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  • Review
  • Open Access

Chinese medicines in the treatment of experimental diabetic nephropathy

  • 1,
  • 1,
  • 2Email author,
  • 1,
  • 1,
  • 3 and
  • 1Email author
Chinese Medicine201611:6

  • Received: 29 November 2014
  • Accepted: 26 January 2016
  • Published:


Diabetic nephropathy (DN) is a severe micro vascular complication accompanying diabetes mellitus that affects millions of people worldwide. End-stage renal disease occurs in nearly half of all DN patients, resulting in large medical costs and lost productivity. The course of DN progression is complicated, and effective and safe therapeutic strategies are desired. While the complex nature of DN renders medicines with a single therapeutic target less efficacious, Chinese medicine, with its holistic view targeting the whole system of the patient, has exhibited efficacy for DN management. This review aims to describe the experimental evidence for Chinese medicines in DN management, with an emphasis on the underlying mechanisms, and to discuss the combined use of herbs and drugs in DN treatment.


  • Diabetic Nephropathy
  • Telmisartan
  • Benazepril
  • Reactive Oxidative Species
  • Incipient Stage


Diabetic nephropathy (DN) is a serious micro vascular complication in patients with diabetes mellitus (DM), affecting approximately 40 % of patients with type 1 or type 2 DM [1, 2]. It is the predominant cause of chronic kidney disease and renal failure, and is closely associated with many micro vascular diseases, leading to financial and medicinal burdens [3]. Continued hyperglycemia associated with DM is the major cause of kidney dysfunction with metabolic and hemodynamic disorders arising from oxidative stress and inflammation [4].

During DN progression, progressive alterations developfrom hyperfiltration through micro albuminuria to macro albuminuria, and finally to renal failure [5]. Renal structural changes are found in the nephrons, especially in the primary part of the glomerulus, including podocyte loss, glomerular basement membrane (GBM) thickening, endothelial cell dysfunction, and mesangial extracellular matrix (ECM) expansion, resulting in protein leakage into the urine [6]. Pulmonary dysfunction [7], hyperlipidemia and non-alcoholic fatty liver disease [8], cardiovascular disease [9], and even heart failure [10] have been reported to be positively associated with DN progression. Therefore, synergistic therapies targeting multiple mediators of DN are required for effective therapeutic strategies [4].

The experimental models used for studying Chinese medicines (CMs) in DN treatment are diverse. For in vivo studies, different doses of streptozotocin (STZ) are administered to mimic type 1 or type 2 DM. Examples of the CMs that have been investigated are Glycyrrhizauralensis (gan-cao), Carumcarvi (zang-hui-xiang), Allium sativum (da-suan), and Mesonaprocumbens (xian-cao) [1114]. In addition, alloxan (ALX)-induced mice, db/db mice, KK-Ay mice, and Otsuka Long-Evans Tokushima Fatty (OLETF) rats have been reported for investigation of CMs in DN treatment [1518]. Meanwhile, glomerular endothelial cells, mouse podocyte cells, renal proximal epithelial cells, murine hepatocytes, mouse mesangial cells, and human mesangial cells are used as in vitro models for anti-DN mechanism studies [1927]. By applying these models, the majority of studies have reported that CMs such as Acacia nilotica pods (jin-he-huan) [28], Artemisia campestris (huang-ye-hao) [29], Paeonialactiflora (shao-yao) [30], and Schisandra chinensis (wu-wei-zi) [21, 31] exhibited beneficial effects on all stages of experimental DN and may protect multiple organs. Grapevine leaf (Vitis labrusca) extract was reported to exert hepatoprotective, cardioprotective, and renoprotective effects [32]. Moreover, CM preparations such as Fufang Xueshuantong Capsule (fu-fang-xue-shuan-tong-jiao-nang), Zhengqing Recipe (zheng-qing-fang), and Danggui Buxue Tang demonstrated benefits for DN patients [3335]. Representative CMs for the treatment of DN at different stages of disease progression and their underlying mechanisms are shown in Fig. 1.
Fig. 1
Fig. 1

