Intro

Introduction
According to the 2020 Global Burden of Disease Study on 1990-2017 report, it is an

estimated increase of 697.5 million instances of chronic renal disease in the globe [1].
This equates to a 9.1% prevalence rate. According to estimations, the prevalence of
CKD increased by 29.3% across all age groups over this period as a result of the
world's growing population. Overall, the percentage of CKD-related mortality
increased by 41.5%. Between 1990 and 2017, the death rate from renal illnesses
stayed steady, whereas it declined by 41.3%, 14.9%, and 30.4% from cancer, chronic
obstructive pulmonary disease, and cardiovascular disease, respectively[2]. It is
necessary to generate new approaches for detecting and treating CKD and also
develop more powerful therapies.
The investigation of the kidney disease inflammasome can assist researchers
in better understanding CKD and identifying possible treatment targets.
Inflammasomes are multiprotein complexes that are required for the innate immune
response[3]. AIM2-like receptors and NOD-like receptors are examples of pattern-
recognition receptors (PRR). PRRs can sense danger or particular modifications in the
cellular environment and activate canonical inflammasomes [4]. Interleukin-1 and -18
are produced when caspase-1 and the canonical inflammasome are activated. These
cytokines can affect receptors that are activated both systemically and locally[5]. The
canonical inflammasomes are activated by PRRs that recognize PAMPs (Pathogen-
associated molecular pattern molecules ) or DAMPs (Damage-associated molecular
patterns). PRRs are expressed in the cytoplasm or on the cell membranes of a variety
of cells, most notably leukocytes. Rig-I-like receptors (RLRs), Toll-like receptors
(TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), C-
type lectin receptors (CLRs), and AIM2-like receptors have all been found in previous
studies (ALR) [6]. Inflammasomes are made up of proteins from the NLR and ALR
families. Toxins, cell signaling pathways, and intracellular lipopolysaccharides can all
activate non-canonical inflammasomes. These inflammasomes control the activation
of several caspases, including caspases 4, 5, 11, and 8. These caspases are responsible
for cell death as well as other cellular processes such as pyroptosis [7]. AIM2 had
been identified as the DNA-sensing inflammasome in a macrophage study[8]. The
pyrin domain and the hematopoietic interferon-inducible nuclear protein with 200
amino acids, make up the protein. It does not bind to RNA or single-stranded DNA,
but it does bind to double-stranded DNA. When dsDNA activates AIM2, ASC and
caspase 1 are recruited to create a typical inflammasome, which must be at least 250-
300 bp in size[9]. The AIM2 inflammasome activates pyroptosis in response to
cytosolic bacteria and certain viruses such as Mycobacterium, Francisella tularensis,
vaccinia virus, and CMV. AIM2 may detect endogenous dsDNA and activate
inflammasomes in stress conditions such as when exposed to radiation or
chemotherapy. It can also be activated due to HIV aspartic protease inhibitor
treatment. The activation of pro-inflammatory macrophages as a result of AIM2
inflammasome activation can induce kidney injury and renal fibrosis. Monocyte-
derived macrophages phagocytosed cellular debris, including necrotic DNA in the
kidneys, as demonstrated by multiphoton intravital imaging. Necrotic DNA is likely a
potent Damage-associated molecular pattern (DAMP) in this instance, activating the
AIM2 inflammasome[10].
There are many types of kidney diseases but the two most common types are
acute kidney injury (AKI) and chronic kidney disease (CKD). Acute kidney injury is
defined as a rapid deterioration in renal excretory function over a short period of time.
The most prevalent causes of AKI include nephrotoxins, ischemic kidney disease
(IMD), obstructive nephropathy, and sepsis[11]. It has been identified as a primary
risk factor for the development and progression of chronic kidney disease, which is
characterized by a progressive loss of kidney function with a lower glomerular
filtration rate and an increase in urine albumin excretion, eventually leading to end-
stage renal disease [12]. Both AKI and CKD are associated with high rates of
morbidity and death due to inadequate treatment, despite advances in supportive care
and diagnosis[13][14]. Thus, it is crucial to provide better treatments and preventative
measures for the advancement of renal illness[14].
Using natural compounds and their structural analogs have substantially
improved pharmacotherapy, despite the challenges of creating novel medications. To
prevent any potential adverse effects from pharmaceutical therapies, customers are
increasingly turning to organically produced ingredients in the form of herbal
medicines or super foods[15]. According to WHO statistics, 60% of people globally
and 80% of individuals in developing countries utilize herbal medicines for medicinal
purposes[16]. The presence of multiple chemical components in natural products and
herbal medicines with therapeutic and nutritional significance demonstrates their
multi-target nature[17].
Several herbal drugs are detected to be useful in enhancing renal function and
decreasing the course of kidney diseases. These drugs include salidroside, betulinic
acid, celastrol, resveratrol, polydatin, and curcumin[17]. The mitochondria are the
center of the cell's energy production machinery. Besides this, they also control
signaling, homeostasis, cell growth, and death. They allow the kidney to remove
waste from the blood as well as maintain the proper balance of water and
electrolytes[18]. AKI and CKD are both caused by mitochondrial dysfunction. The
breakdown of adenosine triphosphate (ATP), the excessive production of reactive
oxygen species (ROS), and the release of proapoptotic proteins such as cytochrome c
lead to apoptosis, inflammation, fibrosis, and oxidative damage to DNA and
proteins[18].
There are multiple circumstances in which cell damage might occur. Natural
products can protect the kidneys from a variety of harmful stimuli by maintaining
mitochondrial normal function [19]. So much study has been done on the potential
nephroprotective benefits of phytoconstituents such as flavonoids, steroids,
terpenoids, and fatty acids [20]. It is nearly unanimously acknowledged that they have
the potential to be helpful in the treatment of kidney-related disorders due to their
capacity to impact oxidative, inflammatory, and apoptotic processes.
This study discusses the molecular mechanisms of action of natural
compounds that can be used to create drugs to treat kidney diseases. The protein
AIM2 is the inflammasome's target for kidney disease. This study aims to examine
the proteome for prospective therapeutic targets using the National Center for
Biotechnology Information's genome database (NCBI). Several strategies will be used
to predict, enhance, and diminish the protein's three-dimensional structure. We'll track
down the stumbling blocks. To find new drugs, pharmacophore modeling and virtual
screening will be used. Here we will also study the correlations between drugs and the
target protein. Further research will be conducted on ADMET features such as
adsorption, distribution, metabolism, excretion, and toxicity.
References
1. https://pubmed.ncbi.nlm.nih.gov/32144399/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292152/
4. https://www.frontiersin.org/articles/10.3389/fimmu.2018.02379/full
6. https://www.nature.com/articles/s41392-021-00687-0
11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919808/#:~:text=The%20primary%20causes
%20of%20AKI,decreases%20in%20renal%20blood%20flow.
16. https://www.hilarispublisher.com/open-access/herbal-medicine-yesterday-today-and-tomorrow-
2327-5162-1000195.pdf

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Introduction

According to the 2020 Global Burden of Disease Study on 1990-2017 report, it is an

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