Tibetan Medicines for the Treatment of Diabetic Nephropathy

Pu, Lili; Yang, Chunhong; Yu, Liqiong; Li, Shiling; Liu, Yaqin; Liu, Xinan; Lai, Xianrong

doi:https://doi.org/10.1155/2021/7845848

Evidence-Based Complementary and Alternative Medicine

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Abstract Introduction Materials Results Discussion Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2021 | Article ID 7845848 | https://doi.org/10.1155/2021/7845848

Tibetan Medicines for the Treatment of Diabetic Nephropathy

Lili Pu,¹Chunhong Yang,¹Liqiong Yu,¹Shiling Li,¹Yaqin Liu,¹Xinan Liu,¹and Xianrong Lai^1,2

Academic Editor: Harry Lee

Received10 Aug 2021

Revised06 Sept 2021

Accepted09 Sept 2021

Published06 Oct 2021

Abstract

As an important part of the traditional Chinese medicine system, Tibetan medicine has its unique treatment methods for diabetes mellitus and its complications. Diabetic nephropathy (DN) is one of the most serious diabetic microvascular diseases. Tibetan medicine believes that the occurrence of DN is closely related to renal function changes, and it can be effectively prevented and treated by improving renal lesions. In this paper, we consult ancient books of Tibetan medicine and summarize the medicines that treat kidney disease in the Tibetan medicine system. The Chinese name, English name, and Latin name of these drugs were searched as keywords in the online database. Thirty-four drugs were found for the treatment of DN. The most commonly used were Amomum kravanh, Terminalia chebula, and Tribulus terrestris, and we introduced the traditional uses and modern pharmacological activities of these drugs. The results indicate that Tibetan medicines for kidney disease could be used as potential candidate drugs for DN; they would expand the range of medications for DN and provide a new idea for the treatment of DN.

1. Introduction

Diabetic nephropathy (DN) is a series of microvascular complications caused by changes in renal structure and function due to chronic diabetic microangiopathy. It is mainly characterized by continuous albuminuria and progressive reductions in renal function. It is one of the most serious chronic complications of diabetes mellitus and one of the most common causes of end-stage renal disease (ESRD) [1]. If it is not treated promptly, it will endanger the life and health of patients. According to relevant epidemiological statistics, diabetic patients are expected to reach 578 million in the world by 2030; meanwhile, DN patients will break through 100 million [2]. The incidence of DN in diabetic patients in China is about 47.66% [3]. Its pathological features include early glomerular hyperfiltration, changes in capillary permeability, increase in mesangial membrane cells and matrix, glomerular basement membrane thickening, deposition of extracellular matrix, subsequent glomerular sclerosis and fibrosis, and ultimately leading to the deterioration of renal function [4], which is the main cause of death in diabetic patients. The pathogenesis of DN is complex. Modern medicine mainly prevents and treats DN by controlling blood glucose and blood pressure, regulating blood lipids, lowering urinary albumin, and following other principles. But diabetes mellitus and its complications cannot be treated well by these simple means only [5, 6]. So it is necessary to combine modern medical treatments with traditional medical methods to obtain better therapeutic results.

Tibetan medicine is an important part of the treasure house of Chinese medicine, which has a long history, complete theory, and rich content. It has made great contributions to the reproduction, survival, and development of Tibetan people and has a unique curative effect on the treatment of diabetes mellitus and its complications. Based on the knowledge of DN from the Tibetan medicine theory, we have found that the occurrence of DN is closely related to kidney lesions. And modern studies have also found that DN can be effectively prevented and treated by protecting kidneys and improving kidney function [7, 8]. Tibetan medicine has a unique therapeutic approach to diabetes mellitus and its complications and has been gradually applied in the treatment of DN. However, the current records on Tibetan medicines for the treatment of DN are not comprehensive enough and lack systematic summary and generalization. Therefore, supported by Tibetan medicine theory, we attempt to find Tibetan medicines for DN from the Tibetan medicines for treating kidney diseases, in order to expand the drug use range of DN and provide new ideas for the treatment of DN.

2. The Knowledge of Tibetan Medicines on DN

Tibetan medicine believes that there are three major factors: rLung, Bad-kan, and mKhris-pa in the physiological activities of the human body. The three factors control the movement changes of the seven material bases (seven essences) in diet essence, blood, meat, fat, bone, bone marrow, semen, and the motion of three excretions (three filth) in stool, urine, and sweat. Under certain conditions, the three basic factors are relatively coordinated, maintaining the balance with the seven essences and the three obscenities and keeping the normal physiological activities of the body. Once one of the three factors changes, this balance will be disrupted, causing various pathological changes that can lead to disease.

