Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice
Vascular endothelial growth factor-a (VEGF-A) and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and are dysregulated in diabetic kidney disease (DKD). While NO availability is consistently low in diabetes, both high and low VEGF-A have been reported in patients with...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-02-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.788886/full |
| _version_ | 1818334123632099328 |
|---|---|
| author | Delma Veron Pardeep K. Aggarwal Qi Li Qi Li Gilbert Moeckel Michael Kashgarian Alda Tufro Alda Tufro |
| author_facet | Delma Veron Pardeep K. Aggarwal Qi Li Qi Li Gilbert Moeckel Michael Kashgarian Alda Tufro Alda Tufro |
| author_sort | Delma Veron |
| collection | DOAJ |
| description | Vascular endothelial growth factor-a (VEGF-A) and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and are dysregulated in diabetic kidney disease (DKD). While NO availability is consistently low in diabetes, both high and low VEGF-A have been reported in patients with DKD. Here we examined the effect of inducible podocyte VEGF-A knockdown (VEGFKD) in diabetic mice and in endothelial nitric oxide synthase knockout mice (eNOS−/−). Diabetes was induced with streptozotocin using the Animal Models of Diabetic Complications Consortium (AMDCC) protocol. Induction of podocyte VEGFKD led to diffuse glomerulosclerosis, foot process effacement, and GBM thickening in both diabetic mice with intact eNOS and in non-diabetic eNOS−/−:VEGFKD mice. VEGFKD diabetic mice developed mild proteinuria and maintained normal glomerular filtration rate (GFR), associated with extremely high NO and thiol urinary excretion. In eNOS−/−:VEGFKD (+dox) mice severe diffuse glomerulosclerosis was associated with microaneurisms, arteriolar hyalinosis, massive proteinuria, and renal failure. Collectively, data indicate that combined podocyte VEGF-A and eNOS deficiency result in diffuse glomerulosclerosis in mice; compensatory NO and thiol generation prevents severe proteinuria and GFR loss in VEGFKD diabetic mice with intact eNOS, whereas VEGFKD induction in eNOS−/−:VEGFKD mice causes massive proteinuria and renal failure mimicking DKD in the absence of diabetes. Mechanistically, we identify VEGFKD-induced abnormal S-nitrosylation of specific proteins, including β3-integrin, laminin, and S-nitrosoglutathione reductase (GSNOR), as targetable molecular mechanisms involved in the development of advanced diffuse glomerulosclerosis and renal failure. |
| first_indexed | 2024-12-13T14:02:32Z |
| format | Article |
| id | doaj.art-41ddbebcb869477b9a37fab161a12f88 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-13T14:02:32Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-41ddbebcb869477b9a37fab161a12f882022-12-21T23:42:42ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-02-011210.3389/fphar.2021.788886788886Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout MiceDelma Veron0Pardeep K. Aggarwal1Qi Li2Qi Li3Gilbert Moeckel4Michael Kashgarian5Alda Tufro6Alda Tufro7Department of Pediatrics, Yale University School of Medicine, Malvern, PA, United StatesDepartment of Pediatrics, Yale University School of Medicine, Malvern, PA, United StatesDepartment of Pediatrics, Yale University School of Medicine, Malvern, PA, United StatesDepartment of Pathology, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Pathology, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Pathology, Yale University School of Medicine, New Haven, CT, United StatesDepartment of Pediatrics, Yale University School of Medicine, Malvern, PA, United StatesDepartment of Cell and Molecular Physiology, Yale University School of Medicine, New Haven, CT, United StatesVascular endothelial growth factor-a (VEGF-A) and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and are dysregulated in diabetic kidney disease (DKD). While NO availability is consistently low in diabetes, both high and low VEGF-A have been reported in patients with DKD. Here we examined the effect of inducible podocyte VEGF-A knockdown (VEGFKD) in diabetic mice and in endothelial nitric oxide synthase knockout mice (eNOS−/−). Diabetes was induced with streptozotocin using the Animal Models of Diabetic Complications Consortium (AMDCC) protocol. Induction of podocyte VEGFKD led to diffuse glomerulosclerosis, foot process effacement, and GBM thickening in both diabetic mice with intact eNOS and in non-diabetic eNOS−/−:VEGFKD mice. VEGFKD diabetic mice developed mild proteinuria and maintained normal glomerular filtration rate (GFR), associated with extremely high NO and thiol urinary excretion. In eNOS−/−:VEGFKD (+dox) mice severe diffuse glomerulosclerosis was associated with microaneurisms, arteriolar hyalinosis, massive proteinuria, and renal failure. Collectively, data indicate that combined podocyte VEGF-A and eNOS deficiency result in diffuse glomerulosclerosis in mice; compensatory NO and thiol generation prevents severe proteinuria and GFR loss in VEGFKD diabetic mice with intact eNOS, whereas VEGFKD induction in eNOS−/−:VEGFKD mice causes massive proteinuria and renal failure mimicking DKD in the absence of diabetes. Mechanistically, we identify VEGFKD-induced abnormal S-nitrosylation of specific proteins, including β3-integrin, laminin, and S-nitrosoglutathione reductase (GSNOR), as targetable molecular mechanisms involved in the development of advanced diffuse glomerulosclerosis and renal failure.https://www.frontiersin.org/articles/10.3389/fphar.2021.788886/fulldiabetic kidney diseaseVEGF knockdowndiffuse glomerulosclerosisS-nitrosylationβ3-integrinlaminin |
| spellingShingle | Delma Veron Pardeep K. Aggarwal Qi Li Qi Li Gilbert Moeckel Michael Kashgarian Alda Tufro Alda Tufro Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice Frontiers in Pharmacology diabetic kidney disease VEGF knockdown diffuse glomerulosclerosis S-nitrosylation β3-integrin laminin |
| title | Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice |
| title_full | Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice |
| title_fullStr | Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice |
| title_full_unstemmed | Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice |
| title_short | Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice |
| title_sort | podocyte vegf a knockdown induces diffuse glomerulosclerosis in diabetic and in enos knockout mice |
| topic | diabetic kidney disease VEGF knockdown diffuse glomerulosclerosis S-nitrosylation β3-integrin laminin |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.788886/full |
| work_keys_str_mv | AT delmaveron podocytevegfaknockdowninducesdiffuseglomerulosclerosisindiabeticandinenosknockoutmice AT pardeepkaggarwal podocytevegfaknockdowninducesdiffuseglomerulosclerosisindiabeticandinenosknockoutmice AT qili podocytevegfaknockdowninducesdiffuseglomerulosclerosisindiabeticandinenosknockoutmice AT qili podocytevegfaknockdowninducesdiffuseglomerulosclerosisindiabeticandinenosknockoutmice AT gilbertmoeckel podocytevegfaknockdowninducesdiffuseglomerulosclerosisindiabeticandinenosknockoutmice AT michaelkashgarian podocytevegfaknockdowninducesdiffuseglomerulosclerosisindiabeticandinenosknockoutmice AT aldatufro podocytevegfaknockdowninducesdiffuseglomerulosclerosisindiabeticandinenosknockoutmice AT aldatufro podocytevegfaknockdowninducesdiffuseglomerulosclerosisindiabeticandinenosknockoutmice |