Editorial: Identification of Effective Biomarkers for Diagnosis and Treatment of Chronic Kidney Disease: Integrating Bioinformatics and Pharmacological Approaches

Swayam Prakash Srivastava^1*Keizo Kanasaki²

• ¹Life Sciences Institute, University of Michigan, Ann Arbour, United States
• ²Shimane University, Matsue, Shimane, Japan

Despite the importance of early detection and management of CKD, there is a lack of reliable diagnostic biomarkers and effective therapeutic targets for this condition. This presents a significant clinical challenge to clinicians and researchers. Therefore, there is an urgent need to explore new strategies for the diagnosis and management of CKD. Several therapeutic agents being evaluated for their efficacy in preclinical models. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown significant antifibrotic effects in mouse models by inhibiting the partial EMT and restoring kidney structure and function 13 . Empagliflozin is a drug belonging to the class of SGLT-2 inhibitors and it has been shown to induce of mitochondrial protein SIRT3 levels, elevate the levels of fatty acid oxidation and these mechanisms ate found suppressed in injured kidney 13 . Concomitantly, Empagliflozin significantly suppressed the abnormal glycolysis and related kidney fibrosis in mouse model of CKD 13 . This aberrant glycolysis mediated through pyruvate kinase M2 type dimers and hypoxia inducible factor 1a (HIF-1a), is the causative mechanisms for the development of CKD 13,14 . SIRT3 activation such as honokiol and AICAR have shown protective effects against CKD 15 . Linagliptin, a DPP-4 inhibitor, exhibits reno-protective effects beyond diabetes 10,16,17 . In addition, linagliptin inhibited partial EMT and EndMT by suppressing hypoxia-related proteins, Snail and Twist levels. ROCK2-TGF-β1-EMT and ROCK2-Nrf2 pathways may offer a novel therapeutic strategy for the treatment of CKD 18 . However, a large cohort clinical trial is needed to analyze its effects in human subjects. Conventional treatment involves reno-protective agents such as angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) and both Deleted: are class of drugs lower the hypertension related fibrogenesis in kidney 19,20 . AcSDKP has been found effective in lowering the late-stage fibrosis in mouse models of CKD by elevating SIRT3 protein and improve mitochondrial functions in tubules, podocytes and endothelial cells 21,22 .The one-drug/one-target/one-disease approach to drug discovery is presently facing many challenges of safety, efficacy, and sustainability. Now a days, network pharmacology and molecular docking are the most utilized system biology approaches and are used in drug discovery to study the mechanism of action of small molecules entites or natural products in the management of CKD. These techniques help identifying therapeutic targets, understanding drug-drug interactions and predict the interventions on the complex signaling pathways related to the CKD progression. Combination of network pharmacology and molecular docking provides a comprehensive approach identifying the potential therapeutic options and offer a promising approaches for identifying effective biomarkers for CKD. Integrated analyses of data from various sources such as, Next generation sequencing analysis, single-cell transcriptomic and single-cell genomics analysis, microarray and metabolomics data can provide a comprehensive overview of the molecular changes associated with CKD. Metabolomics can be utilized to screen differentially expressed metabolites in kidney tissues and predicted potential targets using relevant databases. The interaction networks among endogenous metabolites and target proteins has been established by integrating differentially expressed metabolites and proteins associated with CKD identified through proteomics. Bioinformatics analyses such as gene ontology (GO) analysis, KEGG pathway analysis, and WGCNA can identify key signalling pathways and potential biomarkers associated with CKD development and progression. Pharmacological approaches can provide additional insights through the analysis of drug-gene interactions and the identification of potential therapeutic targets for CKD. The biological functions of the candidate metabolites and their effects on downstream pathways can be verified. Figure 1 demonstrate the schematic chart for the target identification and drug screening against CKD. This article collection aims was to identify 1) effective biomarkers for the diagnosis and treatment of CKD by integrating bioinformatics and pharmacological approaches. 