VEGF-C overexpression in kidney progenitor cells is a model of renal lymphangiectasia

Abstract

BackgroundLymphangiogenesis 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 VEGFR-3 in response to the cognate growth factor VEGF-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 remains poorly defined.MethodsWe generated a new mouse model expressingVegf-Cunder regulation of the nephron progenitor Six2Cre driver strain (Six2Vegf-C). Mice underwent a detailed phenotypic evaluation. Whole kidneys were processed for histology and micro computed tomography 3-dimensional imaging.ResultsSix2Vegf-Cmice had reduced body weight and kidney function compared to littermate controls.Six2Vegf-Ckidneys demonstrated large peripelvic fluid filled lesions with distortion of the pelvicalcyceal system which progressed in severity with age. 3D imaging showed a 3-fold increase in total cortical vascular density. Histology confirmed a substantial increase in LYVE1+/PDPN+/VEGFR3+ lymphatic capillaries extending alongside EMCN+ peritubular capillaries. There was no change in EMCN+ peritubular capillary density.ConclusionsKidney lymphangiogenesis was robustly induced in theSix2Vegf-Cmice. There were no changes in peritubular blood capillary density despite these endothelial cells also expressing VEGFR-3. The model resulted in a severe cystic kidney phenotype that resembled a human condition termed renal lymphangiectasia. This study defines the vascular consequences of augmenting VEGF-C signaling during kidney development and provides new insight into a mimicker of human cystic kidney disease.

Single-Cell RNA Sequencing Identifies Response of Renal Lymphatic Endothelial Cells to Acute Kidney Injury

“…[58][59][60] Several recent elegant studies have characterized lymphatics in the developing kidney. 61,62 The importance of renal lymphatic vessels in pathologic progression in the adult kidney, however, and how manipulation of lymphangiogenic signaling through VEGFR-3 affects functional outcomes is less clear. What is clear is that the lymphatic vasculature and VEGFR-3 signaling is involved in transplant rejection, renal fibrotic remodeling, immune accumulation, and microvascular rarefaction.…”

Renal Lymphangiectasia: The Transcending of Serendipity

“…These effects seem to be associated with an increase in VEGF-C. The mouse model showed a severe cystic kidney phenotype similar to renal lymphangiectasia [ 1 ]. Finally, this alteration dilates the renal lymphatic structures, leading to fluid-filled cavities, which are primarily simple cystic spaces, but they may be septated and located mainly in the renal sinus [ 2 ].…”

“…Some anomalies associated with renal lymphangiectasia include the creation of perinephric arteries and possible mechanisms of abdominal injury that impede renal lymphatic drainage. Furthermore, research in mice reveals a relationship with vascular endothelial growth factor C (VEGF-C), which could be involved in its development [ 1 ]. This alteration favors the dilation of the renal lymphatic systems, which gives rise to fluid-filled cavities, generally simple cysts [ 2 ].…”