DN belongs to the category of “jingnisaku disease” (Chinese direct translation: frequent urination) in Tibetan medicine, and Tibetan medicine believes that “jingnisaku disease” is a consumptive disease, which promotes the consumption and reduction of mKhris-pa (cold), thus losing its counterbalancing effect on Bad-kan (hot) and increasing the effect of Bad-kan. The decrease in mKhris-pa and the increase in Bad-kan lead to the dysfunction of rLung, which makes the originally reduced mKhris-pa in the body or tissues decrease more and more, while the originally increased Bad-kan increases more and more, and the imbalance of the three factors is getting worse, then driving the further deterioration of DN. The “jingnisaku disease” is caused by the imbalance of rLung, Bad-kan, and mKhris-pa due to external factors such as improper diet and living. The ancient book of Tibetan medicine Rgyud bzhi records: “due to eating salty, sweet, cold, or heavy diet, living in a humid place for a long time, growing Bad-kan size, cannot be sublimated to the essence to be absorbed and leak into the bladder, producing body fluids and causing disease.” In the Blue Glaze, it is said that “long-term living in damp places and other reasons weaken the function of the kidneys, unable to differentiate the dregs and essences, directly fall into the bladder, and cause frequent urination.” This is similar to modern medicine, which believes DN is dominated by persistent proteinuria and accompanied by varying degrees of frequent urination, acute pain, and urinary discomfort. Tibetan medicine believes that “jingnisaku disease” can be caused by factors such as weakened kidney function. The prescriptions for the treatment of “jingnisaku disease,” such as Shibawei Hezi diuretic pill and Shiliu Rilun pill, have the effect of benefiting the kidneys. And Tribulus terrestris, a Tibetan medicine for the treatment of kidney disease, has also been used in the Tibetan formula Siwei Jianghuang decoction powder for the treatment of “jingnisaku disease.” In conclusion, the occurrence of “jingnisaku disease” is closely related to kidney pathology.

3. Materials and Methods [9]

We have manually searched eleven Tibetan medicine monographs and drug standards, such as Dictionary of Chinese Ethnic Medicine, Jing Zhu Materia Medica, Chinese Tibetan Materia Medica, Rgyud bzhi, and Blue Glaze. And we have looked up the information on Tibetan medicines for the treatment of kidney diseases and used their dialect, English, or Latin names as keywords to search in Chinese online databases (such as CNKI, VIP, and Wanfang) and English online databases (such as Sci-Hub, ScienceDirect, GeenMedical, etc.) to obtain their modern pharmacological studies on DN. In addition, we consulted the Tibetan prescriptions for the treatment of renal diseases in Treasure House of Tibetan Medicine Prescriptions and Interpretation of Commonly Used Tibetan Medicines and summarized the commonly used Tibetan medicines that are used more frequently and can treat DN from these formulas.

4. Results

In this paper, we reviewed 362 Tibetan medicines for the treatment of kidney diseases (nephritis, kidney deficiency, kidney cold, kidney heat, kidney edema, etc.) in the traditional Tibetan medicine system. Among these 362 Tibetan medicines, 60 have been used to treat kidney diseases in modern studies, of which 34 have been used for the treatment of DN. The 34 Tibetan medicines for DN are all botanicals, distributed in 23 different families, and the most common families are Leguminosae (23%), Umbelliferae (6%), Zingiberaceae (6%), Rubiaceae (6%), and Solanaceae (6%) (Figure 1). The scientific names, Chinese names, Tibetan names, families, medicinal parts, and modern pharmacological effects of the Tibetan medicines for DN are shown in Table 1. In addition, we have found that 16 Tibetan medicines for the treatment of kidney diseases have antidiabetic activity. Therefore, it is necessary to further study the effects of these Tibetan medicines on DN, with a view to using them in the treatment of DN.

4.1. Tibetan Medicines for Treating DN

It can be seen from Table 1 that the above Tibetan medicines can protect the kidney by improving the expression of related factors (TGF, HIF-1α, VEGF, SOD, etc.) in renal tissue, inhibiting the damage of renal epithelial cells, alleviating renal fibrosis, scavenging free radicals, and inhibiting lipid peroxidation and other ways, and play a role in the treatment of DN.

