|Year : 2014 | Volume
| Issue : 2 | Page : 53-57
Prevention and Treatment of Diabetic Nephropathy Using Traditional Chinese Medicine
Xia Chen1, Aili Cao2, Li Wang2, Peihao Yin1, Xuemei Zhang3, Wen Peng4
1 Department of Nephrology, Putuo Hospital, Shanghai, China
2 Department of Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
3 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
4 Department of Nephrology, Putuo Hospital; Department of Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
|Date of Web Publication||27-Oct-2014|
Department of Nephrology, Laboratory of Renal Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 LanXi Road, Shanghai - 200 062
Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai - 201 203
Source of Support: None, Conflict of Interest: None
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide. The mainstay of DN has been management of hyperglycemia, blood pressure and proteinuria using hypoglycemic agents, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Application of traditional Chinese medicine (TCM) for DN has received increasing attention due to its wide availability, low side-effects, proven therapeutic mechanisms and benefits. In this paper, we mainly focus on the recent studies of TCM including Tongxinluo, Chaihuang-Yishen granule, Shenyan Kangfu tablets, Danggui Buxue Tang, Gordon Euryale Seed, Cherokee Rose Fruit and Bawei Dihuang wan, and the effective components of TCM, including Astragalus and Astragalus polysaccharide. The aim of this study is to review the protection and treatment effect of TCM for treating DN in type 1 and type 2 diabetes mellitus. Meanwhile, the possible mechanisms of major compounds and active crude drugs are also summarized.
Keywords: Diabetic, nephropathy, treatment, traditional Chinese medicine
|How to cite this article:|
Chen X, Cao A, Wang L, Yin P, Zhang X, Peng W. Prevention and Treatment of Diabetic Nephropathy Using Traditional Chinese Medicine. J Integr Nephrol Androl 2014;1:53-7
|How to cite this URL:|
Chen X, Cao A, Wang L, Yin P, Zhang X, Peng W. Prevention and Treatment of Diabetic Nephropathy Using Traditional Chinese Medicine. J Integr Nephrol Androl [serial online] 2014 [cited 2019 Feb 18];1:53-7. Available from: http://www.journal-ina.com/text.asp?2014/1/2/53/143374
| Introduction|| |
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes, and is the single most common cause of end-stage renal disease worldwide.  DN is characterized by excessive deposition of extracellular matrix (ECM) with thickening of the glomerular and tubular basement membranes and increased amount of mesangial matrix, which ultimately leads to glomerulosclerosis and tubulointerstitial fibrosis accompanied by the development of albuminuria and a decline in renal function. ,, It is likely to worsen to critical levels in the next decades, with great concern that this disease is rising rapidly in younger population groups, including children and adolescents.  According to data from the International Diabetes Federation, the number of diabetics older than 20 years will rise from 285 million in 2010 to 439 million in 2030. 
Hence, measures to prevent the appearance and progression of DN should be instituted as early as possible. Clarification of the pathogenesis of DN and development of novel and effective therapeutic strategies are therefore high priorities. Proven, effective Western medical methods for the treatment of early DN include a good control of blood glucose, blood pressure and blood lipids and thus mainly involve the use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). Even though their effects are active and steady, the progress of pathological changes is still ongoing. Also, these treatments are specific for a particular cause without multi-target therapeutic drugs. Traditional Chinese medicine (TCM), which can produce a potential effect of multi-target therapy, seems appropriate in the treatment of DN caused by multiple factors. 
The pathogenesis of DN
The pathogenesis of DN is complex. Following the most general principles of TCM, diabetes affects a patient's "qi" (energy/life force) to cause weakness in the circulatory system function. In TCM, the spleen, a controller of blood circulation, is a source of vital energy and blood. When the spleen qi is weakened, its blood controlling function is disturbed thus leading to ischemia and anoxia in the kidney tissue and the kidney capillary endothelial cells are damaged. The damaged kidney endothelial cells will attract infiltration of inflammatory cells in the blood circulation and release the pathogenic inflammatory mediators. Therefore, the process of renal fibrosis is started.  In TCM theory, the kidney is the foremost organ that retains essence and the essence transforms qi and generates blood. Moreover, the kidney is the source of genuine Yin and genuine Yang, which is called "the prenatal base of life" in TCM textbooks. Many of Chinese medicinals have the effects of replenishing the qi of the kidney or tonifying the kidney Yang. In TCM, DN is considered nearly equivalent to the term "Xiao Ke Bing," which has been described in the "Yellow Emperors Medicine Classic" ("Huang Di Nei Jing") more than 2000 years ago. Modern physicians propose the pathogenic theory of "meridian stagnancy" for diabetic microangiopathy, which may be regarded as the development of blood stasis pathogenic theory. Thereby, the therapy of "activating blood circulation to remove stasis" has been universally accepted by Chinese and Western physicians at present, and is widely applied in the treatment of diabetic mellitus and its complications. The incidence of DN is associated with mechanisms of abnormal renal blood flow dynamics.
