International Journal of Trend in Scientific Research and Development (IJTSRD)

Volume 6 Issue 5, July-August 2022 Available Online: www.ijtsrd.com e-ISSN: 2456 – 6470

Gene Expression and Pathway Detection for Diabetic Nephropathy

using Computational Intelligence in Bioinformatics
Dr. Brijendra Gupta1, Tanvi Shinde2, Aarti Pundalik2, Poonam Kedari2
1
IT HOD, Siddhant College of Engineering, Pune, Maharashtra, India
2
IT Engineering, Siddhant College of Engineering, Pune, Maharashtra, India

ABSTRACT How to cite this paper: Dr. Brijendra

It has been observed that in high blood sugar levels over time these Gupta | Tanvi Shinde | Aarti Pundalik |
high glucose level can damage various area of the body including Poonam Kedari "Gene Expression and
cardiovascular system and kidneys. The kidney damage that results is Pathway Detection for Diabetic
known as “Diabetic nephropathy “. Nephropathy using Computational
Intelligence in Bioinformatics"
Diabetes plays a critical role in public health concern with rates of Published in
diabetes increasing globally and approximately 40% of affected International Journal
individuals developing diabetic nephropathy. We have taken of Trend in
bioinformatics and computational approach to studying identification Scientific Research
of diabetic nephropathy associated genes by literature mining for and Development
(ijtsrd), ISSN: 2456-
gene expression and how the genes affected the pathways (DN). IJTSRD50423
6470, Volume-6 |
Numerous datasets has been evaluated for Diabetic nephropathy Issue-5, August
occurs only in a minority of subjects with either type 1 or type 2 2022, pp.48-54, URL:
diabetes and seems to result from the interaction between genetic www.ijtsrd.com/papers/ijtsrd50423.pdf
susceptibility and environmental insults and risk factors for the
development of diabetic nephropathy includes ethnicity and inherited Copyright © 2022 by author(s) and
International Journal of Trend in
genetic differences and Hyperglycemia and arterial hypertension and
Scientific Research and Development
other risk factors are smoking dyslipidemia proteinuria, glomerular Journal. This is an
hyperfiltration and factors. Open Access article
Our result have been evaluated how the pathways are been affected in distributed under the
diabetic nephropathy, the pathogenesis of diabetic nephropathy and terms of the Creative Commons
gene mapping also the development of diagnostic. Attribution License (CC BY 4.0)
(http://creativecommons.org/licenses/by/4.0)

OUTLINE:
We have been working on top genes of diabetic Numerous risk factors for the development of
nephropathy, on based of their score we also gone diabetic nephropathy including ethnicity and
through pathways involved in (DN). And also worked inherited genetic differences and hyperglycemia
on how gene mapping process is usefuls for identify and arterial hypertension. Other risk factors are
exactly which chromosome has which gene and smoking dyslipidemia proteinuria, glomerular
exactly pinpointing where that gene lies on that hyperfiltration and dietary factors. Diabetic
particular chromosome. And the protein misfolding nephropathy is the leading cause of chronical
for diabetic nephropathy. renal disease. Diabetic Nephropathy has been
categorized into stages microalbuminuria.
INTRODUCTION:
Diabetic Nephropathy (DN) is a lethal
Diabetes results in high blood sugar levels over
time these high glucose level can damage various microvascular complication associated with type
1 and type 2 diabetes mellitus.We have to
area of the body including cardiovascular system
and kidneys. The 0kidney damage that results is determine signalling pathways pathogenesis of
diabetic nephropathy at DNA level, RNA level,
known as “Diabetic nephropathy “.
We are working on diabetic nephropathy (DN) MRNA level at epigenetic level and also its
and also its top involved genes based on their transmission factors at gene level.
score the pathways affecting the gene for (DN).It And also which pathways affect the genes for diabetic
has been seen that their multiple factors involved nephropathy.
in the pathogenesis of (DN) while the molecular
mechanism that leads to (DN).

