regarding to COVID-19, a recent study found that CHM combined with antiviral medicine can prevent renal injury in patients with COVID-19 (Zheng et al., 2020) ; In this study, the feasibility and mechanism of CHM for preventing the renal injury that associated with COVID-19 is investigated based on the association rule analysis and network pharmacology. 

The whole workflow was illustrated in Fig. 1. 

CHM treatment has special advantages in the prevention and treatment of renal injury. We collected and summarized prescriptions with clear and definite reports on the clinical treatment of renal injury in CHM.

Prescriptions for the treatment of renal injury in CHM clinical reports retrieved from databases such as CNKI (https://www.cnki.net/), VIP (http://www.cqvip.com/), and Wanfang (http://c.wanfangdata.com.cn/periodical), as well as empirical monographs about the treatment of renal injury by related distinguished veteran CHM practitioners were included.

The primary keywords of the search were "renal injury", and the secondary keywords were "immune function", "inflammation", "drug-induced", "proteinuria", "clinical", "renal failure", and "renal insufficiency".

Prescriptions with reports in the clinical treatment of renal injury were included, e.g. clinical trials, case reports, and expert experience.

Prescriptions with identical ingredients or causing kidney damage were excluded.

Renal diseases unrelated to drug-induced, immunogenic and virus-induced renal injury, including renal calculi, congenital renal diseases, renal tumors, renal cysts and renal artery stenosis, were all excluded.

Herb names were normalized with reference to "Chinese Pharmacopoeia (2015 Edition)" (2015 Edition). standardized prescriptions were entered into Microsoft Excel.

The source and composition of prescriptions were recorded, and consistency checkout and correction after information entry were conducted, so as to ensure the accuracy of data.

R software (V3.6.1) was used to quantify the CHM fields using binary values. The occurrence of CHM was assigned a value of 1 and the absence was assigned a value of 0, and frequency statistics on the CHM were performed among all the prescription herbs recorded. Further analysis was performed by the association rules Apriori algorithm. Setting support ≥ 1%, confidence ≥ 50%, lift ≥ 1 and the number of anterior items ≤ 3 were used as mining conditions, and the association rule results were statistically analyzed. The visual association network was displayed for the CHM herbs with higher strength of association. The circle size indicated the degree of support; the larger the circle, the more chance the two herbs co-occurred. The color depth indicated the degree of improvement; the darker the color, the stronger the association between the two herbs.

The main active ingredients of the core herbs were searched using the Chinese and the obtained target information was normalized using the Uniport database to obtain the gene number of the key target corresponding to the ingredients in the core herbs.

Genes related to renal injury were obtained by searching with the keywords "renal injury" and "kidney injury" using the GeneCards database (https://www.genecards.org/) and NCBI database (https://www.ncbi.nlm.nih.gov/). The species was selected as "Homo sapiens", and the related genes of COVID-19 were retrieved using the keyword "Novel coronavirus". Renal injury targets were mapped to those of COVID-19 using Venny plotting software (V2.1) to obtain potential targets of renal injury after COVID-19 infection. The predicted targets of the herbs were mapped with the targets of the disease to obtain the potential targets of the core herbs of CHM for the treatment of renal injury.

Cytoscape software (V3.7.2) was used to visually analyze the network pharmacology of all active ingredients and the potential targets of the core herbs of CHM for the treatment of renal injury, further to show the correlation and to analyze the number of targets of each active ingredient as well as the frequency of each target being acted by the active ingredient.

The potential targets of CHM core herbs for the treatment of renal injury were used to construct a target protein interaction (PPI) network through the STRING database.

The position and role of targets with high frequency of action of active components in protein networks were further studied.

The core target genes were subjected to functional enrichment and major action pathway analysis, GO (Gene Ontology) enrichment and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis were conducted at P < 0.01 using the Bioconductor bioinformatics package. Enrichment analysis results were then visualized to reveal the possible mechanism of CHM in the treatment of renal injury.

A total of 207 prescriptions related to the treatment of renal injury were collected.

Through statistical analysis of frequency of the herbs in all the prescriptions recorded, it was concluded that the herbs with the highest frequency were Radix Astragali In order to clarify the mechanism of action of the core herb combination and to further explore the key components for the efficacy, the ingredients from the five core herbs with DL > 0.18 and OB > 0.3 were obtained. To simplify the nomenclature of ingredients, their MOL IDs were obtained from TCMSP instead of ingredient names, and a total of 411 targets of the core herbs were further obtained.