4.2. High-Frequency Tibetan Medicines

In order to understand the frequency of Tibetan medicines use for the treatment of DN, we also inquired about Tibetan medicine prescription books such as Treasure House of Tibetan Medicine Prescriptions and Interpretation of Commonly Used Tibetan Medicines and collected 123 Tibetan medicine prescriptions for kidney disease. The Traditional Chinese Medicine Inheritance Support System (version 2.5) [74] is used to get the frequency of Tibetan medicines used in prescriptions. Through data mining, there are 7 drugs that are used more than 20 times and can treat DN (Figure 2); they are Amomum kravanh with the used frequency of 54, Terminalia chebula with 42, Malva verticillata with 40, Rubia cordifolia with 29, T. terrestris with 27, Piper longum with 25, Punica granatum with 22.

(a)

(b)

(c)

(d)

(e)

(f)

(g)

The following is a detailed introduction to the name base sources, traditional effects, and modern pharmacological effects of the three most widely used Tibetan medicines (A. kravanh, T. chebula, and T. terrestris).

4.2.1. Amomum kravanh

This is the dried ripe fruit of the Zingiberaceae plant A. kravanh Pierre ex Gagnep (Tibetan name: སུག་སྨེལ། (transliterated as Jia-na-su-men) and English name: Amomum cardamomum). It is originated in Cambodia and Thailand and is now introduced and cultivated in Yunnan and Guangdong in China, mostly in the wet area of the trench. It is applied for the treatment of diseases such as waist and leg soreness caused by kidney cold in Tibetan clinics (Chinese Materia Medica·Tibetan Medicine Roll). Blue Glaze records that A. cardamomum treats cold nephropathy and various diseases caused by rLung. In Rgyud bzhi, A. cardamomum can cure kidney disease and all cold diseases.

A. cardamomum is widely used in the treatment of kidney diseases, and it is also recorded in Tibetan medicine. The main chemical component of A. cardamomum is a volatile oil, which has various pharmacological activities such as antibacterial, antioxidation, and hypoglycemic activity. A. cardamomum is the main medicine of Tibetan medicine compound preparations (such as Shiwei Cardamom Pill and Shibawei Hezi diuretic pill) for the treatment of kidney diseases. The modern use of cardamom has also shown some efficacy in treating many kidney diseases such as chronic renal failure, chronic pyelonephritis, and DN. Chen et al. [75] found that cardamomum volatile oil can reduce the urine protein content of acute kidney injury rats; reduce renal body index; improve renal tubular pathology; reduce MDA, NO content, and NOS activity in renal tissue; and increase SOD and GSH-Px activity in the kidney tissues so that cardamomum can improve the acute kidney injury of rats caused by gentamicin to a certain extent. Chen et al. [76] showed that A. cardamomum can reduce kidney damage in rats with adriamycin nephropathy, and its mechanisms may be related to the expression of TGF-β1 and PAI-1 in kidney tissue. They also found that A. cardamomum volatile oil can upregulate MMP-2 TGF-β1 and IGF-2 protein expression, significantly reduce the blood glucose of streptozotocin-induced DN model rats, and improve the kidney pathological changes in DN rats. In conclusion, A. cardamomum has a certain therapeutic effect on DN, but there are relatively few studies on its mechanisms. Therefore, modern analytical methods should be used to conduct a more extensive and in-depth experimental study on the effects and mechanisms of A. cardamomum in the treatment of DN, making it a common and effective drug for the treatment of DN.

4.2.2. Terminalia chebula

This is the fruit of the Junzi family plant T. chebula Retz. (Tibetan name: རུ་ར (transliterated as A-ru-re)). Born in the sparse forest at an altitude of 800–1000m, mainly distributed in western and southwestern Yunnan, also cultivated in Guangdong and Guangxi. Rgyud bzhi records that T. chebula has six flavors, eight properties, and seventeen functions. Known as the “King of Tibetan Medicine” in China, it can be used in the treatment of kidney disease, diabetes, and other diseases in the Tibetan medicine system.