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 International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470
Methodology or Materials and Methods:
We have collected over genes based on scores of
gene-disease (GDA) for diabetic nephropathy using
DISGENET and the common pathway (from
GENCARD) for those ten genes, which is responsible
for affecting the gene in DN and also the other
factors.
The pathogenesis and progression of diabetic
nephropathy are likely to be as a result of interaction
between metabolic and hemodynamic pathways. It is
likely that the metabolic and hemodynamic
abnormalities seen in diabetes interact with each other
and pathways linked to reactive oxygen species
(ROS) generation. Figure1:
Gene regulation and activation of transcription factors RESULT:
are influenced by interactions among metabolic We have collected 10 genes associated with Diabetic
stimuli hemodynamic factors and various ROS in Nephropathy using cytoscape we had made network
diabetes. for Diabetic Nephropthy and find out different
We have used cytoscape for making network of genes pathways which are affecting genes for DN. Using
and DN we have made a network by 10 genes of DN. different database we have find out which genes are
Pathways form KEGG database are also added this. responsible for DN. Form KEGG we got pathways
and diagrammatic representation of it. We have gone
We have gone through different databases and
through protein misfloding process for diabetic
website to collect our data for our paper are as
nephropathy and gene mapping process for future
follows:
scope.
DATABASE USED Also gone through different factors for the
GOOGLE development of diabetic nephropathy.
KEGG
PUB-MET.GOV HYPERGLYCEMIA AND ADVANCED
DISGINET GLYCOSYLATION END PRODUCTS
CYTOSCAPE Hyperglycemia is a crucial factor in the
NCBI development of diabetic nephropathy because of
GENECARD its effects on glomerular and mesangial cells, but
alone it is not causative. Mesangial cells are
MDPI( FREE DATABASE)
crucial for maintenance of glomerular capillary
STRING
structure and for the modulation of glomerular
KARGER
filtration via smooth-muscle activity.
Table 1.0
Hyperglycemia is associated with an increase in
Figure 1: mesangial cell proliferation and hypertrophy, as
This image is obtain by CYTOSCAPE we have well as increased matrix production and basement
collected ten genes associated with diabetic membrane thickening.
nephropathy form GENCARD those ten genes share
Glycosylation
common pathway
Glycosylation of tissue proteins contributes to the
Diabetic Nephropathies-Signal Transduction development of diabetic nephropathy and other
(pathway)- REACT:R-HSA-162582 microvascular complications. Protein kinase C
18 genes: AGT | AXL | CDKN1A | COL4A1 | DGKH Other proposed mechanisms by which
| ELMO1 | FN1 | INS | KDR | LEPR | MDK | NOS3 | hyperglycemia promotes the development of
PRKCE | RELA | SERPINE1 | TGFB1 | TGFBR2 | diabetic nephropathy include activation of
VEGFA PKC.31 Specifically, activation of this enzyme
leads to increased secretion of vasodilatory
prostanoids, which contributes to glomerular
hyperfiltration. By activation of TGF-β1, PKC

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 International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470
might also increase production of extracellular therefore, have roles in the pathogenesis of
matrix by mesangial cells CYTOKINES diabetic nephropathy. In patients with type 1 or
type 2 diabetes, the likelihood of developing
Activation of cytokines, profibrotic elements,
diabetic nephropathy is markedly increased in
inflammation, and vascular growth factors such as
those who have a sibling or parent with diabetic
VEGF might be involved in the matrix
nephropathy.
accumulation that arises in diabetic nephropathy.
40–42 Although some evidence suggests that Schematic analysis workflow for delineating
VEGF increases permeability of the glomerular molecular DN disease presentations. With the
filtration barrier to proteins,22 levels of this phenotype at the center, data are gathered from the
growth factor can be low in patients with diabetic scientific literature as well as from different omics
nephropathy. Thus, the role of VEGF in the studies in order to generate a phenotype molecular
pathophysiology of nephropathy is unclear. feature set.
PRORENIN Bioinformatics analyses on the level of GO term
Initial clinical studies in children and adolescents enrichment analysis, molecular pathways as well as
suggest that increased plasma prorenin activity is via identification of process units leads to the
a risk factor for the development of diabetic identification of deregulated molecular processes and
nephropathy. 36, 37 The prorenin receptor in the pathways as well as the construction of molecular
kidney is located in the mesangiumand podocytes, models for the given disease.
and its blockade has a beneficial effect on kidneys
OBSERVATION:
in animal models of diabetes. This effect is We have seen for few databases related Diabetic
mediated by intracellular signals that are both Nephropathy that there are susceptible genes are
dependent on and independent. involved in it which are difficult to identify exact
LIPID MEDIATORS responsible genes. We have tried to collect all the
Small lipids derived from arachidonic acid have data and from that we try to figure out get all the
been implicated in the pathogenesis of diabetic susceptible genes for diabetic nephropathy and
nephropathy. Cyclo-oxygenase 2 breaks down pathways affecting the genes.
arachidonic acid into several different Protein misfolding disorders (PMDs) are disease
prostanoids. In a rat model of streptozotocin- where at least one protein or peptide has been shown
induced diabetes, levels of inflammatory to misfold aggregate an tissues where the disease
prostanoids, such as prostaglandins E2 and I2, specific damage occurs. F or future scope to identify
were raised of the renin–angiotensin system. that genes and its location on DNA and chromosome.
Prorenin binds to a specific tissue receptor that
promotes activation of p44/p42 MAPK.38. This process will help to find out exact which genes is
responsible for diabetic nephropathy and its location
NEPHRIN also is that genes are hereditary or not ? By the help
Podocytes (specialized visceral epithelial cells) of gene mapping process.
are important for the maintenance of the dynamic
functional barrier.66 Nephrin, a protein found in Artificial intelligence (AI) based machine learning
these cells, is crucial for maintaining the integrity techniques with respect to DN are nephropathy. AI-
of the intact filtration barrier. The renal based machine learning models can even provide
expression of nephrin might be impaired in actionable prediction models for faster and accurate
diabetic nephropathy. Patients with diabetic diagnosis of complications associated with DN. The
nephropathy have markedly reduced renal nephrin integration of AI-based analytical techniques, like
expression and fewer electron-dense slit machine learning and deep learning in clinical
diaphragms compared with patients without medicine, will result in improved disease
diabetes and minimal nephropathic changes or management through faster disease detection and the
controls. cost reduction for the treatment.
GENETIC SUSCEPTIBILITY CONCLUSION:
Genotype seems to be an important determinant Diabetic Nephropathy is not clinically detectable until
of both incidence and severity of diabetic significant kidney damage has developed,
nephropathy.9,31,70 The increase in risk cannot highlighting the need to identify early-stage
be explained by the duration of diabetes or biomarkers.
hypertension, or the degree of glycemic control. Figure 2 shows the table of the present study; Some
Environmental and genetic factors must, of these associated genes function as pivotal