To investigate the potential targets of core herbs that might be applied to the treatment of renal injury after COVID-19 infection, renal injury and COVID-19 related targets were collected and collated, and duplicate targets were eliminated, 8044 and 348 targets were included, respectively. Venny 2.1 mapping software was used to take the intersection of the targets regulated by the main active ingredients of five core herbs with the targets of COVID-19 and renal injury; and 60 targets were obtained.

The core herbs may act on those targets to prevent and to treat renal injury after COVID-19 infection. It is worth noting that the intersected targets of the core herbs and COVID-19 can all act the targets of renal injury. (Fig. 4 ) Fig. 4 . Potential targets of core herbs in the treatment of renal injury related to COVID-19.

The total of renal injury targets is 8044, COVID-19 targets is 348, and core herbs targets is 411, individually; and their intersected targets is 60.

In order to explore the frequency of 60 targets related to renal injury after COVID-19 infection that core herbs may act on, potential core targets and herbs were screened;

and herbs-ingredients-targets were further analyzed by network analysis. (Fig. 5 ) Active ingredients that could act on targets associated with renal injury after Statistical analysis of the number of times that each target was associated showed that PTGS2 (COX2), PTGS1 (COX1), NOS2, PPARG, and RELA were the most frequently associated targets, which were mainly associated with inflammation, oxidative stress, and apoptosis. Further, they may be the potential core targets of CHM in the treatment of renal injury after COVID-19 infection. (Fig. 6 ) Among them, PTGS2 or COX2 showed significantly higher frequency of association than other targets, which is an important factor in the inflammatory process.

COX2 can be activated by TNF-α or NK-κB to promote IL6 production via activating PGE2, which in turn mediates a variety of inflammatory responses (Chen et al., 2013; Basudhar et al., 2017) .

To further investigate the importance of core targets in biological processes, 60 intersection genes obtaining from ingredients and disease mapping were subjected to PPI network analysis on the STRING platform. Where nodes represent proteins, each Through GO (Gene Ontology) biological process enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) signaling pathway enrichment analysis, the main pathways that the above CHM acts were obtained. It mainly acts on 100 biological process (P < 0.05) and 165 signaling pathways (P < 0.05). The results

showed that the biological processes or pathways such as cytokine receptor binding, cytokine activity, receptor ligand activity, phosphatase binding, protein phosphatase binding, AGE-RAGE signaling pathway, PI3K-AKT pathway, TNF pathway, IL17 pathway, MAPK pathway, and apoptosis pathway had high degree values, which may be the core mechanism to explain why the core herbs of CHM can be applied to the treatment of renal injury after COVID-19 infection. (Fig. 8) Osteoclast differentiation Combined with current clinical reports, the common causes of COVID-19-induced renal injury may be related to virus, immune system and drug, and its core mechanism is related to inflammation and apoptosis. The conventional treatment to renal injury is continuous renal replacement therapy (CRRT), which is only suitable for supportive treatment of critically ill patients, and there is still no effective treatment strategy. CHM provides good methods and experiences in dealing with renal injury, while its mechanism has not been clarified.

In the theory of CHM, the principle of "mother-child relationship" from five-element theory is often practiced in Chinese Herbal Medicine; the lung belongs to gold, the kidney belongs to water, and gold (mother) generates water (child), so lung disease often causes renal injury. Luca Visconti et al (Visconti et al., 2016) . found that a variety of physiological processes depended on the co-regulation of the kidney and lung, and The ingredients of the core herbs were searched by database and visualized by the method of network pharmacology, and the core ingredients were selected, including quercetin, kaempferol, formononetin, isorhamnetin, astragaloside isoflavanthin, attractylone, diosgenin, stigmasterol, sitogluside, kadsurenone, and aesculin. Among them, the interaction between quercetin and the targets was found with the highest frequency, and it was found that quercetin could reduce the production of cytokines (IL-6, TNF-α, IL-1β, and cox-2), inhibit MAPKs and NF-κB signaling pathways, and then reduce inflammatory damage (Spagnuolo et al., 2018) . Besides, kaempferol helps to reduce the inflammatory response associated with COX2 expression (Kang et al., 2018) . In addition, astragaloside isoflavanthin can regulate the immune system and enhance the body's function of producing interferon (Yang et al., 2014) . Formononetin has pharmacological effects such as lowering blood pressure, regulating inflammatory responses and lipid metabolism .

