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Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy
- Source :
- Acta Pharmacol Sin
- Publication Year :
- 2020
-
Abstract
- Diabetic nephropathy (DN) is characterized by sterile inflammation with continuous injury and loss of renal inherent parenchyma cells. Podocyte is an essential early injury target in DN. The injury and loss of podocytes are closely associated with proteinuria, the early symptom of renal injury in DN. However, the exact mechanism for podocyte injury and death in DN remains ambiguous. In this study we investigated whether pyroptosis, a newly discovered cell death pathway was involved in DN. Diabetic mice were generated by high-fat diet/STZ injections. We showed that the expression levels of caspase-11 and cleavage of gasdermin D (GSDMD-N) in podocytes were significantly elevated, accompanied by reduced expression of podocyte makers nephrin and podocin, loss and fusion in podocyte foot processes, increased inflammatory cytokines NF-κB, IL-1β, and IL-18, macrophage infiltration, glomerular matrix expansion and increased urinary albumin to creatinine ratio (UACR). All these changes in diabetic mice were blunted by knockout of caspase-11 or GSDMD. Cultured human and mouse podocytes were treated with high glucose (30 mM), which significantly increased the expression levels of caspase-11 or caspase-4 (the homolog of caspase-11 in human), GSDMD-N, NF-κB, IL-1β, and IL-18, and decreased the expression of nephrin and podocin. Either caspase-4 or GSDMD knockdown by siRNA significantly blunted these changes. In summary, our results demonstrate that caspase-11/4 and GSDMD-mediated pyroptosis is activated and involved in podocyte loss under hyperglycemia condition and the development of DN.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Kidney Glomerulus
Podocyte foot
Caspase-11
Diet, High-Fat
Streptozocin
Article
Podocyte
Proinflammatory cytokine
Diabetes Mellitus, Experimental
Diabetic nephropathy
Nephrin
03 medical and health sciences
Gene Knockout Techniques
0302 clinical medicine
Internal medicine
medicine
Pyroptosis
Animals
Humans
Pharmacology (medical)
Diabetic Nephropathies
Cells, Cultured
Pharmacology
Inflammation
biology
business.industry
Podocytes
Macrophages
Intracellular Signaling Peptides and Proteins
General Medicine
Phosphate-Binding Proteins
medicine.disease
Caspases, Initiator
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Glucose
030220 oncology & carcinogenesis
biology.protein
Podocin
business
Subjects
Details
- ISSN :
- 17457254
- Volume :
- 42
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Acta pharmacologica Sinica
- Accession number :
- edsair.doi.dedup.....aebe143a4a80a7a1c1e52a4206970999