Natural course of diabetic nephropathy (DN) progression and Chinese medicine (CM) interventions in different stages. a In the early stage characterized by hyperfiltration and hypertrophy, CMs have therapeutic effects based on their anti-oxidant or anti-inflammatory activities. Representatives are Panax quinquefolium, Asparagus racemosus, Rosa laevigata, and Piper auritum [5, 4244]. b In the incipient DN stage characterized by microalbuminuria, CMs such as Cornus officinalis, Abelmoschus manihot, Schisandrae chinensis, and Paeonia lactiflora exhibit anti-microalbuminuric effects and may slow down the propagation of DN [19, 21, 46, 47]. The mechanisms involve protecting podocytes, and suppressing extracellular matrix (ECM) expansion and the endothelin-reactive oxidative species (ET-ROS) axis. As both the early and incipient stages of DN are at least partially reversible, CM interventions, which have superior effects based on their anti-oxidant, anti-inflammatory, and other renoprotective activities, are recommended as early as possible. c In the overt and end-stage renal disease (ESRD) stages of DN characterized by proteinuria and glomerulosclerosis, respectively, CM prescriptions, such as Zhen-wu-tang (ZWT; also called Shinbu-to in Japan) consisting of five herbs including Common Monkshood root, Poria, White Peony root, Atractylodis rhizome, and Zingiberis rhizome, have demonstrated optimal effects on ameliorating proteinuria by suppressing the hyperactivity of the renal renin–angiotensin system [72]

This article aims to review the experimental evidence for the effectiveness of CMs in DN management, with emphasis on their underlying mechanisms, and to discuss the combined use of CM herbs and chemical drugs in DN treatment.

Search strategy and selection criteria

We searched for the terms “traditional Chinese medicine”, “holistic therapy”, and “traditional Chinese medicine prescriptions (or formula)” in combination with “diabetic nephropathy” and “diabetes” in PubMed, Google Scholar, and Web of Science between 1990 and 2014. Manual searches of in-text references from the selected articles were further performed. Studies were included if in vivo models were used to investigate the nephroprotective effects and mechanisms of CMs. Unpublished reports, Letters to the Editor, and the studies that only used in vitro models or did not provide information about the duration of animal studies were excluded.

CMs in experimental DN management

CMs intervention in the early stage of experimental DN

The potential signaling pathways involved in DN pathogenesis regulated by CMs are shown in Fig. 2. The early stage of DN is characterized by hyperfunction and hypertrophy arising from oxidative stress and inflammation [3, 36, 37]. Under chronic hyperglycemia, the extracellular glucose forms advanced glycation end-products (AGEs). Activation of receptor of advanced glycation end-products (RAGE) on the plasma membrane has been proposed to contribute predominantly to the overproduction of reactive oxidative species (ROS) [38]. Meanwhile, the polyol pathway of glucose metabolism activated by the intracellular glucose further aggravates the oxidative stress. Other major sources of excess ROS were reported to be enhanced protein kinase C (PKC) activity caused by activation of the polyol pathway [39] and mitochondrial ROS production in response to mitochondrial damage. As a consequence, nuclear factor (NF)-κB becomes activated, followed by stimulation of pro-inflammatory cytokines (e.g., interleukin [IL]-6), chemokines (e.g., monocyte chemoattractant protein [MCP]-1), adhesion molecules (e.g., intercellular adhesion molecule 1 [ICAM1], vascular cell adhesion protein 1 [VCAM1]), and nuclear receptors (e.g., peroxisome proliferator-activated receptor [PPARs]) [40]. Thereafter, the inflammation induces endoplasmic reticulum (ER) stress via unfolded protein response pathways, resulting in metabolic disorders and apoptosis. Besides, subsequent macrophage infiltration into renal tissues leads to prolonged micro inflammation, thus aggravating the progression of DN. Numerous CMs are applied at this point to control this reversible stage of DN [41]. Asparagus racemosus (lu-sun), Radix Astragali (huang-qi), Rosa laevigata (jin-ying-zi), and Piper auritum (hu-jiao) were reported to enhance the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), leading to attenuation of the oxidative stress [5, 4244].
Fig. 2
Fig. 2

Potential signaling pathways involved in diabetic nephropathy (DN) pathogenesis. Activation of receptor of advanced glycation end-products (RAGE) by advanced glycation end-products (AGEs) results in reactive oxidative species (ROS) overproduction, leading to oxidative stress. Meanwhile, the polyol pathway activated by intracellular glucose further aggravates the oxidative stress. Activation of protein kinase C (PKC) via the polyol pathway is another major source of ROS production. Mitochondrial damage also contributes to ROS production. ROS overproduction and impaired anti-oxidant response cause oxidative stress, which activates nuclear factor (NF)-κB and upregulates monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β. Thereafter, the inflammation induces endoplasmic reticulum (ER) stress via unfolded protein response pathways, resulting in metabolic disorders and apoptosis

