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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 1  |  Page : 8-14

Mechanism of diabetic nephropathy and traditional drugs for management


Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi, India

Date of Submission19-Sep-2019
Date of Decision14-Oct-2019
Date of Acceptance30-Jan-2020
Date of Web Publication23-Apr-2020

Correspondence Address:
Dr. Shabnam Ansari
Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bjhs.bjhs_41_19

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  Abstract 


Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus which affects the kidneys. Recent reports of increasing prevalence of diabetes around the globe suggested that that the prevalence of DN will be doubled by 2025. There is an extremely high risk of progression of DN to end-stage renal disease and cardiovascular morbidity and mortality. Control of sugar levels, blood pressure control via renin–angiotensin–aldosterone system inhibition, and regular monitoring of renal functions have remained the principle of the management for DN for a long time. As conventional drugs cannot fulfill all the clinical needs due to accessibility, clinical efficacy, and safety issues, the need for novel inexpensive traditional drugs from Unani medicine to improve DN treatment and reduce the risk of complications has become urgent. Several herbal and mineral drugs have been mentioned in the old Unani books for the treatment of similar conditions stipulating DN. Through this article, an uttermost effort has been put to rememorize the mechanism of development of DN and available Unani drugs so that effect and mechanism of these drugs could be evidenced in the treatment of DN in future.

Keywords: Albuminuria, diabetes mellitus, diabetic nephropathy, traditional drugs, Unani medicine


How to cite this article:
Ansari S. Mechanism of diabetic nephropathy and traditional drugs for management. BLDE Univ J Health Sci 2020;5:8-14

How to cite this URL:
Ansari S. Mechanism of diabetic nephropathy and traditional drugs for management. BLDE Univ J Health Sci [serial online] 2020 [cited 2020 Aug 6];5:8-14. Available from: http://www.bldeujournalhs.in/text.asp?2020/5/1/8/283083



Diabetes mellitus (DM) is one of the most serious diseases affecting millions across the world. DM and its comorbidities have remained the fourth-largest cause of morbidity and mortality in the developed world.[1] Approximately 382 million people are affected worldwide. Reports have suggested that the prevalence may increase to 592 million by 2035.[2] India is considered as the diabetic capital of the world because of its ever-increasing population with diabetes, with an estimated number of 65.1 million adult diabetics.[3] In India, approximately 52% of adults are not aware of their diabetic status. Epidemiologic surveys have reported that the prevalence of diabetes is comparatively higher in urban than in rural areas.[4] DM is a large group of disorders characterized by hyperglycemia and disturbed metabolism of carbohydrates, proteins, and lipids.[5] Although pancreatic β-cells and hormone insulin are central in the etiology of DM, the pathogenic mechanisms by which high blood glucose levels arise differ widely. DM is mainly classified into three main types, namely Type 1, Type 2, and gestational diabetes, all of which are caused by a complex interaction of environmental factors, genetics, and lifestyle habits. Type 1 diabetes is characterized by insulin deficiency or a genetic abnormality that leads to defective insulin release, while as Type 2 and gestational diabetes depict insulin resistance as their underlying etiology. All categories of DM are characterized by the development of diabetes-specific microvascular complications in the eyes, kidneys, and peripheral nervous system and macrovascular complications in arteries that supply the heart, brain, and lower extremities. As a result of microvascular complications, diabetes is the leading cause of chronic kidney disease (CKD), blindness, and a variety of debilitating nerve pathologies. Diabetic patients are also at a much higher risk of stroke, myocardial infarction, and lower limb amputation. Although diabetic complications comprise a heterogeneous group of diseases, diabetic nephropathy (DN) is the most prevalent form.[6]

The present paper is primarily focused on DN. DN is one of the most serious microvascular complications of DM and a leading cause of end-stage renal disease (ESRD) across the world.[7] It is a chronic disease that mainly targets glomerular and tubular cells resulting in the loss of renal function and integrity. About 20%–30% of Type 1 and 30%–40% of Type 2 diabetic patients develop nephropathy.[8],[9] Clinically, DN is manifested by a progressive reduction of glomerular filtration rate, persistent proteinuria, and renal dysfunction. The most striking characteristics of DN include specific renal structural and functional aberrations, glomerular hyperfiltration and hypertrophy, glomerular basement membrane thickening (BMT), mesangial expansion, and accumulation of extracellular matrix (ECM) proteins.


