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

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-angiotensin-aldosterone 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 meta-analyses, with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments. We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN.

Keywords: ACEI, angiotensin-converting enzyme inhibitor; ADE, adverse event; AGEs, advanced glycation end-products; AM, mesangial area; AMPKα, adenosine monophosphate-activated protein kinase α; ARB, angiotensin receptor blocker; AREs, antioxidant response elements; ATK, protein kinase B; 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; 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; Chinese medicine; D, duration; DAG, diacylglycerol; DG, glomerular diameter; DKD, diabetic kidney disease; DM, diabetes mellitus; DN, diabetic nephropathy; Diabetic kidney disease; Diabetic nephropathy; 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; 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; Gαq, Gq protein alpha subunit; HDL-C, high density lipoprotein-cholesterol; HO-1, heme oxygenase-1; HbA1c, glycosylated hemoglobin; Herbal medicine; ICAM-1, intercellular adhesion molecule-1; IGF-1, insulin-like growth factor 1; IGF-1R, insulin-like growth factor 1 receptor; IKK-β, IκB kinase β; IL-1β/6, interleukin 1β/6; IR, insulin receptor; IRE-1α, inositol-requiring enzyme-1α; IRS, insulin receptor substrate; IκB-α, inhibitory protein α; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LC3, microtubule-associated 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; MYD88, myeloid differentiation primary response 88; Molecular target; N/A, not applicable; N/O, not observed; N/R, not reported; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOX-4, nicotinamide adenine dinucleotide phosphate-oxidase-4; NQO1, NAD(P)H:quinone oxidoreductase 1; NRF2, nuclear factor erythroid 2-related factor 2; OCP, oxidative carbonyl protein; ORP150, 150-kDa oxygen-regulated protein; P70S6K, 70-kDa ribosomal protein S6 kinase; PAI-1, plasminogen activator inhibitor-1; PARP, poly(ADP-Ribose) polymerase; PBG, postprandial blood glucose; PERK, protein kinase RNA-like eukaryotic initiation factor 2A kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α; PGE2, prostaglandin E2; PI3K, phosphatidylinositol 3 kinases; PINK1, PTEN-induced putative kinase 1; 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, Sprague–Dawley 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; Signaling pathway; 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-β, tumor growth factor β; TGFβR-I/II, TGF-β receptor I/II; TII, tubulointerstitial injury index; TLR-2/4, toll-like receptor 2/4; TNF-α, tumor necrosis factor α; 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; cAMP, cyclic adenosine monophosphate; eGFR, estimated GFR; eIF2α, eukaryotic initiation factor 2α; mTOR, mammalian target of rapamycin; p-IRS1, phospho-IRS1; p62, sequestosome 1 protein; α-SMA, α smooth muscle actin.