CMs intervention in the incipient stage of experimental DN

The development of micro albuminuria was reported as an indicator of the incipient stage of DN, arising from endothelial dysfunction [38, 45]. Renal hypertrophy and hyperfiltration induced functional and structural alterations, resulting in micro albuminuria and hypertension, leading to glomerulus sclerosis, and progressing to incipient DN. Cornus officinalis (shan-zhu-yu), Abelmoschus manihot (huang-shu-kui), Schisandrae chinensis (wu-wei-zi), and Paeonia lactiflora (shao-yao) were reported to exhibit anti-micro albuminuria effects, thereby slowing down DN progression [19, 21, 46, 47].

CMs intervention in the overt and end-stage renal disease (ESRD) stages of experimental DN

After the incipient stage of DN and under hyperglycemic conditions, mesangial nodules and tubule interstitial fibrosis develop, leading to proteinuria and nephrotic syndrome, and eventually to the overt stage of DN, which is characterized by persistent proteinuria [6]. Without effective control, patients in this stage will deteriorate to ESRD with uremia. As the kidney disease progresses, physical changes in the kidneys often lead to increased blood pressure and cardiovascular disease. In this stage, angiotensin-converting enzyme (ACE) inhibition is the conventional intervention [48]. The goal of treatment is to prevent the progression from micro albuminuria to macro albuminuria, and multiple and more intensive strategies are strongly advised. Avosentan was reported to reduce albuminuria in patients with type 2 DM and overt nephropathy by inhibiting ACE and blocking angiotensin receptors, but can also induce significant fluid overload and congestive heart failure [49]. Averrhoa carambola L. (yang-tao), Salvia miltiorrhiza (dan-shen), and Picrorrhiza Rhizoma (hu-huang-lian) can ameliorate DN symptoms safely [5052]. Representative CMs and their related mechanisms are summarized in Table 1.
Table 1

Chinese medicines used in the management of experimental diabetic nephropathy


Medicinal part


DN model

Nephro-protective Mechanisms

Pharmacodynamic indicators



Eclipta alba (han-lian-cao)

Ethanol extract

STZ rat

↓α-glucosidase and aldose reductase activities

FBG, HbA1C, urea, uric acid, UCr, insulin

3 weeks


GymnemamontanumHook (shi-geng-teng)

Ethanol extract

ALX rat

↓TBARS, hydroperoxides; ↑SOD, CAT, GSH-Px, GST

FBG, insulin, urea, Cr, uric acid

3 weeks


Cinnamomumzeylanicum (xi-lan-rou-gui)

Aqueous extract

STZ rat


FBG, K/B ratio, insulin, HDL, TC, TG, Cr, histopathology

22 days


Panaxnotoginseng (san-qi)



STZ rat


Cr, CCr, Ualb

4 weeks


MesonaprocumbensHemsl (xiancao)

Aqueous extract

STZ rat


Body weight, FBG, histopathology

4 weeks


Piper auritum (hu-jiao)


Hexane extract

STZ rat

↓AGEs, serum glycosylated protein, LDL glycation, glycation hemoglobin, renal glucose, thiobarbituric acid-reactive substance; ↑SOD, CAT, GPx and GSH

Kidney oxidative stress

4 weeks


Smallanthussonchifolius (xue-lian)


Aqueous extract

STZ rat

↓TGF-β1, Smad2/3, collagen III, collagen IV, laminin-1, FN

FBG, insulin, UAE, Cr, kidney hypertrophy, GBM thickening

4 weeks


Milk thistle (nai-ji-cao)


STZ rat

↓Lipid peroxidation; ↑CAT, SOD, GPx

FBG, serum urea, Cr, Ualb

4 weeks



STZ rat

↓eNOS, ET-1, TGF-β1, FN, NF-κB, p300


4 weeks


Allium sativumL. (da-suan)

STZ rat


FBG, insulin, TG, TC, CCr, UAE, NAG

30 days


PsidiumguajavaL. (fan-shi-liu)


Total triterpenoids

HFD + STZ rat


FBG, insulin, Cr, BUN, capillary, base-membrane incrassation, glomerular swelling, cysts and tubules edema