  Mechanism of Nephropathy in Diabetes Mellitus Top


The DN has multifactorial etiologies. hypertension, hyperglycemia, dyslipidemia, genetic factor, obesity, inflammation, and oxidative stress, and other metabolic disorders have been reported to contribute to the initiation and progression of DN.[10] Upstream to all factors, hyperglycemia is the major driving force for the development of DN. Downstream of the all factors, chronic renal microinflammation and subsequent ECM accumulation, is the important pathway for the progression of DN. Persistent hyperglycemia-induced advanced glycation end product (AGE) formation contributes significantly to the development of DN. AGEs modify the structure and function of intracellular as well as extracellular proteins, which stimulate the production of reactive oxygen species (ROS). ROS favors an increase in the expression and accumulation of ECM proteins in glomerular and mesangial cells.[11],[12] Similarly, increased production of sorbitol through the polyol pathway also plays a significant role in the development of DN. Sorbitol has been liked to trigger osmotic stress, activation of protein kinase C (PKC), production of AGEs, and formation of ROS in diabetic kidneys.[13] In addition, hemodynamic pathways involving the renin–angiotensin system (RAS) and nitric oxide (NO) system activates the proliferation of renal cells and the expression of cytokines or growth factors, which directly or indirectly contribute to the renal damage in diabetes patients.[14] Activation of PKC pathway is another important factor in the etiology of DN. Both metabolic and hemodynamic factors activate PKC and act as a stimulus for the expression of several cytokines and growth factors.[15] The direct action on renal cells or indirectly by stimulating other factors, cytokines and growth factors produce renal damage and thereby affect renal function.[16],[17]

Inflammatory pathways have also been suggested to play a critical part in the pathogenesis of DN beside metabolic and hemodynamic factors.[16],[18] The most convenient evidence concerning the involvement of inflammation in DN comes from the fact that patients with DM and overt nephropathy exhibit the increased levels of acute-phase markers of inflammation, including interleukin-1 beta (IL-1 β), IL-6, tumor necrosis factor-alpha (TNF-α), and fibrinogen.[19] The key mediators of inflammation pathways in DN include transcription factors, pro-inflammatory cytokines, adhesion molecules, chemokines, toll-like receptors, NO, and profibrotic proteins.

Nuclear factor-kappa B (NF-κB), an important transcription factor, regulates the expression of various genes involved in inflammation and ECM turnover such as growth factors, inflammatory cytokines, chemokines, and cell adhesion molecules (CAMs).[20] NF-κB is expressed by almost all cells of the body, including adipocytes, skeletal muscles, macrophages, leukocytes, and intrinsic renal cells. Normally, the majority of NF-κB is present as a heterodimer of p65 (RELA)/p50 proteins and is inhibited by inhibitory κB (IκB) proteins, which inactivate NF-κB by trapping it in the cytoplasm. Phosphorylation and proteasomal degradation of IκB leads to the activation of the NF-κB complex, which then translocates into the nucleus and induces the expression of downstream effector genes. NF-κB is activated by various cell stress-associated stimuli including hyperglycemia, oxidative stress, cytokines, and obesity.[21] NF-κB has been implicated in the development of insulin resistance,[22],[23] and DN.[24] In diabetic kidney, NF-κB activation leads to the increased expression of pro-inflammatory cytokines such as IL-1 β, IL-6, and TNF-α; growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and cytoplasmic transmembrane growth factor (CTGF); chemokines such as chemokine ligand 2; and CAMs such as intercellular CAM 1.[24],[25],[26],[27],[28] Pro-inflammatory cytokines, chemokines, and CAMs cause the infiltration and accumulation of macrophages, monocytes, and leukocytes into the renal tissue and thus initiate an inflammatory cascade, which, in turn, lead to structural and hemodynamic abnormalities in renal tissue.[19],[29],[30],[31] TNF-α has been implicated in the promotion of local oxidative stress,[32] increasing protein permeability,[33] and the induction of renal cell loss.[34] On the other hand, growth factors, such as TGF-β, VEGF and CTGF, stimulate the expression and accumulation of ECM proteins including laminin, fibronectin, and collagen-IV in mesangial cells, thus causing structural abnormalities in nephrons.[35],[36] Suppression of NF-κB activation by various agents, such as 1,25-dihydroxyvitamin D3,[37] thiazolidinediones,[38] curcumin,[39] and cilostazol,[40] has shown promising protective effects against DN in both human subjects and animal models, suggesting the importance of NF-κB as a potential therapeutic target of DN.

