Article ; Online: Emodin mitigates podocytes apoptosis induced by endoplasmic reticulum stress through the inhibition of the PERK pathway in diabetic nephropathy.
Drug design, development and therapy
2018 Volume 12, Page(s) 2195–2211
Abstract: Background: Endoplasmic reticulum stress is associated with podocyte apoptosis in the pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has a protective effect in the kidney by suppressing proliferation of ... ...
| Abstract | Background: Endoplasmic reticulum stress is associated with podocyte apoptosis in the pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has a protective effect in the kidney by suppressing proliferation of mesangial cells and inhibiting the renal tubular epithelial-to-mesenchymal transition. However, the effects of emodin on the podocyte apoptosis in DN and its mechanisms are unknown. Aim: This study aimed to explore the effect of emodin on DN model KK-Ay mice and high glucose induced podocytes apoptosis via the PERK-eIF2α pathway. Methods: KK-Ay mice model of DN were treated with emodin at dose of 40 and 80 mg/kg/day for 8 weeks. Urine albumin, serum creatinine, blood urea nitrogen levels and the renal histopathology in mice were performed. In vitro, conditionally immortalized mouse podocytes exposed to HG (30mM) were incubated with emodin. Cell viability was measured by CCK-8 assay. Additionally, we performed RNA interference and measured the apoptosis in cultured podocytes treated with emodin. Immunohistochemistry, immunofluorescence, western blot, and real-time PCR were used to detect gene and protein expression both in vivo and in vitro. Results: The results showed that emodin treatment ameliorated urine albumin, serum creatinine, and blood urea nitrogen of DN mice. The pathological damage of kidney tissue was also improved after treatment with emodin. Moreover, emodin increased nephrin expression. Podocytes apoptosis and endoplasmic reticulum stress markers (GRP78) were significantly reduced upon emodin treatment. Furthermore, emodin treatment decreased the expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (P-PERK), phosphorylated P-eIF2α, ATF4, and CHOP. In vitro, emodin treatment was further found to decrease the GRP78 level induced by high glucose or tunicamycin (TM). Besides, emodin and PERK knockdown inhibited the apoptosis of podocytes cultured in high glucose by counteracting the upregulation of phosphorylated PERK, phosphorylated eIF2α, ATF4, and CHOP. Conclusion: Overall, the findings indicate that emodin mitigates podocytes apoptosis by inhibiting the PERK-eIF2α signaling pathway in vivo and in vitro, and, therefore, exerts a protective action on podocytes in DN. |
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| MeSH term(s) | Animals ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Diabetic Nephropathies/drug therapy ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Dose-Response Relationship, Drug ; Emodin/administration & dosage ; Emodin/chemistry ; Emodin/pharmacology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects ; Epithelial-Mesenchymal Transition/drug effects ; Male ; Mice ; Mice, Inbred Strains ; Molecular Structure ; Podocytes/drug effects ; Podocytes/metabolism ; Podocytes/pathology ; Protein Kinases/administration & dosage ; Protein Kinases/chemistry ; Protein Kinases/pharmacology ; Structure-Activity Relationship ; eIF-2 Kinase/antagonists & inhibitors ; eIF-2 Kinase/metabolism |
| Chemical Substances | Endoplasmic Reticulum Chaperone BiP ; Hspa5 protein, mouse ; Protein Kinases (EC 2.7.-) ; PERK kinase (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1) ; Emodin (KA46RNI6HN) |
| Language | English |
| Publishing date | 2018-07-13 |
| Publishing country | New Zealand |
| Document type | Journal Article |
| ZDB-ID | 2451346-5 |
| ISSN | 1177-8881 ; 1177-8881 |
| ISSN (online) | 1177-8881 |
| ISSN | 1177-8881 |
| DOI | 10.2147/DDDT.S167405 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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