6 weeks


Panaxnotoginseng (san-qi)



STZ rat

↓TGF-β1; ↑Smad7

FBG, renal index, CCr, UAlb

6 weeks




Aqueous extract

HFD + STZ rat

↓MDA, 8-hydroxy-2′-deoxyguanosine, renal cortex DNA; ↑SOD, CAT

FBG, K/B ratio, Cr, BUN, UAlb, and CCr, GBM

6 weeks


Schisandraechinensis (wu-wei-zi)


Ethanol extract

STZ mice

↓EMT, α-SMA, PAI-1, E-cadherin, Snail; ↑E-cadherin, α-SMA

ACR, UAE, ECM deposition, podocyte loss and integrity of the slit diaphragm

7 weeks



STZ mice

↓COX-2, caspase-3, F- to G-actin cleavage; ↑p38-MAPK, HSP25


7 weeks


Panax ginseng (ren-shen)

ginsenoside 20(S)-Rg(3)

OLETF rats


FBG, CCr, UAE, urine volume

50 days


PolygonummultiflorumThunb (he-shou-wu)


STZ rat

↓TGF-β1, COX-2; ↑CAT, SOD, GSH-Px, SIRT1

TC, TG, BUN, Cr, UAlb, K/B ratio, MDA

8 weeks


PaeonialactifloraPall. (shao-yao)

Total glucosides

STZ rat

↓Macrophages accumulation and proliferation; ↑p-JAK2, p-STAT3


8 weeks


Aceranthussagittatus (yin-yang-huo)


STZ rat

↓MDA, Hyp, TGF-β1, collagen IV; ↑SOD

FBG, Cr, BUN, histopathology

8 weeks


Angelica acutiloba (dang-gui)


Aqueous ethanol extract

STZ rat

↓NF-κB, TGF-β1, FN, AGEs, RAGE

FBG, UAlb, UAE, CCr, ECM expansion

8 weeks


Salvia miltiorrhiza (dan-shen)

Aqueous extract

STZ rat

↓TGF-β1, AGEs, RAGE, collagen IV and ED-1


8 weeks


Tripterygium wilfordii (lei-gong-teng)


STZ rat

↓Mesangial cell proliferation, α-SMA, collagen 1

Body weight, UAlb, FBG, Cr, BUN, histopathology

8 weeks


Hibiscus sabdariffa L (luo-shen-hua)



STZ rat


K/B ratio, proximal convoluted tubules, TG, TC, LDL

8 weeks


Panaxquinquefolium (xi-yang-shen)


Ethanol extract

STZ+ db/db mice

↓Oxidative stress, NF-κB p65, ECM, vasoactive factors

Albuminuria and mesangial expansion

6 and 8 weeks


Rheum officinale (da-huang)


db/db mice

↓TGF-β1, FN


8 weeks


Averrhoa carambola L (yang-tao)



KKAy mice

↓Hyperglycemia, AGE, NF-κB, TGF-β1, CML; ↑SOD and GSH-Px activities

Proteinuria, Cr, CCr, serum urea-N, ECM expansion

8 weeks


Radix Astragali (huang-qi)


Aqueous extract

STZ rat

↓MDA, IL-6, TNF-α, NF-κB, PKCα; ↑SOD and GSH-Px activities

FBG, body weight, Cr

60 days


Glycyrrhizauralensis (gan-cao)

STZ rat


FBG, body weight, histopathology

60 days


Acacia nilotica (jin-he-huan)


Aqueous methanol extract

STZ rat

↓Hyperglycemia, LPO, ↑SOD and GSH activities

FBG, serum urea, Cr, histopathology

60 days


Portulacaoleracea (ma-chi-xian)

Aqueous extract

db/db mice

↓TGF-β1, AGEs, ICAM-1, NF-κB p65

FBG, Cr, water intake and urine volume

10 weeks



STZ mice

↓ICAM-1, gp91 and TBARs; ↑ phospho-tyrosine and phospho-ERK/ERK ratio

FBG, insulin, total protein, UAlb, urinary MCP-1 excretion

10 weeks


Smilax glabraRoxb (tu-fu-ling)



STZ rat


Body weight, survival time, FBS

6 and 12 weeks


PsidiumguajavaL. (fan-shi-liu)