ROS such as hydroxyl radical, hypochlorous acid, and superoxide radical also significantly contribute to renal injury in DM. In the diabetic kidney, ROS generation is stimulated by a number of factors including high glucose level, AGEs, growth factors, and cytokines.[41],[42] The effects of ROS in renal cells include damage of cellular macromolecules, mesangial cell proliferation, expression of growth factors, ECM accumulation, and induction of epithelial–mesenchymal transition.[41],[42],[43]


  Available Drugs in Modern Medicine Top


Most of the conventional drugs employed for DN are directed against hyperglycemia and hypertension. However, these drugs have shown only limited success against DN. Antihyperglycemic drugs such as sulfonylureas (e.g., glibenclamide), biguanides (e.g., metformin), thiazolidinediones (e.g., rosiglitazone), and alpha-glucosidase inhibitors (e.g., acarbose) have been commonly utilized. These drugs act selectively to modulate a specific pathological pathway [44],[45] and control blood glucose at normal levels. Even though these drugs may be valuable in the management of DM, they have certain limitations due to undesirable side effects associated with them such as hypoglycemia, secondary failure, weight gain, liver toxicity, skin allergy, and inability to arrest pancreas degeneration.[46],[47],[48] Moreover, these therapies only partially compensate for secondary target organ derangement seen in diabetics.[49] These antihyperglycemic drugs have lost their role as a stand-alone treatment for DN because of their limited clinical efficacy, prevention of course and associated comorbidities of the disease, and the associated adverse effects. Antihypertensive drugs have been employed in the treatment of DN to reduce proteinuria and renal damage. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockade (ARB) delayed the increase in albuminuria. In type 2 diabetes, ACE inhibitors and ARBs have shown to reduce the risk of DN.[50],[51],[52] However, again, these are often associated with substantial toxicity. In addition, anti-inflammatory agents such as NF-κB inhibitors, TNF-α blocking agents, IL-1 receptor antagonists, monoclonal antibodies against TGF-β, and IL-6 blockers have also shown their potentials in protecting kidneys from damage through inflammatory mediators in variousin vivo studies of DM as well as in clinical trials.[37],[38],[39],[40],[53],[54] Although they are much effective in attenuating renal dysfunction in diabetic patients, many populations are not able to use such agents because of their higher costs.[55] Moreover, since DN is a disorder of multiple etiologies involving numerous pathways, consumption of a drug which acts on only one molecular target is not sufficient to treat DN. Besides, the drugs with multiple pharmacological effects would be ideal to use for treatment. Hence, it is highly desirable to find therapeutic agents that could prevent the initiation as well as the progression of DN through multifactorial pathways and do not produce side effects unlike modern drugs. All these issues have led the experts to search for safe, effective, and economic alternative treatment strategies that are preventive, quite effective, and less toxic.