With increased in-depth studies, investigating the etiology of DN in the medical field has become a hot issue. DN develops as a result of interactions between deleterious hemodynamic and metabolic factors. The interactions lead to the activation of intracellular signaling pathways and transcription factors, triggering inflammatory mediators and release of growth factors. These in turn mediate ECM protein accumulation, vessel permeability alteration and proteinuria. , Vasoactive hormones, the biochemical processes of the advanced glycation end products (AGEs), protein kinase C (PKC) and AMP-activated protein kinases (AMPK) as well as novel pharmacological targets of DN, such as transcription factors nuclear factor erythroid 2-related factor 2 (Nrf2). A hyperglycemic state stimulates the growth and activation of transforming growth factor β1 (TGF-β1). Elevated TGF-β1 can up-regulate the synthesis of plasminogen activator inhibitor, tissue inhibitor of metalloproteinases and connective tissue growth factor. It may also down-regulate matrix metalloproteinase and prevent the degradation of newly synthesized ECM, resulting in renal hyperperfusion and hypertrophy and increased glomerular basement membrane matrix and basement membrane synthesis. By promoting the synthesis of ECM components, such as collagen IV and fibronectin, glomerular sclerosis was seen. 
DN treatment by TCM
Currently, there have been many experiments focusing on the treatment of DN because of its lesser toxicity and/or side-effects, if the herbs or Chinese prescriptions are prescribed strictly according to the recommendation of the pharmacopoeia with attention to their origin, dose, method of preparation and duration of intake. Previous treatment of DN focused on aggressive control of hyperglycemia and blood pressure. At present, glucose-dependent pathways emerged as an important strategy to retard the progression of DN. Several in vitro and in vivo studies have shown DN amelioration by managing the hyperglycemia-induced oxidative stress, inflammation and lipid accumulation. , Despite emerging strategies for retarding the progression of DN, the challenge for arresting the relentless progression of DN remains.
Cordyceps sinensis (CS) is rich in amino acids, polysaccharides, organic acids, trace elements, nucleosides, peptides, steroids and other chemical components. , CS has numerous therapeutic effects, including the regulation of immune function, intrinsic renal cell proliferation, ECM synthesis and cytokines. CS also functions as a growth factor, antagonizes ischemia and toxic injury to the kidneys, improves metabolism and other multi-target, multi-link mechanisms, reduces proteinuria and improves renal function and renal pathological changes. ,
Gordon euryale seed and cherokee rose fruit
A famous classical formula securing the essence and tonifying the kidney is also introduced in the present study for the treatment of proteinuria (Water-land Two Elixirs). It consists of two Chinese medicinals, Gordon Euryale seed and Cherokee Rose fruit. The first ingredient is grown in water and the second one is grown on land, which is the reason why it is named "Water-land." This formula is very effective for treating conditions such as spermatorrhea and enuresis.  However, only securing essence is not enough; because the Yin/Yang has been damaged, it is essential to repair the balance between them.
Tongxinluo (TXL), in capsule form, is a traditional Chinese medicine that consists of herbs and insects (Panax ginseng, leech, scorpion, Radix paeoniae rubra, periostracum cicadae, Ground Beetle, Centipede, Sandalwood, Rosewood Heart Wood, Frankincense, Semen Ziziphi Spinosae, and Borneol). , It was registered in the State Food and Drug Administration of China. TXL has already been proven to have a cohort of potentially therapeutic value such as preventing apoptosis, improving endothelial cell function, reducing inflammation and lowering lipids.  In treating DN, TXL also shows a positive effect. A meta-analysis showed that TXL significantly decreased the 24-h urine albumin excretion ratio (24 h-UAER) and blood urea nitrogen (BUN).  In the treatment of early DN, TXL could improve renal microcirculation, reduce Cys-C and UAER and delay the progress of renal damage.  Fibrosis is a key pathology in DN and excessive ECM synthesis and accumulation, resulting in glomerular and tubular pathology and, ultimately, death in diabetic patients.  Studies have proven the positive effect of TXL and some components of it in suppressing renal fibrosis or EMT. TXL attenuated renal fibrosis and decreased the expression of TGF-β1 in unilateral ureteral occlusion mice. 
