ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes Nephropathy
Diabetes nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, and podocyte injury is the central contributor to the progression of DN. Despite the emerging evidence that has established the importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/24/17603 |
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| author | Shicong Song Tiantian Hu Xu Shi Yongjie Jin Sirui Liu Xuehong Li Wei Zou Cheng Wang |
| author_facet | Shicong Song Tiantian Hu Xu Shi Yongjie Jin Sirui Liu Xuehong Li Wei Zou Cheng Wang |
| author_sort | Shicong Song |
| collection | DOAJ |
| description | Diabetes nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, and podocyte injury is the central contributor to the progression of DN. Despite the emerging evidence that has established the importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of DN, abnormal protein O-GlcNAcylation is also augmented. Currently, the mechanism associating these two hyperglycemia-induced disorders remains poorly understood. This study intended to elucidate whether ER stress drives hyper-protein O-GlcNAcylation to cause podocyte injury in DN. We used both type 1 and type 2 DN models to confirm the occurrence of ER stress and excessive protein O-GlcNAcylation, and then podocyte purification was also conducted for further investigation. Nephroseq V5 data were mined and in vitro studies were applied to reveal the involvement of ER stress and hyper-O-GlcNAcylation in podocyte injury. Our results indicated that ER stress was induced in both type 1 and type 2 DN, and the human RNA-seq data from Nephroseq V5 showed that O-GlcNAcylation-related genes were significantly upregulated in the DN patients. We further demonstrated that ER stress occurred prior to hyper-O-GlcNAc modification and that pharmacologically inhibited protein O-GlcNAcylation can help decrease the podocyte apoptosis induced by hyperglycemia. Together, these discoveries will aid in uncovering the activation of the ER stress–O-GlcNAcylation axis in podocyte injury under DN, which will help open up new therapeutic approaches for preventing DN progression. |
| first_indexed | 2024-03-08T20:40:49Z |
| format | Article |
| id | doaj.art-6f5bde74dd924e22be8cf50916bdb54f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:40:49Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6f5bde74dd924e22be8cf50916bdb54f2023-12-22T14:15:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241760310.3390/ijms242417603ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes NephropathyShicong Song0Tiantian Hu1Xu Shi2Yongjie Jin3Sirui Liu4Xuehong Li5Wei Zou6Cheng Wang7Division of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Internal Medicine Building Room #606, 52 Meihua Dong Road, Zhuhai 519000, ChinaDivision of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Internal Medicine Building Room #606, 52 Meihua Dong Road, Zhuhai 519000, ChinaDivision of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Internal Medicine Building Room #606, 52 Meihua Dong Road, Zhuhai 519000, ChinaDivision of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Internal Medicine Building Room #606, 52 Meihua Dong Road, Zhuhai 519000, ChinaDivision of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Internal Medicine Building Room #606, 52 Meihua Dong Road, Zhuhai 519000, ChinaDivision of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Internal Medicine Building Room #606, 52 Meihua Dong Road, Zhuhai 519000, ChinaDivision of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Internal Medicine Building Room #606, 52 Meihua Dong Road, Zhuhai 519000, ChinaDivision of Nephrology, Department of Medicine, The Fifth Affiliated Hospital Sun Yat-Sen University, Internal Medicine Building Room #606, 52 Meihua Dong Road, Zhuhai 519000, ChinaDiabetes nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, and podocyte injury is the central contributor to the progression of DN. Despite the emerging evidence that has established the importance of podocyte endoplasmic reticulum (ER) stress in the pathogenesis of DN, abnormal protein O-GlcNAcylation is also augmented. Currently, the mechanism associating these two hyperglycemia-induced disorders remains poorly understood. This study intended to elucidate whether ER stress drives hyper-protein O-GlcNAcylation to cause podocyte injury in DN. We used both type 1 and type 2 DN models to confirm the occurrence of ER stress and excessive protein O-GlcNAcylation, and then podocyte purification was also conducted for further investigation. Nephroseq V5 data were mined and in vitro studies were applied to reveal the involvement of ER stress and hyper-O-GlcNAcylation in podocyte injury. Our results indicated that ER stress was induced in both type 1 and type 2 DN, and the human RNA-seq data from Nephroseq V5 showed that O-GlcNAcylation-related genes were significantly upregulated in the DN patients. We further demonstrated that ER stress occurred prior to hyper-O-GlcNAc modification and that pharmacologically inhibited protein O-GlcNAcylation can help decrease the podocyte apoptosis induced by hyperglycemia. Together, these discoveries will aid in uncovering the activation of the ER stress–O-GlcNAcylation axis in podocyte injury under DN, which will help open up new therapeutic approaches for preventing DN progression.https://www.mdpi.com/1422-0067/24/24/17603podocyte injurydiabetes nephropathyER stressO-GlcNAcylation |
| spellingShingle | Shicong Song Tiantian Hu Xu Shi Yongjie Jin Sirui Liu Xuehong Li Wei Zou Cheng Wang ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes Nephropathy International Journal of Molecular Sciences podocyte injury diabetes nephropathy ER stress O-GlcNAcylation |
| title | ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes Nephropathy |
| title_full | ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes Nephropathy |
| title_fullStr | ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes Nephropathy |
| title_full_unstemmed | ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes Nephropathy |
| title_short | ER Stress-Perturbed Intracellular Protein O-GlcNAcylation Aggravates Podocyte Injury in Diabetes Nephropathy |
| title_sort | er stress perturbed intracellular protein o glcnacylation aggravates podocyte injury in diabetes nephropathy |
| topic | podocyte injury diabetes nephropathy ER stress O-GlcNAcylation |
| url | https://www.mdpi.com/1422-0067/24/24/17603 |
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