  Treatment With Traditional Drugs Top


Plants are the basic source of drugs for traditional and alternative medicine systems that have been in existence for thousands of years. Till now, herbal and traditional systems continue to play an essential role in providing health care at all levels. Old data of the World Health Organization (WHO) project that approximately 80% of the world's population from developing countries count solely on traditional medicines (mostly derived from plants) for their primary health care.[56],[57] Plant products also play an important role in health care for the remaining 20% in developing countries and for those in industrialized countries as well.[58] Medicinal plants and the compounds obtained from them are being looked up for the treatment of DM and its secondary complications. Many conventional drugs have been derived from medicinal plants, such as metformin and curcumin. The committee for the WHO on diabetes has recommended that traditional medicine must be further investigated for their antihyperglycemic effect.[59] Therefore, contrary to the modern synthetic drugs, herbal or traditional medicine has emerged as a promising alternative to the lowest degree of toxicities and negligible side effects. India has an extensive flora and fauna area enriched with a large number of medicinal and aromatic plants. Hence, there is a huge potential for investigating such traditionally important medicinal plants to elucidate their potential therapeutic applications. Unani medicine is also one of the oldest traditional and herbal systems of medicines, which treats various diseases and ailments with drugs of mostly 90% herbal and rest with mineral and animal origin. The practice, research, and education of Unani medicine are governed through the Ministry of AYUSH, government of India. The present study is a step in this direction to outline those traditional herbal and Unani drugs which could be utilized in the treatment of DN [Table 1].
Table 1: Traditional drugs for diabetic nephropathy

Click here to view



  Conclusion Top


DM is a noncommunicable disease of global healthcare burden with approximately 400 million people affected worldwide and expected to be around 600 million by the year 2035. It is the fourth leading cause of mortality throughout the world. The diabetes-induced disease burden is increasing in every country due to the prevalence of obesity, emotional stress, unhealthy lifestyles, lack of screening strategies and their proper implementation, reluctant population, and awareness.

DN remains one of the most common etiologies for the development of CKD and end-stage renal failure worldwide. Experimental studies have explored the pathophysiology of DN which led to the availability of range of potential novel therapies. DN not necessarily develops in all the diabetics. However, the main modifiable risks are hypertension, glycaemic control, and dyslipidaemia. DN is a multistage condition that makes several years to develop ESRD. Incipient nephropathy is the veryfirst presence of low but microamounts of urine albumin, referred to as microalbuminuria (persistent albuminuria at level 30–299 mg/24 h). Overt nephropathy or macroalbuminuria (persistent albuminuria at level ≥300 mg/24 h) develops after many years in type 1 diabetes but may be present at the time of diagnosis of type 2 diabetes. Macroalbuminuria patients are more likely to develop ESRD. Various guidelines have suggested screening with a spot urine albumin/creatinine ratio (normal >30 mg/g creatinine) from eitherfirst morning (preferred) or random specimens along with an assessment of kidney function test. Novel strategies to slow down the progression of different types of pathway to renal damage have emerged. However, arresting the progression of DN remains a major challenge. Glycemic management, blood pressure control, and the RAS inhibitors are used primarily for the treatment for DN and have been evidenced in reducing the risk and progression of the disease. However, novel potential therapies are the requisite for the patients who are intolerant to conventional therapies and those patients with deteriorating renal function with normoalbuminuria.

India is the fourth country with the highest number of people suffering from DM. Due to restricted resources and deficient systematic treatment strategies in rural areas of India, traditional drugs from Indian system of medicine (AYUSH) can be investigated as novel potential therapeutic agents to prevent the risks and progression of DN. Various herbal and mineral origin drugs have been cited in the literature of Unani medicine to be beneficial in the treatment of DN. Unani drugs such as giloy, ginger, horse gram, Indian horse-chestnut, Indian olibanum, Indian rhubarb, isabgol/psyllium husk, Levant cotton, maidenhair fern, muskmelon, opium, pistachio, pomegranate, quince, rose, turmeric, watermelon, Arabic gum, asafoetida, black asphalt, black henbane, black piper, and celery are mentioned in Unani classics for the treatment of albuminuria. Thus, these drugs plausibly could be a better candidate to study for their efficacy and ascertaining them under the canvas of mechanism of development of DN.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

[72]

 
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