APOL1-associated kidney disease: modulators of the genotype-phenotype relationship
Current Opinion in Nephrology & Hypertension,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 6, 2025
Apolipoprotein-L1
(APOL1)
G1
and
G2
risk
variants,
found
in
people
of
recent
west
sub-Saharan
African
ancestry,
dramatically
increase
the
likelihood
kidney
disease,
yet
incomplete
penetrance
an
diverse
clinical
manifestations
underscore
need
to
understand
molecular
environmental
factors
that
modulate
APOL1-mediated
toxicity.
Recent
studies
confirm
variants
exert
a
toxic
gain-of-function
effect,
exacerbated
by
inflammatory
triggers
such
as
HIV
infection
COVID-19.
Epigenetic
mechanisms
microRNA
pathways
further
APOL1
expression,
influencing
disease
penetrance.
Multiple
models
have
clarified
how
subcellular
localization,
signal
peptide
processing,
interactions
with
endoplasmic
reticulum
may
contribute
pathogenesis.
Therapeutic
advances
include
inhibitors
targeting
ion
channel
activity
strategies
block
key
signaling
pathways.
These
findings
highlight
multifaceted
process
driven
both
intrinsic
potential
numerous
extrinsic
triggers.
Understanding
this
complex
interplay
will
be
pivotal
for
stratification
development
precision
therapies,
potentially
improving
outcomes
populations
disproportionately
affected
APOL1-associated
disease.
Language: Английский
The Two Levels of Podocyte Dysfunctions Induced by Apolipoprotein L1 Risk Variants
Kidney and Dialysis,
Journal Year:
2024,
Volume and Issue:
4(2), P. 126 - 143
Published: June 7, 2024
Apolipoprotein
L1
(APOL1)
nephropathy
results
from
several
podocyte
dysfunctions
involving
morphological
and
motility
changes,
mitochondrial
perturbations,
inflammatory
stress,
alterations
in
cation
channel
activity.
I
propose
that
this
phenotype
increased
hydrophobicity
of
the
APOL1
risk
variants,
which
induces
two
distinct
types
dysfunctions.
On
one
hand,
hydrophobic
interactions
with
APOL3
cause
intracellular
variant
isoforms
to
impair
both
control
Golgi
PI(4)P
kinase-B
(PI4KB)
activity
membrane
fusion,
triggering
actomyosin
reorganisation
together
mitophagy
apoptosis
inhibition
(hit
1).
other
plasma
may
extracellular
activate
toxic
Ca2+
influx
K+
efflux
by
TRPC6
BK
channels,
respectively
2),
presumably
due
APOL1-mediated
cholesterol
clustering
microdomains.
hit
2
depends
on
low
HDL-C/high
ratio,
such
as
occurs
cell
culture
vitro,
or
during
type
I-interferon
(IFN-I)-mediated
inflammation.
Language: Английский
Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease
Cells,
Journal Year:
2024,
Volume and Issue:
13(20), P. 1738 - 1738
Published: Oct. 20, 2024
Apolipoprotein-L1
(APOL1)
is
a
membrane-interacting
protein
induced
by
inflammation,
which
confers
human
resistance
to
infection
African
trypanosomes.
APOL1
kills
Trypanosoma
brucei
through
induction
of
apoptotic-like
parasite
death,
but
two
T.
clones
acquired
APOL1,
allowing
them
cause
sleeping
sickness.
An
C-terminal
sequence
alteration,
such
as
occurs
in
natural
West
variants
G1
and
G2,
restored
these
clones.
However,
unfolding
or
G2
mutations
enhances
hydrophobicity,
resulting
kidney
podocyte
dysfunctions
affecting
renal
filtration.
The
mechanism
involved
debated.
ability
generate
ion
pores
trypanosome
intracellular
membranes
synthetic
was
provided
an
explanation.
transmembrane
insertion
strictly
depends
on
acidic
conditions,
cytopathology
mainly
results
from
secreted
activity
the
plasma
membrane,
under
non-acidic
conditions.
In
this
review,
I
argue
that
besides
inactivation
APOL3
functions
membrane
dynamics
(fission
fusion),
induce
inflammation-linked
toxicity
not
pore
formation,
disturbance
increased
interaction
with
cholesterol,
cation
channels
activity.
A
mutation
domain
(N264K)
abrogates
variant
at
expense
slightly
sensitivity
trypanosomes,
further
illustrating
continuous
mutual
adaptation
between
host
parasite.
Language: Английский
Apolipoprotein-L Functions in Membrane Remodeling
Cells,
Journal Year:
2024,
Volume and Issue:
13(24), P. 2115 - 2115
Published: Dec. 20, 2024
The
mammalian
Apolipoprotein-L
families
(APOLs)
contain
several
isoforms
of
membrane-interacting
proteins,
some
which
are
involved
in
the
control
membrane
dynamics
(traffic,
fission
and
fusion).
Specifically,
human
APOL1
APOL3
appear
to
remodeling
linked
pathogen
infection.
Through
its
association
with
Non-Muscular
Myosin-2A
(NM2A),
controls
Golgi-derived
trafficking
vesicles
carrying
lipid
scramblase
Autophagy-9A
(ATG9A).
These
deliver
together
phosphatidylinositol-4-kinase-B
(PI4KB)
activated
Stimulator
Interferon
Genes
(STING)
mitochondrion-endoplasmic
reticulum
(ER)
contact
sites
(MERCSs)
for
induction
completion
mitophagy
apoptosis.
direct
interactions
PI4KB
activity
controllers
(Neuronal
Calcium
Sensor-1,
or
NCS1,
Calneuron-1,
CALN1,
ADP-Ribosylation
Factor-1,
ARF1),
PI(4)P
synthesis.
is
required
different
processes
infection-induced
inflammation:
(i)
STING
activation
at
Golgi
subsequent
lysosomal
degradation
inflammation
termination;
(ii)
mitochondrion
MERCSs
apoptosis;
(iii)
phagolysosome
formation
antigen
processing.
In
addition,
governs
mitophagosome
fusion
endolysosomes
completion,
APOL3-like
murine
APOL7C
phagosome
permeabilization
cross-presentation
dendritic
cells.
Similarly,
can
induce
intracellular
bacterial
membranes,
a
role
also
be
proposed
endothelial
APOLd1
adipocyte
mAPOL6,
promote
angiogenesis
adipogenesis,
respectively,
under
inflammatory
conditions.
Thus,
APOL
play
distinct
roles
associated
inflammation.
Language: Английский