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Diabetes & Obesity International Journal Research Article 11 min read

Essential Genes Associated with Diabetic Nephropathy

Keerthana S, Aswathi P and Ramakrishnan V*
* Corresponding author
ISSN: 2574-7770  10.23880/doij-16000192  Received: January 21, 2019  Published: February 05, 2019
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Keywords
Type 1 and 2 diabetes Diabetic Nephropathy End Stage Renal Disease Genetic Factors
Abstract

The main source which causes kidney diseases is Diabetic Nephropathy, consider as a causative factor leading to significant morbidity and death rate among diabetic patients. The developments of disease risk factors seen in DN are strongly concerned with genetic factors in diabetic patients which eventually develop kidney disease. Numerous genetic factors that are considered to be a risk variant and each possess an insignificant effect, and they are collectively involved in causing disease. The vulnerability loci of several genes like MTHFR, ACE, FRMD3, GLUTI, and TNF-α, eNOS, VGFR, UMOD and RAGE are suspected for developing diabetic nephropathy which is eventually increasing several times. Evolving works in current research recommending that the mutable genetic risk factors associated with DN. In this article mainly highlights the four major genes ACE, TNF-α, UMOD and NOS3, identification of those novel genes can be used as prognostic biomarkers for screening and better understanding of DN pathogenesis.

Introduction

A cluster of disease that alters the typical biological mechanism in human with the prevalence of elevated blood sugar over a prolonged period is known as Diabetic Mellitus (DM). This disease is classified as two major types either it is due to the pancreas, which doesn’t produce sufficient amount of insulin or the type the body cells are not properly functioning to the produced insulin [1]. DKD have enhanced the mortality and morbidity in many countries and it is mainly caused by both types 1&2 diabetes disorders which deliberate to be the primary single source that leads to chronic illness in kidney [2]. In presence of persistent microalbuminuria is the clinical categorization of DN in synchronicity with types 1 and 2 diabetes [3]. The progressive increase of albuminuria and subsequent decline seen in GFR the patient medical history of diabetes for several years and renal failure develops DN. Though, current studies presenting that the development of ESRD are observed in patients with autoimmune diabetes progress as compared to those with type 2 DM [4]. The progression of DN associates with Hyperglycemia, congealing of the Glomerular basement membrane and Glomerular hyper-filtration (Figure 1).

Figure 1: Representing the progression of DN in Type 1 and 2 Diabetes patients.
Click to enlarge
Figure 1: Representing the progression of DN in Type 1 and 2 Diabetes patients.

Figure1: Representing the progression of DN in Type 1 and 2 Diabetes patients.

Abbreviations:DM: Diabetic Mellitus; ACE:
Angiotensin-Converting Enzyme; UMOD: Uromodulin;
TNF-α: Tumor Necrosis Factor; NOS3: 12. Nitric Oxide
Synthase 3.

Prevalence of DN

The prevalence of this disease globally reached the widespread proportions. Though diabetes will affect 8% worldwide which is already predictable but this is foreseeable to increase in upcoming years [5]. Every year diabetic nephropathy disease tends to increase randomly every year. This disease is recognized as the most common problem in diabetes patients. It has been estimated diabetic about 40% patients are predisposed to emerging renal dysfunction, and family-based studies stated that a significant genetic component deliberates risk for DN who will get ESRD requiring renal replacement therapies (dialysis and or transplantation) [6, 7, 8, 9]. Governments expend huge amounts for kidney disease patients every year due to its collective occurrence in Native Americans, Mexican-Americans, Asians, Indians and white Europeans was tended to possess the maximum prevalence of DN [10].

Pathogenesis of DN

The presence of microalbuminuria is the initial clinical symptoms of nephropathy. Proteinuria occurs when the micro albuminuria progresses over the following 7 to 10 years (Figure 2). Kidney function progressively drops and after 10 years ESRD will occur once over proteinuria develops. Many mechanisms donate to the growth and Ramakrishnan V, et al. Essential Genes Associated with Diabetic Nephropathy. Diabetes Obes Int J 2019, 4(1): 000192.

results to DN [11, 12, 13]. The two main mediators which involve in the kidney injury are Hyperglycemia-induced metabolic and hemodynamic stimuli, these factors stimulate inflammatory, pro-oxidant, and a fibrotic pathway eventually leads to the buildup of mesangial matrix, podocyte effacement loss and congealing of the GBM followed by endothelial dysfunction and renal arteriolar hyalinosis.

