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Basic Research
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Heterozygous Mutation of Vegfr3 Reduces Renal Lymphatics without Renal Dysfunction

Hao Liu, Chitkale Hiremath, Quinten Patterson, Saumya Vora, Zhiguo Shang, Andrew R. Jamieson, Reto Fiolka, Kevin M. Dean, Michael T. Dellinger and Denise K. Marciano
JASN December 2021, 32 (12) 3099-3113; DOI: https://doi.org/10.1681/ASN.2021010061
Hao Liu
1Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas
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Chitkale Hiremath
1Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas
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Quinten Patterson
1Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas
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Saumya Vora
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas
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Zhiguo Shang
3Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas
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Andrew R. Jamieson
3Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas
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Reto Fiolka
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas
3Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas
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Kevin M. Dean
3Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas
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Michael T. Dellinger
4Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
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Denise K. Marciano
1Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas
2Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas
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Significance Statement

Defects in renal lymphatics occur in various kidney diseases, but the role of the lymphatics in maintaining kidney structure and function is unknown. We combine tissue clearing, light-sheet microscopy, and computational analysis to characterize lymphatics and find that mice with a heterozygous mutation in Vegfr3 (Vegfr3Chy/+) have severely reduced renal lymphatics. Strikingly, these mice have indistinguishable renal function and histology compared with controls. Even after low-dose cisplatin injury, there are no differences in renal function, although Vegfr3Chy/+ mice developed more perivascular inflammation. Our data present a novel method of lymphatic quantification and suggest that a normal complement of renal lymphatics is not essential for renal structure and function at baseline or after mild injury.

Abstract

Background Lymphatic abnormalities are observed in several types of kidney disease, but the relationship between the renal lymphatic system and renal function is unclear. The discovery of lymphatic-specific proteins, advances in microscopy, and available genetic mouse models provide the tools to help elucidate the role of renal lymphatics in physiology and disease.

Methods We utilized a mouse model containing a missense mutation in Vegfr3 (dubbed Chy) that abrogates its kinase ability. Vegfr3Chy/+ mice were examined for developmental abnormalities and kidney-specific outcomes. Control and Vegfr3Chy/+ mice were subjected to cisplatin-mediated injury. We characterized renal lymphatics using tissue-clearing, light-sheet microscopy, and computational analyses.

Results In the kidney, VEGFR3 is expressed not only in lymphatic vessels but also, in various blood capillaries. Vegfr3Chy/+ mice had severely reduced renal lymphatics with 100% penetrance, but we found no abnormalities in BP, serum creatinine, BUN, albuminuria, and histology. There was no difference in the degree of renal injury after low-dose cisplatin (5 mg/kg), although Vegfr3Chy/+ mice developed perivascular inflammation. Cisplatin-treated controls had no difference in total cortical lymphatic volume and length but showed increased lymphatic density due to decreased cortical volume.

Conclusions We demonstrate that VEGFR3 is required for development of renal lymphatics. Our studies reveal that reduced lymphatic density does not impair renal function at baseline and induces only modest histologic changes after mild injury. We introduce a novel quantification method to evaluate renal lymphatics in 3D and demonstrate that accurate measurement of lymphatic density in CKD requires assessment of changes to cortical volume.

  • lymphatics
  • kidney
  • kidney development
  • lymphangiogenesis
  • light-sheet microscopy
  • Vegfr3
  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (12)
Journal of the American Society of Nephrology
Vol. 32, Issue 12
December 2021
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Heterozygous Mutation of Vegfr3 Reduces Renal Lymphatics without Renal Dysfunction
Hao Liu, Chitkale Hiremath, Quinten Patterson, Saumya Vora, Zhiguo Shang, Andrew R. Jamieson, Reto Fiolka, Kevin M. Dean, Michael T. Dellinger, Denise K. Marciano
JASN Dec 2021, 32 (12) 3099-3113; DOI: 10.1681/ASN.2021010061

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Heterozygous Mutation of Vegfr3 Reduces Renal Lymphatics without Renal Dysfunction
Hao Liu, Chitkale Hiremath, Quinten Patterson, Saumya Vora, Zhiguo Shang, Andrew R. Jamieson, Reto Fiolka, Kevin M. Dean, Michael T. Dellinger, Denise K. Marciano
JASN Dec 2021, 32 (12) 3099-3113; DOI: 10.1681/ASN.2021010061
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Keywords

  • lymphatics
  • kidney
  • kidney development
  • lymphangiogenesis
  • light-sheet microscopy
  • Vegfr3

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