Liu, Hao;
Hiremath, Chitkale;
Patterson, Quinten;
Vora, Saumya;
Shang, Zhiguo;
Jamieson, Andrew R.;
Fiolka, Reto;
Dean, Kevin M.;
Dellinger, Michael T.;
Marciano, Denise K.
Heterozygous Mutation of Vegfr3 Reduces Renal Lymphatics without Renal Dysfunction
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Medientyp:
E-Artikel
Titel:
Heterozygous Mutation of Vegfr3 Reduces Renal Lymphatics without Renal Dysfunction
Beteiligte:
Liu, Hao;
Hiremath, Chitkale;
Patterson, Quinten;
Vora, Saumya;
Shang, Zhiguo;
Jamieson, Andrew R.;
Fiolka, Reto;
Dean, Kevin M.;
Dellinger, Michael T.;
Marciano, Denise K.
Beschreibung:
<jats:sec>
<jats:title>Significance Statement</jats:title>
<jats:p>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 <jats:italic toggle="yes">Vegfr3</jats:italic> (<jats:italic toggle="yes">Vegfr3Chy/+
</jats:italic>) 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 <jats:italic toggle="yes">Vegfr3Chy/+
</jats:italic> 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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Background</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>We utilized a mouse model containing a missense mutation in <jats:italic toggle="yes">Vegfr3</jats:italic> (dubbed <jats:italic toggle="yes">Chy</jats:italic>) that abrogates its kinase ability. <jats:italic toggle="yes">Vegfr3Chy/+
</jats:italic> mice were examined for developmental abnormalities and kidney-specific outcomes. Control and <jats:italic toggle="yes">Vegfr3Chy/+
</jats:italic> mice were subjected to cisplatin-mediated injury. We characterized renal lymphatics using tissue-clearing, light-sheet microscopy, and computational analyses.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>In the kidney, VEGFR3 is expressed not only in lymphatic vessels but also, in various blood capillaries. <jats:italic toggle="yes">Vegfr3Chy/+
</jats:italic> 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 <jats:italic toggle="yes">Vegfr3Chy/+
</jats:italic> 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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>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.</jats:p>
</jats:sec>