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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
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Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway
P Saurus1, S Kuusela1, E Lehtonen2
1Department of Pathology, University of Helsinki, Helsinki, Finland.
Cell Death & Disease
|May 8, 2015
Summary
High lipopolysaccharide (LPS) activity in type 1 diabetes (T1D) reduces kidney cell survival factor PDK1, promoting podocyte apoptosis. Blocking Toll-like receptor (TLR) signaling with GIT27 may prevent diabetic nephropathy (DN) progression.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- High serum lipopolysaccharide (LPS) activity in normoalbuminuric type 1 diabetes (T1D) patients predicts diabetic nephropathy (DN) progression.
- The underlying mechanisms linking LPS activity to DN development are not fully understood.
Purpose of the Study:
- To investigate the role of lipopolysaccharide (LPS) and 3-phosphoinositide-dependent kinase-1 (PDK1) in the pathogenesis of diabetic nephropathy (DN).
- To explore the potential of Toll-like receptor (TLR) pathway inhibition as a therapeutic strategy for DN.
Main Methods:
- Cultured human podocytes were treated with sera from T1D patients and lipopolysaccharide (LPS).
- PDK1 knockdown and Toll-like receptor (TLR) pathway inhibition using GIT27 were performed in vitro and in vivo.
- Podocyte apoptosis, Akt pathway, and p38 MAPK pathway activation were assessed.
Main Results:
- Sera from T1D patients with high LPS activity downregulated PDK1 and induced podocyte apoptosis.
- PDK1 knockdown inhibited the Akt survival pathway, activated the proapoptotic p38 MAPK pathway, and increased apoptosis.
- LPS reduced PDK1 expression and induced apoptosis in podocytes and mice, effects prevented by GIT27 via TLR inhibition.
- PDK1 downregulation was observed in diabetic rat and human kidney glomeruli before proteinuria onset.
Conclusions:
- Lipopolysaccharide (LPS) downregulates the cell survival factor PDK1, leading to podocyte apoptosis and contributing to diabetic nephropathy (DN) development.
- Inhibition of the Toll-like receptor (TLR) pathway with GIT27 may offer a non-nephrotoxic therapeutic approach to prevent DN progression.
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