Chaihuang-Yishen granule (CHYS, which is composed of Radix Astragali, Angelica, Dioscorea nipponica, Radix bupleuri, Pyrrosia lingua, Polyporus and leech) is formulated based on the TCM theory for the treatment of chronic kidney disease. Treatment with CHYS significantly reduced urinary protein excretion and serum creatinine in puromycin aminonucleoside-induced nephrotic syndrome in rats.  The present study demonstrates that CHYS may be a novel therapeutic agent for DN. It is suggested that blockade of TGF-β/Smad3-mediated renal fibrosis by down-regulating TGF-β1 and microRNA-21 expression, thereby restoring the balance of Smad signaling by up-regulating an inhibitory Smad7, results in a possible underlying mechanism by which CHYS inhibits DN associated with fibrosis. 
Shenyan kangfu tablets
Shenyan Kangfu tablets (nephritis recovery tablets, literally; hereafter referred to as SYKFT), a Chinese patent drug originally designated for the clinical treatment of chronic nephritis patients diagnosed with qi-yin deficiency syndrome (a TCM syndrome characterized by the lack of qi and yin energy in the body) is composed of American ginseng, ginseng, Radix Rehmanniae, the bark of eucommia, Rhizoma Dioscoreae, Radix Salviae miltiorrhizae, Oldenlandia diffusa, motherwort, Rhizoma alismatis and Platycodon grandiflorus. SYKFT has been considered for use in DN treatment because DN patients may share the same TCM syndrome and clinical symptoms with nephritis sufferers.
Danggui buxue tang
Danggui Buxue Tang (DBT), an ancient traditional Chinese herbal formula composed of Huangqi (Radix Astragali) and Danggui (Radix Angelica sinensis) with a weight ratio of 5:1 has wide pharmacological actions. DBT was first recorded in Neiwaishang Bianhuo Lun by Li Dongyuan in China in AD1247. Li described that the DBT formula should include the following: Ten qian (about 31.25 g) of Radix Astragali (RA, Huangqi), roots of Astragalus membranaceus (Fisch.) Bunge or Astragalus membranaceus (Fisch.) Bunge var. mongholicus (Bunge) P. K. Hsiao and two qian (about 6.25 g) of Radix Angelicae sinensis (RAS, Danggui), roots of Angelica sinensis (Oliv.) Diels. The mixed herbs were boiled in two bowls of water over moderate heat until the volume was reduced by half (Dong et al., 2006). Previous studies have demonstrated that the drug ratio of RA and RAS should be maintained at 5:1 to achieve the best chemical composition and biological responses (Dong et al., 2006; Ning et al., 2002), which is in accord with the ancient preparation. DBT is well known for its remarkable efficacy in raising "Qi" (the vital energy) and in nourishing the "Blood" (the body circulation). Pharmacological studies have indicated that DBT has the ability to promote hematopoietic functions, stimulate cardiovascular circulation, prevent osteoporosis, increase anti-oxidation activity and stimulate the immune system (Gao and Chen, 2000). DBT inhibits high glucose-induced proliferation and the expression of ECM proteins in glomerular mesangial cells. These findings indicate that DBT may be used, at least, as an adjuvant for controlling the progression and complications of diabetes mellitus, such as DN and renal failure. However, further experimental and clinical studies, especially those in animal diabetic models and clinical trials, are required to explore the mechanisms and verify its effects. 
Bawei dihuang wan
Bawei Dihuang wan (Hachimi-jio-gan), one of traditional herbal medicines (remedies composed of Rehmannia Glutinosa, Fructus Corni, Rhizoma dioscoreae, Poria cocos, Cortex moutan, Rhizoma alismatis, Ligusticum wallichii and Cortex cinnamomi), was originated from "The Synopsis of Prescriptions of the Golden Chamber" in the Eastern Han Dynasty. It is a famous Chinese herbal formula that has been used for a long time in the treatment of DN. Hachimi-jio-gan reduced fibronectin and TGF-β1 protein expression in the renal cortex. Furthermore, renal lipid peroxidation levels of WBN/Kob rats given Hachimi-jio-gan were significantly lower than those of untreated controls. Renal superoxide dismutase activity was elevated by Hachimi-jio-gan treatment in a dose-dependent manner. These results suggested that Hachimi-jio-gan could prevent diabetic kidney damage by reducing renal oxidative injury and expression of fibronectin and TGF-β1 proteins, which are all involved in the pathophysiology of DN. 
