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Oral treatment with PBI-4050 reduces kidney fibrosis
Lyne Gagnon, Brigitte Grouix, Kathy Hince, Lilianne Geerts, Liette Gervais, Mikaël Tremblay, François Sarra-Bournet,
Alexandra Felton, Shaun Abbott, Jean-Simon Duceppe, Martin Leduc, Boulos Zacharie, Christopher Penney and Pierre Laurin
ProMetic BioSciences Inc., Laval, Québec, Canada
p < 0.05
*
0.8
0.6
0.4
0.2
Fibroblast
Proliferation
& Differention
Myofibroblast
Proliferation,
Survival &
Migration
EXTRACELLULAR
MATRIX
DEPOSITION
FIBROSIS:
ORGAN LOSS
FUNCTION
PBI-4050 IMPROVES
KIDNEY FUNCTION
Urine Protein (g/24 h)
GROWTH
FACTORS,
BONE
CYTOKINES &
MARROW
CHEMOKINES FIBROCYTES
21
153
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
Days
168
NX
*p < 0.05
CKD: 5/6-NEPHRECTOMY
INFLAMMATION
DKD: db/db MODEL
0
Macrophages
& Immune Cells
*
1.0
GFR (ml/min)
INJURY
GFR
1.2
AKI: DOXORUBICININDUCED NEPHROPATHY
CKD: 5/6-NEPHRECTOMY
190
NX + PBI-4050
Proteinuria
*
*
*
*
21
42
*p < 0.05
63
84
Days
105
NX
KIDNEY
Urinary MCP-1
Protein Level
(% of Day 21)
CKD: 5/6-NEPHRECTOMY
PBI-4050 reduces fibrosis via the regulation
of macrophages, T cells, fibrocytes/
fibroblasts/myofibroblasts and epithelial
cells. In a pro-fibrotic phase, PBI-4050 plays
a regulatory role by promoting a Type 1,
anti-fibrotic cytokine production phenotype
in macrophages and T cells, resulting in a
reduction of the over-expression or overproduction of TGF-β, MCP-1, CTGF, IL-6
and IL-23. Interestingly, MCP-1 is also an
important inducer of fibrocyte precursor
migration in tissue. Fibrocyte differentiation,
resident fibroblast activation and EMT are
the key sources of activated myofibroblasts
and successive accumulation of extracellular matrix protein deposition and
fibrosis.
PBI-4050
inhibits
fibrocyte
differentiation, fibroblast activation and EMT
as demonstrated by a reduction in alpha
smooth muscle actin (α-SMA), collagen I
and SPARC mRNA expression. PBI-4050
also plays a role in tissue remodeling by
regulating MMP and TIMP expression.
CKD: 5/6-NEPHRECTOMY
SUMMARY
CONCLUSION
Taken together, these preclinical results suggest that
PBI-4050 offers the potential as a novel therapy for
the treatment of kidney fibrosis.
126
153
NX + PBI-4050