Figure 2: Representing pathogenesis of DN to ESRD [14].
Click to enlarge
Figure 2: Representing pathogenesis of DN to ESRD [14].

Genetic Aspects of DN

Diabetes kidney disease is the multifaceted disorder that tends to cluster in relations. This disease and DKD- related behaviors are assessed between 30–75% [14, 15, 16, 17]. Intended for many years, investigators have been identifying the predisposition of genetic factors that cause DK. Multiple genes have been found to be complicated in the development of DN with many allele polymorphisms showing properties on the development of the disorder therefore possessing to the overall risk. Familial aggregation of this disease has shown a positive association in many populations. The hereditary origin of kidney complication of DM is heterogeneous, suggesting that the involvement of individual genetic factors is uncertain. Several genetic variants related with human metabolic disorders data’s have been already provided to us by Genomics research tools likewise candidate gene approach, SNP detection, linkage analysis has identified the genetic risk factors of Diabetic nephropathy. Based on the biological process the susceptibility genes which are directly involved with this disease have been listed out in Table1.

Copyright© Ramakrishnan V, et al.

Cl
AuthorsReGlobal MAF
hromosomaPhenotypeClinical
GeneSNP-IDisk-allel
locationsignificance
Zhou TB, et al. [17]ACErs4341C/G17:63488629Type 2 diabetesBenignG=0.4700/2354
Zhang, et al. [18]MTHFRrs1801133C/T1:11796321Type 2 diabeticdrug-responseA=0.2454/1229
Buffon,et al. [19]FRMD3rs1888747C/G9:83540636Type 2 diabetesNilC=0.1979/991
GLUT1
GLUT1		rs3820589
rs1385129		A/T
A/C/G		1:42960373
1:42943295		Type 1 diabetesNilT=0.0988/495
Marques, et al. (2017)
A=0.2404/1204
Umapathy, et al. [20]TNF-αrs1800629A/G6:31575254Type 2 diabeticdrug-responseA=0.0903/452
Saliha Rizv, et al. [21]eNOSrs1799983A/G/T7:150999023Type 2 diabetesPathogenic
other		T=0.1763/883
rs2070744C/T7:150992991C=0.2344/1174
Li Sun [22]VEGFrs3025039C/T6:43784799Diabetes mellitusNilT=0.1336/669
Kumar.v, et al. [23]UMODrs4293393C/T16:20353266Type 2 diabetesNilG=0.1997/1000
Ying Zhang, et al. [18]RAGErs1800625C/T6:32184665Type 2 diabetesNilG=0.1366/684

Table 2: Predominant functional candidate genes studied in DN [17-23].

Major Genes Associated with Diabetic Nephropathy

In general, initial genetic factors associated studies for DN focused on aspirant genes that had biologically probable roles in the development of this disease. Various genes and SNPs were stated to be significantly related with DN. In this review, we empathize the current scenario, recent advancements and enduring challenges of susceptibility of four major genes associated with DN those are progressively involved in the development of ESRD according to their function.

Angiotensin-Converting Enzyme (ACE) Gene

The translation of angiotensin II is encoded by enzyme catalyzing of ACE gene. The effective use of two peptides that are vasopressor and aldosterone-stimulating peptide usually regulates BP and also balances the fluid- electrolyte when it is passed out by Angiotensin II. This ACE gene extends 21 Kb (26 exon) on chromosome its genomic position is 17q23 [19, 20]. The Genetic polymorphism studies describing that ACE projecting as an assumed negotiator of DN. This ACE gene polymorphism was related with ACE levels and involve as a key role in controlling of bp, sodium breakdown and kidney hemodynamics because it acts as a key enzyme in the reninangio-tensin system (RAS) and sensible to conjecture that genetic dissimilarity of ACE I/D subsidizes to the growth of DN and many studies emphasize the functional part of this gene in the multifaceted factor of DN. The pathway of DN the leading source of ESRD which is not clearly understood, but the administration of ACE Ramakrishnan V, et al. Essential Genes Associated with Diabetic Nephropathy. Diabetes Obes Int J 2019, 4(1): 000192.

gene tends to possess beneficial effects in retarding the development and progression of DN.

