Gasdermin D deficiency aggravates nephrocalcinosis-related chronic kidney disease with rendering macrophages vulnerable to necroptosis
Abstract Several forms of regulated necrosis contribute to the pathogenesis of crystal nephropathy, however, the role of pyroptosis, an inflammatory form of cell death involving the formation of gasdermin-D pores in internal and external cell membranes, in this condition remains unknown. Our transcr...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-04-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07620-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849737748432289792 |
|---|---|
| author | Yoshihiro Kusunoki Chenyu Li Hao Long Kanako Watanabe-Kusunoki Meisi Kuang Julian Aurelio Marschner Andreas Linkermann Stefanie Steiger Hans-Joachim Anders |
| author_facet | Yoshihiro Kusunoki Chenyu Li Hao Long Kanako Watanabe-Kusunoki Meisi Kuang Julian Aurelio Marschner Andreas Linkermann Stefanie Steiger Hans-Joachim Anders |
| author_sort | Yoshihiro Kusunoki |
| collection | DOAJ |
| description | Abstract Several forms of regulated necrosis contribute to the pathogenesis of crystal nephropathy, however, the role of pyroptosis, an inflammatory form of cell death involving the formation of gasdermin-D pores in internal and external cell membranes, in this condition remains unknown. Our transcriptional and histological analyses suggest that Gsdmd in tubulointerstitital cells may contribute to the pathogenesis of chronic oxalate nephropathy. However, genetic deletion of Gsdmd exacerbated oxalate nephropathy in mice in association with enhanced CaOx crystal deposition and accelerated tubular epithelial cell injury. Pharmacological inhibition of necroptosis reversed this effect. Indeed, Gsdmd −/− bone marrow-derived macrophages were more prone to undergo necroptosis when stimulated with CaOx crystals compared to their wildtype counterparts. We conclude that gasdermin D suppresses the necroptosis pathway, which determines the outcome of oxalate nephropathy-related nephrocalcinosis. |
| format | Article |
| id | doaj-art-39edf185fc3e43d2a2351cf78bee139d |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-39edf185fc3e43d2a2351cf78bee139d2025-08-20T03:06:50ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111210.1038/s41419-025-07620-1Gasdermin D deficiency aggravates nephrocalcinosis-related chronic kidney disease with rendering macrophages vulnerable to necroptosisYoshihiro Kusunoki0Chenyu Li1Hao Long2Kanako Watanabe-Kusunoki3Meisi Kuang4Julian Aurelio Marschner5Andreas Linkermann6Stefanie Steiger7Hans-Joachim Anders8Renal Division, Department of Medicine IV, Hospital of the Ludwig-Maximilians-UniversityRenal Division, Department of Medicine IV, Hospital of the Ludwig-Maximilians-UniversityRenal Division, Department of Medicine IV, Hospital of the Ludwig-Maximilians-UniversityRenal Division, Department of Medicine IV, Hospital of the Ludwig-Maximilians-UniversityRenal Division, Department of Medicine IV, Hospital of the Ludwig-Maximilians-UniversityDepartment of Pharmacy, Ludwig-Maximilians-UniversityDepartment of Medicine V, University Medical Centre Mannheim, University of HeidelbergRenal Division, Department of Medicine IV, Hospital of the Ludwig-Maximilians-UniversityRenal Division, Department of Medicine IV, Hospital of the Ludwig-Maximilians-UniversityAbstract Several forms of regulated necrosis contribute to the pathogenesis of crystal nephropathy, however, the role of pyroptosis, an inflammatory form of cell death involving the formation of gasdermin-D pores in internal and external cell membranes, in this condition remains unknown. Our transcriptional and histological analyses suggest that Gsdmd in tubulointerstitital cells may contribute to the pathogenesis of chronic oxalate nephropathy. However, genetic deletion of Gsdmd exacerbated oxalate nephropathy in mice in association with enhanced CaOx crystal deposition and accelerated tubular epithelial cell injury. Pharmacological inhibition of necroptosis reversed this effect. Indeed, Gsdmd −/− bone marrow-derived macrophages were more prone to undergo necroptosis when stimulated with CaOx crystals compared to their wildtype counterparts. We conclude that gasdermin D suppresses the necroptosis pathway, which determines the outcome of oxalate nephropathy-related nephrocalcinosis.https://doi.org/10.1038/s41419-025-07620-1 |
| spellingShingle | Yoshihiro Kusunoki Chenyu Li Hao Long Kanako Watanabe-Kusunoki Meisi Kuang Julian Aurelio Marschner Andreas Linkermann Stefanie Steiger Hans-Joachim Anders Gasdermin D deficiency aggravates nephrocalcinosis-related chronic kidney disease with rendering macrophages vulnerable to necroptosis Cell Death and Disease |
| title | Gasdermin D deficiency aggravates nephrocalcinosis-related chronic kidney disease with rendering macrophages vulnerable to necroptosis |
| title_full | Gasdermin D deficiency aggravates nephrocalcinosis-related chronic kidney disease with rendering macrophages vulnerable to necroptosis |
| title_fullStr | Gasdermin D deficiency aggravates nephrocalcinosis-related chronic kidney disease with rendering macrophages vulnerable to necroptosis |
| title_full_unstemmed | Gasdermin D deficiency aggravates nephrocalcinosis-related chronic kidney disease with rendering macrophages vulnerable to necroptosis |
| title_short | Gasdermin D deficiency aggravates nephrocalcinosis-related chronic kidney disease with rendering macrophages vulnerable to necroptosis |
| title_sort | gasdermin d deficiency aggravates nephrocalcinosis related chronic kidney disease with rendering macrophages vulnerable to necroptosis |
| url | https://doi.org/10.1038/s41419-025-07620-1 |
| work_keys_str_mv | AT yoshihirokusunoki gasderminddeficiencyaggravatesnephrocalcinosisrelatedchronickidneydiseasewithrenderingmacrophagesvulnerabletonecroptosis AT chenyuli gasderminddeficiencyaggravatesnephrocalcinosisrelatedchronickidneydiseasewithrenderingmacrophagesvulnerabletonecroptosis AT haolong gasderminddeficiencyaggravatesnephrocalcinosisrelatedchronickidneydiseasewithrenderingmacrophagesvulnerabletonecroptosis AT kanakowatanabekusunoki gasderminddeficiencyaggravatesnephrocalcinosisrelatedchronickidneydiseasewithrenderingmacrophagesvulnerabletonecroptosis AT meisikuang gasderminddeficiencyaggravatesnephrocalcinosisrelatedchronickidneydiseasewithrenderingmacrophagesvulnerabletonecroptosis AT julianaureliomarschner gasderminddeficiencyaggravatesnephrocalcinosisrelatedchronickidneydiseasewithrenderingmacrophagesvulnerabletonecroptosis AT andreaslinkermann gasderminddeficiencyaggravatesnephrocalcinosisrelatedchronickidneydiseasewithrenderingmacrophagesvulnerabletonecroptosis AT stefaniesteiger gasderminddeficiencyaggravatesnephrocalcinosisrelatedchronickidneydiseasewithrenderingmacrophagesvulnerabletonecroptosis AT hansjoachimanders gasderminddeficiencyaggravatesnephrocalcinosisrelatedchronickidneydiseasewithrenderingmacrophagesvulnerabletonecroptosis |