The effective components of T. chebula are complex, of which phenolic acids are the main components; it has many pharmacological activities such as antioxidation, antidiabetic, antipathogenic microorganism, anti-inflammatory, analgesic, and so on [77]. T. chebula has a strong antioxidant capacity, which is the basis of its efficacy in protecting kidney function and preventing diabetes, and studies have found that polyphenols are the material basis for the antioxidant effect of T. chebula [78]. Tayal et al. [79] found that the aqueous extract of T. chebula had a protective effect against oxalate-induced injury to NRK-52E and MDCK renal epithelial cells; it can enhance cell viability, reduce LDH release, and inhibit the nucleation and growth of calcium oxalate crystals, thus playing a role in protecting the kidneys. Rao and Nammi [80] found that T. chebula extract can reduce blood glucose in streptozotocin-induced diabetic rats, has strong antidiabetic and renal protection, and can be used for the treatment of DN. Kim et al. [81] showed that T. chebula extract can reduce blood glucose, blood lipids and serum MAD levels in diabetic rats caused by streptozotocin, improve the kidney pathological tissue morphology, and reduce the formation of AGEs in diabetic rats. Li et al. [11] found that T. chebula acid can affect the phosphorylation of VEGF-2, which cannot normally promote angiogenesis after VEGF binding to the receptor, thereby inhibiting the progression of DN. Therefore, T. chebula cannot only protect the kidneys and prevent and treat diabetes but also be used in the treatment of DN. It is the first choice for Tibetan medicine to treat various diseases.

4.2.3. Tribulus terrestris

This is the mature fruit of the Tribulaceae plant T. terrestris L. (Tibetan name: གཟེ་མ། (transliterated as Se-ma) and English name: Tribulus). Mostly born on barren hills and fields, distributed in sandy land in Tibet and other regions. Se-ma is sweet, astringent in taste and warm in nature and functions to benefit water and dispel dampness. It is mainly used for kidney heat, urinary atresia, malnourished edema, and other diseases. Rgyud bzhi records that se-ma can treat diuresis and cure rheumatoid arthritis and kidney disease.

Tribulus mainly contains flavonoids, saponins, amides, and other compounds [82]; the current pharmacological research mainly focuses on T. terrestris saponins. T. terrestris saponins have pharmacological effects of antifatigue, protect myocardium, lower blood lipids, lower blood pressure, lower blood sugar, and so on [83]. Yang et al. [84] evaluated the effects of T. terrestris in preventing and treating renal calcium oxalate stones and found that blood urea nitrogen, creatinine, urine oxalic acid, Ca²⁺, and malondialdehyde contents of renal homogenate were increased, while blood Ca²⁺ and renal GPX content decreased significantly, renal calcium oxalate crystals was decreased, and kidney damage was alleviated after T. terrestris treatment. It is concluded that T. terrestris can effectively prevent and treat kidney calcium oxalate stones in rats and protect kidney function. Meng et al. [85] found that Tribulus can reduce the expression of LepR in the kidney, inhibit the response of the JAK2/STAT3 pathway, reduce the sensitivity of the kidney to leptin, reduce selective leptin resistance, lower blood pressure, and protect the kidney. Lamba et al. [86] found that the ethanol extract of T. terrestris had a significant protective effect on streptozotocin-induced diabetic rats by inhibiting oxidative stress. Zhao et al. [87] showed that T. terrestris extract can reduce TLR2 and TLR4 mRNA levels in pancreatic islet cells, inhibit inflammation, and significantly improve the clinical symptoms of polydipsia and polyphagia, which can be used for the treatment of type 2 diabetes. Zhao et al. [88] found that T. terrestris saponins also have a certain protective effect on the retina of type 2 diabetic rats. It has been reported that the hydroalcoholic extract of T. terrestris is able to reduce the urinary total protein and albumin content in streptozotocin-induced diabetic rats, thereby improving diabetic kidney damage and being used in the treatment of DN. In addition, among Professor Nian Li’s 158 prescriptions for the treatment of DN, T. terrestris is the fifth most commonly used drug for the treatment of DN [89].

In summary, the high-frequency drugs used in the Tibetan medicine system for the treatment of kidney diseases are also commonly used drugs for the treatment of kidney diseases, diabetes, and DN in modern medicine. It should invest more on research to clarify its effects on DN and its mechanisms, so as to improve the safety and effectiveness of the clinical application.