2) Conducting bioinformatics analyses, including GO analysis, KEGG pathway analysis, and WGCNA, to identify key signaling pathways and potential biomarkers, 3) Exploring potential pharmacological implications by analyzing druggene interactions and identifying potential therapeutic targets, 4) examining immune infiltration features and related hub genes that might play a role in CKD development. In this issue, , Patil et al. report to elucidate the disulfiram-modulated targets and pathways in renal fibrosis. The authors analyzed the protein-protein interactions, pathway enrichment, cluster, and gene ontology analysis between disulfiram and renal fibrosis by using the molecular docking procedure. Moreover, molecular dynamics simulation was performed to infer protein-ligand stability, and conformational changes were analysed by free energy landscape. These analysis determines the renal Deleted: While discussing the efficacy, ACEi are more prominent in lowering the renal fibrosis as it increases the plasma urine levels of N-seryl-acetyl-lysyl-proline ( AcSDKP), a naturally occurring peptide, has been shown potential to protect against kidney fibrosis by inhibiting EMT and EndMT related fibroblast proliferation and collagen deposition. In conclusion, A better understanding of these interactions can inform the development of targeted therapies that can improve the diagnosis and management of CKD.Deleted: ¶ Deleted: Renal fibrosis in CKD contributes to kidney failure and hence, global morbidly and mortality rates, addressing its demand for treatment options of CKD (O'Callaghan-Gordo et al., 2019). There have been several hypothesis proposed for the generation and proliferations of myofibroblasts, myofibroblasts derive from tubules by process of partial epithelialmesenchymal transition (EMT), from the endothelial cells through, endothelial-to-mesenchymal transition (EndMT), from the M2-type macrophages via macrophage-to-mesenchymal transition (MMT) and myofibroblasts can be derived from activated resident fibroblasts and can be of bone marrow origin (Srivastava et al., 2019;Srivastava et al., 2020c). In CKD, the accelerated rate of myofibroblasts formations or development and alterations in endothelial cells permeability and pericytes coverage leads to impaired infiltrations of inflammatory cytokines and chemokines and, contribute in the excessive fibrosis in the form of producing diverse sets of collagens, fibronectin, desmins and integrins deposition in the extracellular spaces, and these process ultimately disrupts kidneys structure, function and metabolism and, leading to renal fibrosis and failure (Rayego-Mateos et al., 2021). Renal fibrosis is driven by several key signalling pathways such as inductions of TGF-β signaling, WNT, ANGPTL4 pathway, Hedgehog signaling, NOTCH signaling, DPP-4-integrin b1 mediated mechanisms, and mineralocorticoid receptors related mechanisms, and reduction in key pathways that are protective such as, glucocorticoid receptors, SIRT3, fibroblasts growth factor receptors are central to fibrogenesis, promoting ... [1] Deleted: ¶ Despite the importance of early detection and management of CKD, there is a lack of reliable diagnostic biomarkers and effective therapeutic targets for this condition. This presents a significant clinical challenge to clinicians and researchers alike. Therefore, there is an urgent need to explore new strategies for the diagnosis and management of CKD. The management of renal fibrosis is still a challenge for the researchers. However, several therapeutic agents being evaluated for their efficacy in preclinical models. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown significant antifibrotic effects in mouse model of diabetes by inhibiting the partial EMT and restoring kidney structure and function (Li et al., 2020b). Empagliflozin, a class of SGLT-2 inhibtor has been ... [2] Moved up [1]: Despite the importance of early detection management of CKD, there is a lack of reliable diagnostic biomarkers and effective therapeutic targets for this condition. This presents a significant clinical challenge to clinicians and researchers alike. Therefore, there is an urgent need to explore new strategies for the diagnosis and management of CKD. The management of renal fibrosis is still a challenge for the researchers. However, several therapeutic agents being evaluated for their efficacy in preclinical models. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown significant antifibrotic effects in mouse model of diabetes by inhibiting the partial EMT and restoring kidney structure and function (Li et al., 2020b). Empagliflozin, a class of SGLT-2 inhibtor has been shown to induce of mitochondrial protein SIRT3 levels,