Aqueous + methanol extract

STZ mice

↓AR activity, ROS, IL-6, TNF-α, IL-1β, CML, MDA, AR and AGEs; ↑GSH, CAT, GSH-Px

Body weight, insulin

12 weeks


Caffeic acid, ellagic acid

STZ mice

↓Sorbitol dehydrogenase, AR, IL-1, IL-6, TNF-α, MCP-1

Body weight, urine volume, insulin, FBG, BUN, CCr, HbA1c, UAlb

12 weeks


TrigonellafoenumgraecumL. (hu-lu-ba)


Seed powder

ALX rat

↓Glucose, urea, creatinine, sodium, potassium and IL-6 in serum, MDA and IL-6 in kidney; ↑SOD and CAT activities, GSH

Glomerular mesangial expansion

12 weeks


Cornus officinalis (shan-zhu-yu)


HFD + STZ rat

↓FBG, NAG, mALB; ↑insulin and Wilms tumor 1 in glomeruli

FBG, mALB, UCr, BUN, NAG, histopathology

12 weeks


Euonymus alatus (wei-mao)

Leaves and branches

Aqueous extract

Uninephrectomy + STZ rat


Blood lipids, UAlb, HbA1c, ECM expansion and glomerulus sclerosis

12 weeks


Aster koraiensis (zi-yuan)

Aerial part

Ethanol extract

STZ rat

↓AGEs accumulation, Bax; ↑Bcl-2

FBG, HbA1c, UAE, histopathology

13 weeks


Rosa laevigataMichx. (jin-ying-zi)


Aqueous extract

STZ rat

↓MDA, ROS, NF-κB p65, MCP-1;↑SOD and antioxidant activities, IκBα

Kidney oxidative stress

24 weeks


AbelmoschusmanihotL. (huang-shu-kui)


Total flavone glycosides, hyperoside

STZ rat

↓Glomerular cell and podocytes apoptosis, caspase-3, caspase-8


24 weeks


AGEs advanced glycation end products, ALX alloxan, AR aldose reductase, ACR urinary microalbumin to creatinine ratio, BMP bone morphogenetic protein, BUN blood urea nitrogen, CAT catalase, CCr creatinine clearance rate, CML N(epsilon)-(carboxymethyl) lysine, CTGF connective tissue growth factor, COX cyclooxygenase, ECM extracellular matrix, ED-1 monocyte/macrophage, ET-1 endothelin-1, EMT epithelial-to-mesenchymal transition, ERK extracellular signal-regulated kinases, FBG fasting blood glucose, FN fibronectin, GBM glomerular basement membrane, GLUT glucose transporter, GSH-Px glutathione peroxidase, GST glutathione-S-transferase, HFD high fat diet, HDL high density lipoprotein, HSP heat shock protein, Hyp hydroxyproline, ICAM intercellular adhesion molecule, JAK janus kinase, K/B kidney/body weight, LDL low density lipoprotein, LPO lipid peroxidation, iNOS inducible nitric oxide synthase, eNOS endothelial nitric oxide synthase, NAG N-acetyl-beta-D-glucosaminidase, NF-κB nuclear factor κB, MAPK mitogen-activated protein kinase, mALB microalbuminuria, MCP monocyte chemotactic protein, MDA malondialdehyde, PAI plasminogen activator inhibitor, ROS reactive oxidative species, RAGE receptor of advanced glycation end-products, STAT3 signal transducer and activator of transcription 3, α-SMA α-smooth muscle actin, STZ Streptozotocin, SIRT1 Sirtuin 1, SOD superoxide dismutase, TARS thiobarbituric acid reactive substances, TGF transforming growth factor, TG triglyceride, TC total cholesterol, TSP-1 thrombospondin-1, UAlb urinary microalbumin, UAE urinary albumin excretion, UCr urinary creatinine, UCP uncoupling protein, VEGF vascular endothelial growth factor

Besides targeting the specific molecules involved in DN pathogenesis to exert anti-hyperglycemic and nephroprotective effects, CM has unique characteristics in DN management. In CM, DN is not only a kidney disease, but also an embodiment of the systemic disease in the kidney, which is in accordance with the latest findings for DN pathogenesis [7, 8, 38]. The pathogenesis of DN may be closely related to the dysfunction or impairment of other organs, and therefore treatments for diseases in other organs may be helpful for the amelioration of DN, especially in the overt and ESRD stages. The normal functioning of the human body relies on the coordination of yinand yang, and the five zang organs (wuzang), i.e., the liver (gan), heart (xin), spleen (pi), lung (fei), and kidney (shen), are respectively related to wood (mu), fire (huo), earth (tu), metal (jin), and water (shui) and connected under the laws of inter promotion and interaction (Fig. 3) [53]. Once a significant imbalance occurs, certain symptoms of the kidneys inevitably and predictably arise.
Fig. 3
Fig. 3

