Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management.

Acta Pharmaceutica Sinica B 2021;11(9):2749e2767 Chinese Pharmaceutical Association Institute of Materia Medica, Chinese Academy of Medical Sciences Acta Pharmaceutica Sinica B w w w. e l s ev i e r. c o m / l o c a t e / a p s b w w w. s c i e n c e d i r e c t . c o m REVIEW Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management Guoyi Tang, Sha Li, Cheng Zhang, Haiyong Chen, Ning Wang, Yibin Feng* School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR 999077, China Received 17 August 2020; received in revised form 17 October 2020; accepted 25 December 2020 Abbreviations: a-SMA, a smooth muscle actin; ACEI, angiotensin-converting enzyme inhibitor; ADE, adverse event; AGEs, advanced glycation endproducts; ATK, protein kinase B; AM, mesangial area; AMPKa, adenosine monophosphate-activated protein kinase a; ARB, angiotensin receptor blocker; AREs, antioxidant response elements; BAX, BCL-2-associated X protein; BCL-2, B-cell lymphoma 2; BCL-XL, B-cell lymphoma-extra large; BMP-7, bone morphogenetic protein-7; BUN, blood urea nitrogen; BW, body weight; C, control group; cAMP, cyclic adenosine monophosphate; CCR, creatinine clearance rate; CD2AP, CD2-associated protein; CHOP, C/EBP homologous protein; CI, confidence interval; COL-I/IV, collagen I/IV; CRP, C-reactive protein; CTGF, connective tissue growth factor; D, duration; DAG, diacylglycerol; DG, glomerular diameter; DKD, diabetic kidney disease; DM, diabetes mellitus; DN, diabetic nephropathy; eGFR, estimated GFR; eIF2a, eukaryotic initiation factor 2a; EMT, epithelial-to-mesenchymal transition; EP, E-prostanoid receptor; ER, endoplasmic reticulum; ESRD, end-stage renal disease; ET-1, endothelin-1; ETAR, endothelium A receptor; FBG, fasting blood glucose; FN, fibronectin; Gaq, Gq protein alpha subunit; GCK, glucokinase; GCLC, glutamate-cysteine ligase catalytic subunit; GFR, glomerular filtration rate; GLUT4, glucose transporter type 4; GPX, glutathione peroxidase; GRB 10, growth factor receptor-bound protein 10; GRP78, glucose-regulated protein 78; GSK-3, glycogen synthase kinase 3; HbA1c, glycosylated hemoglobin; HDL-C, high density lipoprotein-cholesterol; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule-1; IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IkB-a, inhibitory protein a; IKK-b, IkB kinase b; IL-1b/6, interleukin 1b/6; IR, insulin receptor; IRE-1a, inositol-requiring enzyme-1a; IRS, insulin receptor substrate; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LC3, microtubuleassociated protein light chain 3; LDL, low-density lipoprotein; LDL-C, low density lipoprotein-cholesterol; LOX1, lectin-like oxidized LDL receptor 1; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemotactic protein-1; MD, mean difference; MDA, malondialdehyde; MMP-2, matrix metallopeptidase 2; mTOR, mammalian target of rapamycin; MYD88, myeloid differentiation primary response 88; N/A, not applicable; N/O, not observed; NOX-4, nicotinamide adenine dinucleotide phosphate-oxidase-4; NQO1, NAD(P)H:quinone oxidoreductase 1; N/R, not reported; NRF2, nuclear factor erythroid 2-related factor 2; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; OCP, oxidative carbonyl protein; ORP150, 150-kDa oxygen-regulated protein; p62, sequestosome 1 protein; P70S6K, 70-kDa ribosomal protein S6 kinase; PAI-1, plasminogen activator inhibitor-1; PARP, poly(ADP-Ribose) polymerase; PBG, postprandial *Corresponding author. E-mail address: (Yibin Feng) Peer review under the responsibility of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. https://doi.org/10.1016/j.apsb.2020.12.020 2211-3835 ª 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 2750 Guoyi Tang et al. blood glucose; PERK, protein kinase RNA-like eukaryotic initiation factor 2A kinase; PGC-1a, peroxisome proliferator-activated receptor gamma coactivator 1a; PGE2, prostaglandin E2; PI3K, phosphatidylinositol 3 kinases; PINK1, PTEN-induced putative kinase 1; p-IRS1, phospho-IRS1; PKC, protein kinase C; PTEN, phosphatase and tensin homolog; RAGE, receptors of AGE; RASI, renin-angiotensin system inhibitor; RCT, randomized clinical trial; ROS, reactive oxygen species; SCr, serum creatinine; SD, standard deviation; SD-rat, SpragueeDawley rat; SIRT1, sirtuin 1; SMAD, small mothers against decapentaplegic; SMD, standard mean difference; SMURF-2, SMAD ubiquitination regulatory factor 2; SOCS, suppressor of cytokine signaling proteins; SOD, superoxide dismutase; STAT, signal transducers and activators of transcription; STZ, streptozotocin; T, treatment group; TBARS, thiobarbituric acid-reactive substance; TC, total cholesterol; TCM, traditional Chinese medicine; TFEB, transcription factor EB; TG, triglyceride; TGBM, thickness of glomerular basement membrane; TGF-b, tumor growth factor b; TGFbR-I/II, TGF-b receptor I/II; TII, tubulointerstitial injury index; TLR-2/4, toll-like receptor 2/4; TNF-a, tumor necrosis factor a; TRAF5, tumor-necrosis factor receptor-associated factor 5; UACR, urinary albumin to creatinine ratio; UAER, urinary albumin excretion rate; UMA, urinary microalbumin; UP, urinary protein; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor; WMD, weight mean difference; XBP-1, spliced X box-binding protein 1. KEY WORDS Chinese medicine; Herbal medicine; Diabetic nephropathy; Diabetic kidney disease; Signaling pathway; Molecular target Abstract Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society worldwide. Conventional strategies, such as renin-angiotensinaldosterone system blockade, blood glucose level control, and bodyweight reduction, may not achieve satisfactory outcomes in many clinical practices for DN management. Notably, due to the multi-target function, Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment. Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines. Signaling pathways involved in glucose/lipid metabolism regulation, antioxidation, anti-inflammation, anti-fibrosis, and podocyte protection have been identified as crucial mechanisms of action. Herein, we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials, systematic reviews, and (...truncated)