Chinese herbal components
Many researchers investigated astragalus for the treatment of DN, and the results seemed intriguing. Zhang et al. systematically reviewed the published animal experiments that had assessed the renal protective effects of astragalus in diabetic rat models. Their results showed significant beneficial effects of astragalus involving improvement of fasting blood glucose levels, glomerular filtration rate (GFR), urinary albumin excretion rate and thickness of the glomerular basement membrane. Hong and co-workers  reported that astragalus might "play protective roles in diabetic nephropathy through multiple pathways." Zhang and his co-workers studied the effects of astragalus polysaccharide (APS), an aqueous extract from the astragalus membraneous roots, on gene expressions of nuclear factor-kappaB (NFκB) and an inhibitory protein of NFκB in experimental DN rats induced by streptozotocin. The results showed that APS improved proteinuria and renal function and the mRNA level of NFκB in the renal cortex was decreased and IkappaB mRNA expression was raised by APS.  AS-IV dose dependently inhibited UUO-induced renal fibrosis and function injury, which are associated with TGF-β-stimulated Smad 2/3 phosphorylation, profibrotic genes TGFβ1, myofibroblast marker a-SMA and ECM accumulation in a rat renal injury model. In addition, AS-IV also effectively inhibited TGF-β1-stimulated Smad 2/3 phosphorylation, profibrogenic genes, a-SMA and ECM protein expression in a rat NRK-49F cell line. Furthermore, blockade of TGF-β/Smad signaling via induction of renal Smad7 could be the underlying mechanism by which AS-IV attenuated UUO-induced renal fibrosis in vivo and TGF-β1-stimualted profibrogenic factors and ECM production in vitro.  Another study demonstrated the inhibitory effect of AS-IV on the Wnt/β-catenin signaling pathway in a rat UUO model, and further suggested that AS-IV may affect renal interstitial fibrosis through this pathway, indicating that AS-IV may potentially act as a renal protective agent. 
Turmeric (the common name for Curcuma Longa, known as haldi in Hindi) is an Indian spice that belongs to the ginger family.  Besides its use as a spice, food preservative and coloring agent, turmeric has been traditionally used in Ayurvedic medicine for the treatment of various ailments such as arthritis, ulcers, jaundice, wounds, fever, trauma as well as skin diseases like psoriasis.  Curcumin, a hydrophobic polyphenol, is a principal active constituent of turmeric. Curcumin, a major polyphenol from the golden spice Curcuma longa, commonly known as turmeric, has been recently discovered to have renoprotective effects on DN. Down-regulation of the SphK1-S1P pathway is probably a novel mechanism by which curcumin improves the progression of DN. Inhibiting AP-1 activation is one of the therapeutic targets of curcumin to modulate the SphK1-S1P signaling pathway, thereby preventing diabetic renal fibrosis. Curcumin ameliorates macrophage infiltration by inhibiting NF-κB activation and proinflammatory cytokines in streptozotocin-induced DN. 
Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is purified from rhubarb (Rheum officinale), a widely used traditional Chinese herb. In previous studies, rhein was shown to be effective in ameliorating diabetic renal pathological changes and attenuating hyperlipidemia. Statins have also been proven to ameliorate renal pathological changes associated with DN through lipid-dependent and -independent mechanisms. Meanwhile, there was a study to prove the protective and regulatory effects of rhein on renal injury and dyslipidemia in db/db mice with DN using simvastatin as the control and to provide information on the mechanisms by which rhein protects against renal damage from DN. 
Tripterygium wilfordii polyglycosidium
Numerous studies have shown that Tripterygium wilfordii polyglycosidium (TWP) exhibits immunosuppressive effects and a therapeutic effect on podocyte injury. TWP is widely used to treat various glomerular diseases. ,
Glomerular hypertrophy and tubular deformation were significantly reduced in the DN rats treated with TWP. Other lesions, including fusion of the podocyte foot processes, disappearance of membrane slits and reduced number of slits, markedly improved. The combination therapy group, in particular, showed recovery of a clear continuous linear distribution. 
| Perspectives and future directions|| |
Most TCM remedies are formulated to contain different herbs in combination in order to enhance the curative efficacy and also reduce the side-effects; it is relatively difficult to figure out which component from the formula is the main effective monomer for the therapy of DN. In summary, TCM exhibits broad applicability and good efficacy in the treatment of DN.
Further studies will be required to identify the ingredients and/or chemicals in the TCM formulas that are responsible for the beneficial renal effects observed. Side-effects during early treatment need to be evaluated and further studies are required. Depending on evidence-based medicine theory, rational appraisal of side-effects and adverse reactions require large samples and polycentric and randomized double-blind clinic trials to prove the efficacy of TCM treatment for DN.
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