Schematic diagram integrating the Chinese medicine (CM) view on the holistic therapy and modern pathogenesis concepts of diabetic nephropathy (DN). The core shows the holistic view of DN under CM theory, which is based on the Yin-Yang and Five Elements theories. The regular functioning of the human body relies on the coordination of Yin and Yang in a unity of opposites, and the liver, heart, spleen, lung, and kidneys are respectively related to wood, fire, earth, metal, and water [53]. In particular, the spleen in CM is a functional organ that governs transport and transformation in a close relationship with the stomach and pancreas [7375]. This theory reflects the unification and integration together with the impact caused by the breakdown of the balance as a consequence of overacting and counteracting relationships, which is of practical significance in CM clinical practice. The peripheral annotations imply recent therapeutic strategies against DN specific to individual organs. The solid arrows denote interpromoting relationships. The dashed arrows indicate interacting/counteracting relationships

Under hyperglycemic conditions, the oxidative stress and inflammation affect the blood circulatory system, consequently leading to the dysfunction of multiple organs. Cardiovascular disease causes even more deaths than ESRD in patients with DN [38]. The degree of pulmonary function impairment was found to be positively associated with the stage of DN progression [7]. Besides, liver X receptor (LXR) agonists, which are commonly used to treat hyperlipidemia and non-alcoholic fatty liver disease, were shown to ameliorate DN by inhibiting the expressions of osteopontin and other inflammatory mediators in the kidney cortex [8]. Moreover, during DN pathogenesis, glomerular hypertrophy was found to be associated with hyperinsulinemia [54], and has been proposed as a novel therapeutic target for DN [55]. As a systematic micro vascular thrombosis combined with metabolic disorders, DN influences the whole internal environment, and its pathogenesis may be closely related to the dysfunction of other organs.

From this perspective, CM as a therapeutic approach targeting multiple organs is preferred to improve the overall health of DN patients. Experimentally, grapevine (Vitis labrusca L.) leaves exhibited hepatoprotective, cardioprotective, and renoprotective effects in Wistar rats [32]. Besides, extracts from S. miltiorrhiza exhibited a regulatory effect on the expression of LXR-α in hyperlipidemic rats [56]. Furthermore, Liuwei Dihuang Decoction exhibited a protective effect on early DN in STZ rats [57]. Additionally, a CM prescription, kangen-karyu, exhibited hepatoprotective/renoprotective activities through the inhibition of AGE formation and fibrosis-related protein expressions in type 2 diabetes [58]. Yamabe and colleagues systematically conducted a series of experiments to investigate the anti-diabetic effects of a CM prescription, hachimi-jio-ga, and reported findings for the whole prescription and its constituents as well as for the bioactive compound [5964]. Other selected CM prescriptions for DN treatments and their respective molecular mechanisms are shown in Table 2. In particular, single herbs (e.g., Auricularia auricula, hei-mu-er) and CM prescriptions (e.g., Danggui Buxue Tang and Gui Qi Mixture) produced better beneficial effects than conventional anti-DN drugs by regulating blood lipid metabolism and lipoprotein lipase activity through the regulation of blood glucose based on their complex compound matrices [6567]. The changes in blood glucose, triglyceride (TG), total cholesterol (TC), and high-density lipoprotein (HDL) were reversed by Gui Qi Mixture, but not by the ACE inhibitor benazepril in diabetic rats [68]. Similarly, the increases in fasting blood glucose (FBG), TG, and TC were attenuated, and the renal kidney/body weight (K/B) ratio, urinary albumin excretion (UAE), and creatinine clearance rate (CCr) in STZ-induced diabetic rats were ameliorated after 8 weeks of treatment with Danggui Buxue Tang compared with benazepril [69]. Collectively, CMs may exert synergetic effects targeting multiple organs, and benefiting the whole internal milieu of DN patients.
Table 2

Experimental studies on selected CM prescriptions in diabetes nephropathy management

