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Tmem30a protects against podocyte injury through suppression of pyroptosis
Yanpei Hou1, Sipei Chen1, Lei Peng1
1Department of Nephrology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Sichuan Clinical Research Center for Kidney Diseases, Chengdu 610072, China.
Abstract:
Podocytopathies, such as focal segmental glomerulosclerosis (FSGS), are characterized by podocyte injury and can easily progress to end-stage kidney disease. However, the mechanisms underlying podocyte injury remain unclear. We observed podocyte injury along with pyroptosis in patients with FSGS. Bioinformatic analysis of public datasets revealed that transmembrane protein 30a (Tmem30a) might be associated with FSGS. The expression of Temem30a and the podocyte-related protein, nephrin, were significantly downregulated in patients with FSGS, adriamycin (ADR)-induced mice, and podocyte-specific Tmem30a ; NPHS2-Cre mice, whereas the expression of NLR family pyrin domain containing 3 (NLRP3) and ASC, two pyroptosis-related proteins, were significantly upregulated. Meanwhile, the pyroptosis inhibitor MCC950 and disulfiram (DSF) increased Tmem30a and podocyte-related proteins expression, and inhibited pyroptosis-related proteins expression in ADR-induced mouse podocytes and Tmem30a knockdown (KD) mouse podocytes. Therefore, Tmem30a might protect against podocyte injury by inhibiting pyroptosis, suggesting a potential therapeutic target for podocytopathies.
Insights
Transmembrane protein 30a (Tmem30a) protects against podocyte injury by inhibiting pyroptosis, a cell death process. This finding suggests Tmem30a as a potential therapeutic target for podocytopathies like focal segmental glomerulosclerosis (FSGS).
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Podocytopathies, including focal segmental glomerulosclerosis (FSGS), involve podocyte injury and can lead to end-stage kidney disease.
- The precise mechanisms driving podocyte injury in these conditions remain incompletely understood.
- Pyroptosis, a pro-inflammatory form of programmed cell death, was observed alongside podocyte injury in FSGS patients.
Purpose of the Study:
- To investigate the role of transmembrane protein 30a (Tmem30a) in podocyte injury and pyroptosis.
- To explore the potential of Tmem30a as a therapeutic target for podocytopathies.
Main Methods:
- Bioinformatic analysis of public datasets to identify genes associated with FSGS.
- Quantitative analysis of Tmem30a, nephrin, NLRP3, and ASC expression in FSGS patients, ADR-induced mice, and genetically modified mice.
- In vitro studies using mouse podocytes treated with pyroptosis inhibitors (MCC950, disulfiram) or subjected to Tmem30a knockdown.
Main Results:
- Tmem30a and nephrin expression were significantly downregulated in FSGS patients and relevant mouse models.
- Expression of pyroptosis markers NLRP3 and ASC was significantly upregulated in these models.
- Pyroptosis inhibitors increased Tmem30a and nephrin expression while decreasing NLRP3 and ASC expression in podocytes.
Conclusions:
- Tmem30a plays a protective role against podocyte injury, potentially by inhibiting pyroptosis.
- Targeting Tmem30a presents a promising therapeutic strategy for treating podocytopathies.