5. Deficiencies and Prospects

Although Tibetan medicine has a positive effect on the treatment of DN, there are still many gaps and limitations in the research of Tibetan medicine. First of all, there are 362 kinds of Tibetan medicines in the Tibetan medicine system that can be used for the treatment of kidney diseases. Only 60 kinds have been proved to have kidney-related pharmacological activities; 34 kinds can be used for the treatment of DN; and most drugs still lack experimental evidence for the treatment of DN. For example, Malva seed is commonly used in the Tibetan medicine system to treat nephropathy, and it is also used by many physicians in the treatment of DN. However, there is no research on its biologically active ingredients and pharmacological mechanisms in the treatment of DN. Therefore, it is necessary to carry out deep researches combined with modern medical research methods to clarify the bioactive components of these drugs and their action and mechanism on DN, so as to be used in the clinical treatment of DN as soon as possible. Secondly, we found that among the 60 kinds of Tibetan drugs for treating kidney diseases, 16 have antidiabetic activity, but there is no research report on DN. For example, modern research has found that Althaea rosea can be used for the treatment of kidney stones, kidney damage, and so on. The hypoglycemic and antioxidant capacity of its seeds indicate that it has a certain effect in the treatment of diabetes and its complications [90, 91], but there is no experimental research on DN at present. Therefore, we hope to invest some researches on these drugs to determine their effects on DN and find more drugs for the treatment of DN. In addition, the potential toxicity of Tibetan medicines should not be overlooked. For example, Radix Rubiae has a good therapeutic effect on DN, but some studies have found that the alcohol extract of Radix Rubiae has slight hepatotoxicity and nephrotoxicity [92]. Thus, while using these drugs to treat diseases, the same attention should be paid to the evaluation of their potential toxicity, and certain processing or compatibility methods can be used to improve the safety of the clinical medication.

6. Discussion

Tibetan medicine is an important part of Chinese traditional medicine and excellent traditional culture, and it is one of the most influential ethnic medicine in China, which possesses a complete theoretical system and has rich experience in the treatment of “jingnisaku disease.” By regulating the balance of the three major factors of rLung, Bad-kan, and mKhris-pa, Tibetan medicine put forward unique treatment methods against the “jingnisaku disease” from the aspects of drugs, diet, and daily life, which has considerable prospects for the treatment of diabetes mellitus and its complication DN. At the same time, we think that the occurrence of “jingnisaku disease” is closely related to the weakening of renal function through the understanding of Tibetan medicine. And modern medicine believes that DN is a secondary kidney disease caused by diabetes mellitus. For the treatment of DN, consideration should be given to renal lesions while treating diabetes. Therefore, the occurrence and development of DN can be effectively prevented and treated by improving renal function and protecting the kidneys.

In view of the knowledge of Tibetan medicine on DN, the search for Tibetan medicines to treat DN will become an idea of new drug development. The results show that there are 60 kinds of drugs for the treatment of kidney diseases in the Tibetan medicine system, and 34 kinds of them have been used in the treatment of DN. These Tibetan medicines are all derived from botanicals and are mainly distributed in 23 families, among which the most frequently used is the leguminous family. It is worth mentioning that A. kravanh, T. chebula, M. verticillata, R. cordifolia, T. terrestris, P. longum, P. granatum, and other Tibetan medicines that are most commonly used to treat kidney diseases can also be used in the treatment of DN. Therefore, drugs for the treatment of kidney disease are expected to become a potential source of drugs for the treatment of DN. We find that these drugs mainly exert their effects in the treatment of DN by improving kidney function, lowering blood sugar and blood lipids, and reducing urine protein content, anti-inflammatory, and antioxidative stress and other pathways. However, the mechanisms of some drugs are not yet clear; multidisciplinary approaches should be integrated to perform more pharmacological studies to reveal their mechanisms of action.

To sum up, this study finds that drugs for the treatment of kidney disease can be used as potential drug candidates for the treatment of DN and sorts out the drugs used by Tibetan medicine in the treatment of DN, which expanded the scope of DN medication and provided a new idea for the treatment of DN. In order to make better use of Tibetan medicines, it is necessary to conduct in-depth research of existing Tibetan medicines combined with modern pharmacology, phytochemistry, and other methods to clarify the bioactive ingredients and mechanism of potential drugs for DN and to evaluate their toxic and side effects to improve the effectiveness and safety of Tibetan medicines in the treatment of DN.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Authors’ Contributions

Lili Pu conducted the research; performed data analysis; collected, organized, and wrote the Tibetan names of natural medicines; and wrote the paper. Xianrong Lai conceived and designed the study. Chunhong Yang, Liqiong Yu, Shiling Li, Yaqin Liu, and Xinan Liu amended the paper.

Acknowledgments

This research was funded by the National Natural Science Foundation of China (no. 81473427) and National Key R&D Project (2017YFC1703900).

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