CM preparations

DN model

Nephro-protective mechanisms

Pharmacodynamic indicators





STZ rat

↓TGF-β1, FN, and collagen IV,↑BMP-7, SOD

FBG, BUN, SCr, renal hypertrophy

200 mg/kg b.w

4 weeks


LiuweiDihuang Decoction

STZ rat

↓MDA, iNOS, tNOS, cNOS, ET-1, ET(A), ↑NO, MMP-2, MMP-9, GSH-Px, SOD

FBG, plasma insulin level

5, 10, or 15 g/kg b.w

4 weeks


Tangshenling mixture plus benazepril

STZ rat


UAE, CCr, K/B ratio

5 g/kg b.w

6 weeks


DangguiBuxue Tang

STZ rat


K/B ratio, UAE, β(2)-MG concentrations, CCr, FBG, TC, TG

8 weeks


Dang-gui and Huang-qi mixture

STZ rat

↓TGF-β1, Ang II

FBG, TG, CHO, HDL, SCr, CCr, BUN, β(2)-MG,K/B ratio, GA

8 weeks


Tangshenning Recipe

STZ rat

↓TXB(2), TXB(2)/6-keto-PGF1 α, CGRP, MDA; ↑ET, SOD, GSH

35 g/kg b.w

8 weeks


Shenbao Recipe

STZ rat


UAlb, FBG, TC, SCr

13 g/kg b.w

8 weeks



STZ rat

↓NF-κB, TGF-β1, FN, AGEs, mitochondrial TBARS, CML

UAE, UAlb, CCr, mesangial matrix expansion

2.5 g/kg b.w

10 weeks



STZ rat

↓Ang II, ↑nephrin, podocin

Body weight, polyurea, UAE, SCr, BUN

320 mg/kg b.w.

12 weeks


FufangXueshuantong Capsule

HFD + STZ rat

↑GSH-px, SOD

UAE, CCr, masengial matrix expansion

450, 900, or 1800 mg/kg b.w

12 weeks



STZ rat

↓AGEs, sorbitol

FBG, UAE, CCr, serum glycosylated protein, BUN, serum albumin level, TG, TC

50,100, or 200 mg/kg b.w

15 weeks



STZ mouse

↓AGEs, TGF-β1, collagen IV


100, 200 mg/kg b.w

18 weeks



OLETF rats

↓NF-κB, TGF-β1, FN, iNOS, cyclooxygenase-2, AGEs, TBARS


50, 100, or 200 mg/kg b.w

32 weeks


Yiqiyangyinhuayutongluo recipe

HFD + STZ rat


FBG, UAE, 24 h U-nephrin

0.8 g/kg b.w

32 weeks


AGEs advanced glycation end products, ANF atrial natriuretic factor, Ang II angiotensin II, BMP bone morphogenetic protein, BUN blood urea nitrogen, CCr creatinine clearance rate, CHO cholesterol, CML N(epsilon)-(carboxymethyl)lysine, CGRP calcitonin gene-related peptide, CTGF connective tissue growth factor, ET endothelin, FBG fasting blood glucose, GA glomerular area, GLUT glucose transporter, TGF transforming growth factor, FN fibronectin, GSH-Px glutathione peroxidase, HDL high density lipoprotein, HFD high fat diet, K/B kidney/body weight, NF-κB nuclear factor κB, NO nitric oxide, cNOS constitutive nitric oxide synthase, eNOS endothelial nitric oxide synthase, iNOS inducible nitric oxide synthase, nNOS constitutive nitric oxide synthase, tNOS total nitric oxide synthase, MDA malondialdehyde, MMP matrix metalloproteinase, β (2)-MG Urine β (2)-microglobin, OLETF otsuka long-Evans Tokushima Fatty, PGF prostaglandin F, SCr serum creatinine clearance rate, STZ streptozotocin, SOD superoxide dismutase, TGF transforming growth factor, TG triglyceride, TC total cholesterol, TARS thiobarbituric acid reactive substances, TXB(2) thromboxane B 2, UAE urinary albumin excretion rate, UAlb urinary microalbumin

At the ESRD stage, it is almost impossible to prevent the disease from becoming more severe, and dialysis may be the final resort for these patients. To provide a more cost-effective therapeutic approach, other potent remedies are urgently needed. In this regard, the combined use of herbs and drugs, and the development of new therapies are receiving increasing attention.

