Abstract
BACKGROUND: Lymphangiogenesis is believed to be a protective response in the setting of multiple forms of kidney injury and mitigates the progression of interstitial fibrosis. To augment this protective response, promoting kidney lymphangiogenesis is being investigated as a potential treatment to slow the progression of kidney disease. As injury-related lymphangiogenesis is driven by signaling from the receptor VEGFR3 (vascular endothelial growth factor receptor 3) in response to the cognate growth factor VEGF (vascular endothelial growth factor)-C released by tubular epithelial cells, this signaling pathway is a candidate for future kidney therapeutics. However, the consequences to kidney development and function to targeting this signaling pathway remain poorly defined. METHODS: We generated a new mouse model expressing Vegfc under regulation of the nephron progenitor Six2Cre driver strain (Six2Vegfc). Mice underwent a detailed phenotypic evaluation. Whole kidneys were processed for histology and 3-dimensional imaging. RESULTS: Six2Vegfc mice had reduced body weight and kidney function compared with littermate controls. Six2Vegfc kidneys demonstrated large peripelvic fluid-filled lesions with distortion of the pelvicalcyceal system which progressed in severity with age. Three-dimensional imaging showed a 3-fold increase in total cortical vascular density. Histology confirmed a substantial increase in LYVE1+ (lymphatic vessel endothelial hyaluronan receptor-1)/PDPN+ (podoplanin)/VEGFR3+ lymphatic capillaries extending alongside EMCN+ (endomucin) peritubular capillaries. There was no change in EMCN+ peritubular capillary density. CONCLUSIONS: Kidney lymphatic density was robustly increased in the Six2Vegfc mice. There were no changes in peritubular blood capillary density despite these endothelial cells also expressing VEGFR3. The model resulted in malformation of the lymphatic hilar plexus, resulting in severe hydronephrosis that resembled a human condition termed renal lymphangiectasia. This study defines the vascular consequences of augmenting VEGFC signaling during kidney development and provides new insight into human renal lymphatic malformations.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 104-112 |
| Number of pages | 9 |
| Journal | Arteriosclerosis, thrombosis, and vascular biology |
| Volume | 45 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2025 |
Funding
The authors thank Dr Guillermo Oliver and Dr Wanshu Ma for the VegfcGOF mouse line. This publication was made possible through core services and support from the Northwestern University George M. O'Brien Kidney Research Core Center (NU GoKidney), a National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-funded program (P30 DK114857). Histology services were provided, in part, by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Mouse magnetic resonance imaging (MRI) was performed through the Center for Translational Imaging at Northwestern University. Serum creatinine and blood urea nitrogen measurements were performed by the UAB-USCD (University of Alabama at Birmingham - University of California San Diego) O'Brien Center for Acute Kidney Injury Research and are supported by a P30 grant (DK 079337) from the NIDDK. M.D. Donnan acknowledges his United States Department of Veterans Affairs (VA) employment as a Staff Physician, Medical Service, at Jesse Brown VA Medical Center, Chicago, IL. M.D. Donnan and S.E. Quaggin contributed to the design of the experiments. Animal experiments and histology were performed by M.D. Donnan, V. Dalal, and D.K. Deb. Micro-computed tomography imaging and analysis was performed by V. David. MRI and analysis was performed by D. Procissi. M.D. Donnan, D.K. Deb, V. Dalal, V. David, D. Procissi, and S.E. Quaggin contributed to analysis of the data. The manuscript was written by M.D. Donnan and S.E. Quaggin. S.E. Quaggin supervised the study. All authors contributed to the review and approval of the manuscript. This work was funded by a fellowship grant from the American Society of Nephrology Ben J. Lipps Research Fellowship (M.D. Donnan), a research grant from the National Kidney Foundation of Illinois (M.D. Donnan), and a research grant from the National Institutes of Health: P30DK114857 (S.E. Quaggin). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US government. The authors thank Dr Guillermo Oliver and Dr Wanshu Ma for the VegfcGOF mouse line. This publication was made possible through core services and support from the Northwestern University George M. O\u2019Brien Kidney Research Core Center (NU GoKidney), a National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)\u2013funded program (P30 DK114857). Histology services were provided, in part, by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by NCI P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Mouse magnetic resonance imaging (MRI) was performed through the Center for Translational Imaging at Northwestern University. Serum creatinine and blood urea nitrogen measurements were performed by the UAB-USCD O\u2019Brien Center for Acute Kidney Injury Research and are supported by a P30 grant (DK 079337) from the NIDDK. M.D. Donnan acknowledges his VA employment as a Staff Physician, Medical Service, at Jesse Brown VA Medical Center, Chicago, IL. M.D. Donnan and S.E. Quaggin contributed to the design of the experiments. Animal experiments and histology were performed by M.D. Donnan, V. Dalal, and D.K. Deb. Micro-computed tomography imaging and analysis was performed by V. David. MRI and analysis was performed by D. Procissi. M.D. Donnan, D.K. Deb, V. Dalal, V. David, D. Procissi, and S.E. Quaggin contributed to analysis of the data. The manuscript was written by M.D. Donnan and S.E. Quaggin. S.E. Quaggin supervised the study. All authors contributed to the review and approval of the manuscript. This work was funded by a fellowship grant from the American Society of Nephrology Ben J. Lipps Research Fellowship (M.D. Donnan), a research grant from the National Kidney Foundation of Illinois (M.D. Donnan), and a research grant from the National Institutes of Health : P30DK114857 (S.E. Quaggin). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US government.
Keywords
- kidney
- lymphatic vessels
- mice
- vascular endothelial growth factor c
- vascular malformations
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