Attractylone may inhibit apoptosis by regulating PI3K-AKT pathway and other mechanisms . Diosgenin can reduce apoptosis by regulating PI3K/Akt, ERK and JNK signaling pathways (Hsieh et al., 2017) . Furthermore, ingredients such as stigmasterol, sitogluside, kadsurenone, and aesculin also have anti-inflammatory, antioxidant, and inhibitory effects on apoptosis (Agatonovic-Kustrin et al., 2018; . The above ingredients may play the role of preventing renal injury by acting on multiple targets in oxidative stress, inflammation, or apoptotic pathways.

In order to determine the core targets, it was found that PTGS2, IL6, PTGS1, TNFα, NOS2, PPARG, and RELA, etc., may play an important role in the treatment of renal injury by CHM after COVID-19 infection by counting the frequency of active ingredients acting on different targets, as well as the interaction network between targets. Among them, PTGS2 and PTGS1, also known as COX2 and COX1, are the most frequently interacted targets by ingredients of core herbs. COX1/2 are often induced by various inflammatory stimuli and injurious factors, being one of the major pharmaceutical targets for anti-inflammatory medicine. COX1/2 can directly promote the production of IL6 via activating PGE2. IL6, the target with the highest degree value in PPI network, is a clinical warning indicator for critical illness according to the "China Novel Coronavirus Diagnosis and Treatment Scheme". Moreover, the core herbal targets (IL6, IL1A/B, IL2, etc.,) are key players in triggering inflammatory storm and subsequently exacerbating COVID-19 disease to critically ill stage. Inflammation storm attributes to renal damage as well. In addition, targets such as TNF-α, NOS2, PPARG, and RELA, are closely related to oxidative stress, inflammation, or apoptosis.

It is worth mentioning that active ingredients of CHM herbs have been screened out for their potential to interfere the binding of covid-19 to ACE2 (NIU et al., 2020); ACE2 was highlighted, as it was found high in kidney, which increases the risk for renal related complications in COVID-19 patients. However, the beneficial role of ACE2 could also protect patients from getting worse after infection. For instance, in mice model, infected with the SARS virus or treated with the SARS spike protein, the expression of ACE2 plays a protective role by cutting Ang II for avoidance of lung function failure happened Imai et al., 2005) . This complicated role of ACE2 gives ways to the major causes of renal injury that were found from our analysis, namely inflammation storm and anti-apoptosis. Based on the above analysis, the potential mechanisms of CHM that implicated in the treatment of COVID-19 related renal injury can be summarized. (Fig. 9 ). Furthermore, in order to clarify the directionality of interaction of core herbs with their core targets (COX1/2, IL6, TNF-α, CASP3, etc.,), we systematically assessed their relationships via literature searching. Consistent results were illustrated in Fig 9, where a few key players of inflammation storm were found being unanimously inhibited by one or more core of herbs. Inflammation and apoptosis and other immune regulation-related steps are mainly involved after making a general survey at the pharmacological effects of ingredients, classification of targets, biological processes and pathways. Studies have confirmed that CHM prescriptions and CHM monomers mainly protect the kidney and treat renal injury by reducing inflammation, inhibiting apoptosis, necrosis and inhibiting oxidative stress . Analysis of the pharmacological effects of the core herbs showed that Huang Qi is good at tonifying Qi and can play a therapeutic role in renal dysfunction and pathological changes through anti-oxidation . The main mechanisms of action include inhibiting the expression of TNF-α and COX2, relieving apoptosis and necrosis of renal cells (Fan et al., 2005) , inhibiting levels of interleukin to reduce renal inflammation , and reducing the possibility of microthrombosis by inhibiting MAPK pathways, which in turn protects the kidney . Besides, Huang Qi ameliorates renal fibrosis via the inhibition of CASP3 activation . In addition, studies have shown that astragalus can inhibit the expression of BAX protein in the kidney and has a protective effect on multiple organs (Fei et al., 2016) . Fu Ling has the effect of inducing diuresis to reduce edema, at the same time, Poria polysaccharide can improve human immune function and improve renal fibrosis by inhibiting MAPK pathway . Poria acid activates RAS/TGF-β/Smad axis in kidney cells and inhibits oxidative stress injury in the kidney (Ming et al., 2017) . Moreover, Bax and CASP3 expression was decreased by Fu Ling, resulting in anti-apoptotic effect to protect kidney (Lee et al., 2013 . At the same time, it can reduce the production of proinflammatory mediators NO, reduce the levels of TNF and IL, and then relieve the damage of renal cells (Ishii et al., 2020) . Meanwhile, it can reduce CASP3 activation and may enhance immunity (Guo et al., 2012) . Shan Yao has the effect of tonifying kidney, and it can inhibit the PI3K-Akt pathway, stimulate monocyte proliferation, upregulate SOD2, and then protect kidney cells . Study shows that Shan Yao can Alternatively, Shan Yao extract can reduce IL-1β, IL-6, and TNF-α levels to reduce renal inflammation (Qiao et al., 2019) . Di Huang is often used to treat kidney diseases. Acteoside, the main nature component of Di Huang, can inhibit the excessive release of proinflammatory cytokines, prevent the synthesis of TGF-β1, and reduce the inflammatory injury of renal cells by regulating the chemotaxis and proliferation of Th22 lymphocytes (Gan et al., 2018 In addition, for drug-induced renal injury, it has been shown that Huang Qi can protect against gentamicin-induced renal injury by inhibiting oxidative stress response and inflammatory factors . The triterpenoids extracted from Fu Ling have protective effects on cisplatin nephrotoxicity, and the mechanism is related to the anti-apoptotic activity of the ingredients (Lee et al., 2017) . Extracts of Shan Yao have protective effects on renal injury induced by non-steroidal anti-inflammatory drugs (NSAID) such as paracetamol. Pathological sections show that it can effectively inhibit the necrosis and disintegration of renal tubules (Lee et al., 2002) . Diosgenin in Shan