Modern drugs specifically aim to target disease-related molecules through definite pathways, whereas CM aims to exert synergetic effects and benefit the whole internal milieu of patients, leading to the possibility that the combined use of CMs and modern drugs may exert better therapeutic effects on diseases, especially for chronic and comprehensive DN. Currently, the combined use of herbs and drugs in the treatment of DN has been well-investigated. For example, the CM prescription tangshenling was combined with telmisartan to treat 80 patients with DN, and exhibited a better effect than telmisartan treatment alone [70]. Basic research corroborated that the tangshenling mixture had a synergetic effect with benazepril through a different signaling pathway, which involved down regulation of atrial natriuretic factor (ANF) in plasma and glucose transporter 1 (GLUT1) in the kidney when treating DN [71]. Herbs may reduce the permeability of the drug into the intestinal tract, and may also affect its metabolism in the liver and cause hypoglycemia. Huang Kui capsule reduced the absorption of glibenclamide and accelerated its metabolism. This herb–drug interaction deserves further research on the herb–drug pharmacokinetic interaction to enhance the therapeutic effects and avoid side effects.

Limitations of this review

In many studies included in this review, the bioactivities of the CMs responsible for the anti-DN effects and their molecular targets were not identified. Phytochemical and molecular biological studies are needed to identify the bioactive constituents and to elucidate the underlying mechanisms. Moreover, this review only focused on studies using in vitro or in vivo DN models. Results from clinical trials investigating the use of CMs for the treatment of DN are needed to confirm the therapeutic effects of CMs in the future.


CMs provides an alternative for DN management in all stages of experimental DN models, especially in the early and incipient stages of DN, and the synergistic administration of CM herbs with conventional drugs exhibited better efficacy than drugs alone in DN treatment.



atrial natriuretic factor


advanced glycation end products

Ang II: 

angiotensin II




aldose reductase


angiotensin-converting enzyme


angiotensin receptor blocker


urinary microalbumin to creatinine ratio


blood urea nitrogen


bone morphogenetic protein




creatinine clearance rate


calcitonin gene-related peptide




connective tissue growth factor




diabetes mellitus


diabetic nephropathy


endoplasmic reticulum




end-stage renal disease


epithelial-to-mesenchymal transition


extracellular matrix


extracellular matrix metalloproteinase inducer


extracellular signal-regulated kinases




fasting blood glucose




glomerular area


glomerular filtration rate


glomerular mesangial cells


glomerular basement membrane


glutathione peroxidase




glucose transporter


high density lipoprotein


high fat diet




inducible nitric oxide synthase


intercellular adhesion molecule


insulin-like growth factor


kidney/body weight


lipid peroxidation


lipoprotein lipase


liver X receptor


low density lipoprotein




endothelial nitric oxide synthase


constitutive nitric oxide synthase


total nitric oxide synthase


mitogen-Activated Protein Kinase






matrix metalloproteinase


monocyte chemotactic protein


otsuka Long-Evans Tokushima Fatty


peroxisome proliferator-activated receptor


plasminogen activator inhibitor


protein kinase 1


prostaglandin F


reactive oxidative species


receptor of advanced glycation end-products


serum and glucocorticoid induced protein kinase




superoxide dismutase


α-smooth muscle actin


serum creatinine clearance rate


transforming growth factor


chinese medicine


thiobarbituric acid reactive substances


tissue inhibitor of metalloproteinase




total cholesterol




thromboxane B 2


urinary creatinine

β (2)-MG: 

urine β (2)-microglobin


uncoupling protein


urinary microalbumin


unfolded protein response


urinary albumin excretion


vascular endothelial growth factor


Authors’ contributions

YBZ and SCWT designed and conceived the study. JYL, XXC, SCWS, YBF, and KFL select and analyzed the data. JYL, XXC, SCWS, KFL, and YBF wrote the manuscript. YBZ and SCWT revised the manuscript. All authors agree to be responsible to all aspects of the work to ensure that no questions concerning the accuracy or integrity of the work remain unsolved. All authors read and approved the final manuscript.


This study was supported by grants from Seed Funding Programme for Basic Research from HKU (Project No. 201111159043); the Innovation and Technology Support Programme (Project code: ITS/313/11); and the Government of Hong Kong Special Administrative Region. The funders had no role in the design, analysis or writing of this article.

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Hong Kong, People’s Republic of China
Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Hong Kong, People’s Republic of China
Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Hong Kong, People’s Republic of China


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