Curtailing Endothelial TGF-β Signaling Is Sufficient to Reduce Endothelial-Mesenchymal Transition and Fibrosis in CKD

Abstract

Excessive TGF-b signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-b signaling on development of fibrosis, there is a lack of information on ablating TGF-b signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-b receptor knockout (TbRII endo+/2 ) mice to explore whether curtailed TGF-b signaling significantly modifies nephrosclerosis.These mice developed normally, but showed enhanced angiogenic potential compared with TbRII endo+/+ mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TbRII endo+/2 mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TbRII endo+/+ counterparts. In addition, partial deletion of TbRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-b-induced canonical Smad2 signaling was reduced in TbRII +/2 ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in TbRII +/2 ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in TbRII +/2 ECs compared with TbRII +/+ ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-b signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-b signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.

Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases

“…[1][2][3][4][5][6][7] Several recent studies suggested that restoring the renal microvasculature may provide novel therapeutic options for patients with CKD. [8][9][10][11][12] Thus far, however, quantitative imaging tools allowing for the noninvasive monitoring of morphologic and functional alterations of the renal microvasculature during disease progression have been lacking, and studies investigating vessel rarefaction in CKD have been largely restricted to invasive microscopic end-point analyses. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] We here employed in vivo and ex vivo mCT-based imaging techniques, alongside conventional immunohistochemical methodologies, to demonstrate that (1) contrast-enhanced in vivo mCT imaging is highly suitable for accurate and noninvasive monitoring of vessel functionality during progressive kidney diseases, via quantifying the renal rBV; (2) the renal rBV continuously decreases during early-to-late-stage renal disease progression; (3) vessel functionality is reduced immediately after renal injury prior to the onset of interstitial fibrosis, supporting the assumption that endothelial injury might be a major initiating cause of fibrosis development; and (4) in addition to peritubular capillaries, arterial vessels of virtually all calibers undergo substantial alterations during progressive renal disease with regard to vessel branching, size, and tortuosity.…”

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

“…35,36 The TGF-b pathway is an important promoter of renal fibrosis often involved in renal disease from different etiologies. 37 In addition, TGF-b can also lead to renal fibrosis by promoting endothelial-to-mesenchymal transition and blunting angiogenesis, 38 an effect that may have contributed to MV rarefaction and the subsequent improvement following treatment. Therefore, an improvement in MMP-2/TIMP-1 coupled with an augmented MV proliferation may explain the expansion of the renal MV architecture after ELP-VEGF therapy.…”

Vascular Endothelial Growth Factor Therapy for the Kidney

“…Indeed, microvascular dysfunction, damage, and even loss are hallmarks of renal disease in humans, which correlate with the development of renal dysfunction and injury and may both initiate and promote interstitial fibrosis, tubular atrophy, and glomerulosclerosis. 2,3 Unlike nephrons, with numbers that are determined at birth and (still) cannot be regenerated or recreated de novo, the vessels in the kidney are subject to changes in their diameter, remodeling, and possibly, repair and regeneration. Development of new vessels in the kidney is not limited to the developmental phase of the organ and serves as compensatory mechanism in response to insults that could also be activated or stimulated by therapeutic interventions.…”