Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High Glucose
Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Characterized by overproduction and accumulation of extracellular matrix (ECM) proteins, glomerular sclerosis is its earliest manifestation. High glucose (HG) plays a central role by increasing matrix production by glome...
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MDPI AG
2022-09-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/9/2247 |
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| author | Jackie Trink Renzhong Li Evan Squire Kian O’Neil Phoebe Zheng Bo Gao Joan C. Krepinsky |
| author_facet | Jackie Trink Renzhong Li Evan Squire Kian O’Neil Phoebe Zheng Bo Gao Joan C. Krepinsky |
| author_sort | Jackie Trink |
| collection | DOAJ |
| description | Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Characterized by overproduction and accumulation of extracellular matrix (ECM) proteins, glomerular sclerosis is its earliest manifestation. High glucose (HG) plays a central role by increasing matrix production by glomerular mesangial cells (MC). We previously showed that HG induces translocation of GRP78 from the endoplasmic reticulum to the cell surface (csGRP78), where it acts as a signaling molecule to promote intracellular profibrotic FAK/Akt activation. Here, we identify integrin β1 as a key transmembrane signaling partner for csGRP78. We show that it is required for csGRP78-regulated FAK/Akt activation in response to HG, as well as downstream production, secretion and activity of the well characterized profibrotic cytokine transforming growth factor β1 (TGFβ1). Intriguingly, integrin β1 also itself promotes csGRP78 translocation. Furthermore, integrin β1 effects on cytoskeletal organization are not required for its function in csGRP78 translocation and signaling. These data together support an important pathologic role for csGRP78/integrin β1 in mediating key profibrotic responses to HG in kidney cells. Inhibition of their interaction will be further evaluated as a therapeutic target to limit fibrosis progression in DKD. |
| first_indexed | 2024-03-10T00:37:58Z |
| format | Article |
| id | doaj.art-0aad5278e68e4392a5815b2be2161b9c |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T00:37:58Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-0aad5278e68e4392a5815b2be2161b9c2023-11-23T15:11:36ZengMDPI AGBiomedicines2227-90592022-09-01109224710.3390/biomedicines10092247Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High GlucoseJackie Trink0Renzhong Li1Evan Squire2Kian O’Neil3Phoebe Zheng4Bo Gao5Joan C. Krepinsky6Division of Nephrology, McMaster University, St. Joseph’s Healthcare, Hamilton, ON L8N 4A6, CanadaDivision of Nephrology, McMaster University, St. Joseph’s Healthcare, Hamilton, ON L8N 4A6, CanadaDivision of Nephrology, McMaster University, St. Joseph’s Healthcare, Hamilton, ON L8N 4A6, CanadaDivision of Nephrology, McMaster University, St. Joseph’s Healthcare, Hamilton, ON L8N 4A6, CanadaDivision of Nephrology, McMaster University, St. Joseph’s Healthcare, Hamilton, ON L8N 4A6, CanadaDivision of Nephrology, McMaster University, St. Joseph’s Healthcare, Hamilton, ON L8N 4A6, CanadaDivision of Nephrology, McMaster University, St. Joseph’s Healthcare, Hamilton, ON L8N 4A6, CanadaDiabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Characterized by overproduction and accumulation of extracellular matrix (ECM) proteins, glomerular sclerosis is its earliest manifestation. High glucose (HG) plays a central role by increasing matrix production by glomerular mesangial cells (MC). We previously showed that HG induces translocation of GRP78 from the endoplasmic reticulum to the cell surface (csGRP78), where it acts as a signaling molecule to promote intracellular profibrotic FAK/Akt activation. Here, we identify integrin β1 as a key transmembrane signaling partner for csGRP78. We show that it is required for csGRP78-regulated FAK/Akt activation in response to HG, as well as downstream production, secretion and activity of the well characterized profibrotic cytokine transforming growth factor β1 (TGFβ1). Intriguingly, integrin β1 also itself promotes csGRP78 translocation. Furthermore, integrin β1 effects on cytoskeletal organization are not required for its function in csGRP78 translocation and signaling. These data together support an important pathologic role for csGRP78/integrin β1 in mediating key profibrotic responses to HG in kidney cells. Inhibition of their interaction will be further evaluated as a therapeutic target to limit fibrosis progression in DKD.https://www.mdpi.com/2227-9059/10/9/2247cell surface GRP78integrin β1TGFβ1diabetic kidney diseasecell signalingfibrosis |
| spellingShingle | Jackie Trink Renzhong Li Evan Squire Kian O’Neil Phoebe Zheng Bo Gao Joan C. Krepinsky Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High Glucose Biomedicines cell surface GRP78 integrin β1 TGFβ1 diabetic kidney disease cell signaling fibrosis |
| title | Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High Glucose |
| title_full | Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High Glucose |
| title_fullStr | Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High Glucose |
| title_full_unstemmed | Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High Glucose |
| title_short | Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High Glucose |
| title_sort | integrin β1 cell surface grp78 complex regulates tgfβ1 and its profibrotic effects in response to high glucose |
| topic | cell surface GRP78 integrin β1 TGFβ1 diabetic kidney disease cell signaling fibrosis |
| url | https://www.mdpi.com/2227-9059/10/9/2247 |
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