Yao can protect acetaminophen-induced liver injury from niacin induced renal injury by inhibiting inflammation and oxidative stress . Formononetin can prevent methotrexate-induced oxidative stress, inflammation, and renal injury in rats by upregulating the Nrf2/HO-1 signaling pathway (Huang et al., 2017) . In the "Novel

Coronavirus Pneumonia Diagnosis and Treatment Scheme (Trial Edition 7)", antiviral drugs as well as common antibacterial drugs are used for conventional medicine treatment, and most of them have adverse effects of renal impairment, or are contraindicated in patients with renal insufficiency, including remdesivir, lopinavir, ritonavir and ribavirin Grein et al., 2020; Han et al., 2020) . Antiviral drugs mainly lead to crystalline renal injury. The mechanisms of injury relate to damage to mitochondria, interference with tubular transport, and increase of oxidative stress (Pannu and Nadim, 2008; Douros et al., 2018) .

Furthermore, some of the core herbs, e.g. Huang Qi, Fu ling, Bai Zhu and Shan

Yao have been used in many TCM remedies for combating COVID-19, therefore, the beneficial effects from these core herbs are beyond their renal protection. Intriguingly, a clinical report of 98 patients who administered of "Qin-Fei-Pai-Du" decoction (QFPD), which encompassed 3 out of 5 our core herbs, reported an above 90% curative rate based on clinical lab results, with no death or deterioration to severe stage . Besides, a controlled clinical trial of 52 patients from Hubei Province found that compared with those treated Western Medicine (33.3%), patients treated with integrated Chinese Herbal and Western Medicine (including Bai Zhu, Fu Ling and Di

Huang) were less likely to deteriorate to severe stage and damage the kidney (5.9%) .

CHM protects the kidney through the mechanisms of anti-oxidation, inhibition of inflammation and apoptosis pathways. Herein, 207 prescriptions for clinical treatment of renal injury were sorted out. Further, association rules analysis showed that the core herbs implicated in treatment of renal injury includes Huang Qi, Bai Zhu, Fu Ling, Shan

Yao and Di Huang. They could regulate core pathways (AGE-RAGE, PI3K-AKT, TNF pathway, etc.) via interactions of ingredients (quercetin, formononetin, soniferol, etc.,) on targets (PTGS2 (COX2), PTGS1 (COX1), NOS2, IL6, CASP3, and TNF, etc.) to prevent the pharmacological and non-pharmacological renal injury comparable to that from covid-19 infection. Therefore, the application of CHM in treatment of renal injury after COVID-19 infection can not only improve the quality of life of patients, but also prevent drug-induced renal injury.

In summary, CHM is promising to protect the kidney in the clinical practice of COVID-19 pneumonia to provide ideas in order to reduce the incidence of severe disease and mortality in patients.

This work was supported by the Beijing research fund for double first-class and high-level talents (No. 1000041510053).

TL directed the research and revised the manuscript; TH performed the research and wrote the paper; RQ and CQ modified the tables and figures and revised the manuscript; ZW, YZ and XS revised the manuscript. All authors have read and approved the manuscript

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The authors would like to thank professor Yan Feng, in Communication University of China, and Dr Biyuan Liu, Dr Yuanfeng Zhang, Dr Xinqi Deng, Dr Xiting Wang in Beijing University of Chinese Medicine, for their help to provide constructive advice.