Uromodulin (UMOD) Gene

The gene which is exclusively involved in expression of thick ascending loop in Henle and distal convoluted tubule of the mammalian kidney and secreted into the urine is UMOD gene [22, 23] . The copious protein in normal individual’s urine under various physiological conditions is the protein encoded by this gene. Biological function remains elusive for this gene. This gene is present in human chromosome number 16 that converts protein uromodulin which is otherwise called as urinary protein in normal individuals [24]. This gene is copied particularly in the kidneys and infrequent alterations in this gene are related with monogenic forms of renal disease [23]. The biological properties of UMOD make it an aspirant for presents a host defense feature used in clearance of microorganism from the urinary tract [25, 26]. The UMOD mutation occurs in clinical phenotype is characterized by dominant inheritance; so far, above 100 mutations in this gene have been recognized by various genetic studies out of which the majority UMOD mutations collection reported in exonic region 4 and 5 [23].

Tumor Necrosis Factor (TNF- α) Gene

A TNF α gene is a multifunctional proinflammatory cytokine which belongs to a TNF super family. The Class III location of the MHC on chromosome number 6 is the locus of gene TNF [27]. The TNF-α_gene production occurs in transcriptional and post-transcriptional stages, with regulatory sequences occurring within the 5’end of TNF-_ Copyright© Ramakrishnan V, et al.

α_gene regulating the rate of transcription mechanism. This gene is associated with pathological processes, like cell death, proliferation, inflammatory response and immune-regulation. Possible effects of SNP within TNF- αon inflammatory response disorders have concerned with wide attention [28]. In human _TNF-α gene promoter region has been identified with several SNPs has the possible cause involve the changes within structural functional sites which would alter the regulatory pathway in TNF-α production amplified the prospect that SNPs within this locus may subsidize the growth of the extensive range of diabetes diseases [28].

Nitric Oxide Synthase 3 (NOS3) Gene

NOS3 is a Protein coding genes act as a biological mediator in several factors and its genomic location is 7q36.1. The other name of this gene is eNOS. L-arginine by eNOS gene produces NO, a vasodilator molecule. It involves has a key factor in the regulating of homeostasis and mainly regulates endothelial function. The complication in endothelial dysfunction leads to nephropathy in the presence of eNOS gene variants through reduced production of NO. In intron 4 region of NOS3, number of variable tandem repeats has been reported in association with cardiac and kidney diseases [26]. The two allelic polymorphisms of this gene comprise 27-repeats tandem repeats with 4 and 5 tandem repeats with 4b. Pathogenesis mechanism in DN has been altered due to the endothelial dysfunction. The eNOS gene has an important function in the regulatory pathway of endothelial function by producing NO [29]. The abnormal level eNOS might be involved in the progression of High blood pleasure, atherosclerosis and Reno vascular associated injury in diabetic patients due to variations seen in NOS3 polymorphism.

Conclusion

In conclusion, DN consider to be a one of the major common causes of ESRD and there is now a consensus that genes contribute to risk for DN. Emerging evidence also suggests that patient with type 1 and 2 diabetes likely to show different cause of this disease and diverse racial population may tend to have varying risk factors linked with precise genes there is a still challenging issues ongoing in this area of research. It is important to emphasize the current issue with DN in which various genes show the positive correlation. Hence, this assessment highlights the essential focus on genetic changes and structural dissimilarity of ACE, UMOD, TNF- Ramakrishnan V, et al. Essential Genes Associated with Diabetic Nephropathy. Diabetes Obes Int J 2019, 4(1): 000192.

α and NOS3 genes, so that these variants can be used as potential bio markers in early diagnosis and drug target for Diabetic Nephropathy.

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@article{keerthana2019,
  title   = {Essential Genes Associated with Diabetic Nephropathy},
  author  = {Keerthana S, Aswathi P and Ramakrishnan V},
  journal = {Diabetes & Obesity International Journal},
  year    = {2019},
  volume  = {4},
  number  = {1},
  doi     = {10.23880/doij-16000192}
}
Keerthana S, Aswathi P and Ramakrishnan V (2019). Essential Genes Associated with Diabetic Nephropathy. Diabetes & Obesity International Journal, 4(1). https://doi.org/10.23880/doij-16000192
TY  - JOUR
TI  - Essential Genes Associated with Diabetic Nephropathy
AU  - Keerthana S, Aswathi P and Ramakrishnan V
JO  - Diabetes & Obesity International Journal
PY  - 2019
VL  - 4
IS  - 1
DO  - 10.23880/doij-16000192
ER  -