The Role of Platelets in Chronic Kidney Disease and Renal Fibrosis

Chronic Kidney Disease (CKD), is characterized by a deterioration of kidney
function as a result of progressive loss of functional kidney parenchyma and
tissue fibrosis and its treatment remains inadequate. Innovative therapeutic
targets can only be identified through better understanding of primary
pathogenetic mechanisms. Recent studies emphasize the links between CKD as a
result of persistent renal damage caused by underlying medical conditions such
diabetes, high blood pressure, glomerular diseases, urinary tract issues like
prolonged obstruction, and other renal illnesses which result in inflammation
and renal injury.
There is growing evidence that platelet activation contributes to progression
of CKD due to factors such as inflammation, oxidative stress, and endothelial
dysfunction. Although platelets are best known for their pivotal role in
hemostasis, mounting evidence shows that platelets are active players in
inflammation and many other biological processes as well, wound healing and
fibrosis. Besides their ability to directly interact with endothelial cells and
leukocytes, platelets are known to produce many inflammatory and
immune-modulating factors.
We and others have previously shown that activated platelets contribute to
renal inflammation, oxidative stress, immunoreactivity, and fibrosis processes.
Our prior research has revealed the involvement of platelets in experimental
acute kidney injury (AKI) and diabetic kidney disease (DKD). We observed that
activated platelets promote renal injury, platelet-granulocyte interaction and
formation of neutrophil extracellular traps (NETs) and fibrosis.
The concept that platelets can actively promote ETosis in neutrophils and
macrophages (NETs/METs) is a novel concept of which we are only beginning to
understand the implications. The involvement of platelets in the mechanism of
Epithelial-to-Mesenchymal Transition (EMT), which is a pivotal step in the
pathogenesis of fibrosis, also still largely limited to studies on
malignancies. While the potential contribution of systemic endothelial
dysfunction to CKD pathology has been explored, the precise role of platelet
interaction with renal endothelium in initiating and perpetuating kidney
inflammation remains uncertain.
Understanding the molecular mechanisms involved in renal injury and renal
fibrosis in CKD is an active area of research. Targeting these processes may
offer potential therapeutic avenues for slowing down or preventing the
progression of CKD and associated renal fibrosis. This study aims to explore
the potential contribution of platelets to renal EMT, their interactions with
endothelial cells and monocytes, the roles of platelets and NETs/METs in renal
disease and uncovering its underlying mechanism. Thus, understanding platelets'
functions and mechanisms in CKD, especially, holds promise for reducing
morbidity and mortality in CKD patients.

The objective of this study is to investigate the role of platelets in fibrosis
and inflammation by examining their effects on key cellular processes.
Specifically, we aim to:

1. Determine whether activated platelet stimulation induces fibrosis through
epithelial-to-mesenchymal transition (EMT) in epithelial cells, and whether
inhibiting platelet activation can mitigate these effects.
2. Explore the molecular pathways potentially involved in these processes,
particularly those influencing EMT and fibrosis.
3. Examine the impact of activated platelet stimulation on endothelial
integrity, as well as its effects on monocyte/macrophage adhesion and
transendothelial migration.
4. Investigate the mechanisms of platelet-macrophage interactions that
contribute to inflammation, including extracellular trap formation.

By studying these mechanisms, the research aims to gain insights into how
platelets contribute to the progression of fibrosis and inflammation, with
potential implications for understanding conditions like chronic kidney disease
and other inflammatory disorders.

In vitro experimental study

We will draw blood from each donor up to three times within a year, should they
agree to donate more than once. However, if a donor prefers to donate only
once, that is also acceptable. Each collection will require 10-30 ml of blood.
Since blood collection is a routine procedure in medical settings and will be
performed by a doctor, the risk of injury is minimal. The potential risks for
volunteers include pain during the blood draw, minor bleeding, or hematoma at
the blood draw site.

As this is an in vitro experimental study, there are no direct benefits for the
volunteers participating. We will, however, provide compensation for travel
expenses to the participants.

Although there are no direct benefits for the volunteers, this study will help
researchers gain a better understanding of the effect of platelet
hyper-reactivity in the progression of chronic kidney disease and renal
fibrosis. This research may contribute to advancing medical knowledge and
potential treatments in the future.