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 International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470
regulators in the pathogenesis of DN, such as those In our future scope for Diabetic Nephropathy to
related to glycometabolism and lipid metabolism. identify exact which genes are susceptible for DN
However, the functions of most of these genes remain using GENE MAPPING process.
unclear. A graphical representation of the arrangements of
genes or DNA sequence on chromosome. The human
Some of these genes function as pivotal regulators in
genome map completed in 1996 locates 5264 markers
the pathogenesis of DN, such as those related of
for gene. A genome map are used to identify and
glycometablism and lipid metabolism.
record the location of gene and distances between
genes on chromosome
Types of gene mapping are:
Physical mapping: A physical map provides detail of the actual physical distance between genetic markers, as
well as exact location of the genes.
Genetic mapping: Genetic mapping looks how genetic information is shuffled between chromosome or between
different regions in the same chromosome.
The susceptibility genes in diabetic nephropathy

Fig. 2.
The susceptibility genes in diabetic nephropathy. As shown in the figure, the susceptibility genes in diabetic
nephropathy are divided into different categories according to their main functions.
The pathophysiology of diabetic nephropathy. As a consequence of prolonged hyperglycaemia, diabetic
nephropathy (DN) typically initiates as renal cellular hypertrophy and hyperfiltration, followed by progressive
albuminuria and a decline in glomerular filtration rate (GFR). Microalbuminuria (urinary albumin excretion rate
of 30–300 mg per day) develops 10–15 years after the onset of diabetes followed by macroalbuminuria (urinary
albumin excretion rate of >300 mg per day) 15–25 years after diabetes onset. A combination of hyperglycaemia,

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 International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470
inflammation, and hypertension drive the development and progression of DN. Presently, it is unclear why some
diabetics are susceptible and others appear protected against the development of DN. Currently unknown causal
and protective genetic variants have been suggested as one possible mechanism. At the cellular level, high
glucose, Ang II, ROS, and profibrotic cytokines including TGF-β1, VEGF and CTGF have been identified as
important modulators driving renal fibrosis. More recently, miRNA-mediated regulation and histone
modifications have also been implicated in DN pathogenesis. Mutations in one or more key signaling pathways
implicated in DN may act to suppress or drive DN progression

Figure 3:
Table 3:
The results of pathway enrichment analysis for the down-regulated genes:
SSS Pathway
Count p-value Genes
Category Name
Arrhythmog
ACTG1, ATP2A2, ACTN4, DMD, DAG1,
enic right
KEGG_PAT CACNB2, ITGB5, ITGA3, CTNNA1,
ventricular 11 1.41E-04
HWAY CTNNB1…ACTN4, ROCK1, ITGB5, RDX, ITGA3,
cardiomyopa
ARPC5, MYL12A, MYH9, MYL9, ACTG1…
thy (ARVC)
Regulation
KEGG_PAT
of actin 19 1.65E-04
HWAY
cytoskeleton
Hypertrophic
KEGG_PAT TNNT2, ACTG1, ATP2A2, TNNC1, DMD, DAG1,
cardiomyopa 9 0.00575
HWAY CACNB2, ITGB5, ITGA3
thy (HCM)
Complement
KEGG_PAT and CD55, F3, CD46, CD59, C1R, SERPING1, C1S,
8 0.00641
HWAY coagulation F2R
cascades
Dilated
KEGG_PAT TNNT2, ACTG1, ATP2A2, TNNC1, DMD, DAG1,
cardiomyopa 9 0.00920
HWAY CACNB2, ITGB5, ITGA3
thy
Pathogenic
KEGG_PAT ACTG1, EZR, ROCK1, TUBB2A, YWHAQ,
Escherichia 7 0.00956
HWAY ARPC5, CTNNB1
coli infection

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