Sonic hedgehog selectively promotes lymphangiogenesis after kidney injury through noncanonical pathway

Abstract

Kidney fibrosis is associated with an increased lymphangiogenesis, characterized by the formation and expansion of new lymphatic vessels. However, the trigger and underlying mechanism responsible for the growth of lymphatic vessels in diseased kidney remain poorly defined. Here, we report that tubule-derived sonic hedgehog (Shh) ligand is a novel lymphangiogenic factor that plays a crucial role in mediating lymphatic endothelial cell proliferation and expansion. Shh was induced in renal tubular epithelium in various models of fibrotic chronic kidney disease, and this was accompanied by an expansion of lymphatic vessels in adjacent areas. In vitro, Shh selectively promoted the proliferation of human dermal lymphatic endothelial cells (HDLECs) but not human umbilical vein endothelial cells, as assessed by cell counting, MTT assay, and bromodeoxyuridine incorporation. Shh also induced the expression of vascular endothelial growth factor receptor-3, cyclin D1, and proliferating cell nuclear antigen in HDLECs. Shh did not affect the expression of Gli1, the downstream target and readout of canonical hedgehog signaling, but activated ERK-1/2 in HDLECs. Inhibition of Smoothened with small-molecule inhibitor or blockade of ERK-1/2 activation abolished the lymphatic endothelial cell proliferation induced by Shh. In vivo, inhibition of Smoothened also repressed lymphangiogenesis and attenuated renal fibrosis. This study identifies Shh as a novel mitogen that selectively promotes lymphatic, but not vascular, endothelial cell proliferation and suggests that tubule-derived Shh plays an essential role in mediating lymphangiogenesis after kidney injury.

Sonic hedgehog connects podocyte injury to mesangial activation and glomerulosclerosis

“…The most interesting finding of the present study is that Shh connects podocyte damage to mesangial activation and glomerulosclerosis by mediating a unique podocyte-mesangial communication via a paracrine fashion. This conclusion is supported by the observations that Shh is able to promote mesangial cell activation in different model systems, in vitro, ex vivo, and in vivo, but does not affect the proliferation of podocytes (Figure 2) or endothelial cells (24). Furthermore, genetic ablation or pharmacologic inhibition of Shh decouples podocyte injury from glomerulosclerosis.…”

“…Similar results were obtained using a quantitative colorimetric MTT assay ( Figure 2, F and G). However, Shh did not affect the growth of podocytes ( Figure 2, H and I) or endothelial cells (24). We further assessed the ability of Shh to promote mesangial cells to enter cell cycle and undergo DNA synthesis, which was reflected by BrdU incorporation.…”

Network-Based Expression Analyses and Experimental Verifications Reveal the Involvement of STUB1 in Acute Kidney Injury

“…In our analysis, CCL5 , CCL19 , CCL21 , CXCR5 , and CXCL2 were upregulated in AKI, which was consistent with that reported in previous studies ( Sanz et al, 2010 ; Winterberg et al, 2013 ; Wohlfahrtova et al, 2015 ; Sobbe et al, 2020 ). Moreover, Hedgehog signaling was reported to be upregulated and protected tubular cells in various AKI models, such as ischemia/reperfusion ( Zhuo et al, 2019 ) and obstructive kidney injury ( Rauhauser et al, 2015 ). For the downregulated pathways in the AKI group, the metabolism of amino acids and fatty acid pathways, such as “butanoate metabolism,” “cysteine and methionine metabolism,” and “fatty acid metabolism,” were downregulated, indicating the impaired renal function.…”

Emerging roles for lymphatics in acute kidney injury: Beneficial or maleficent?

“…30 Furthermore, TGF-β signaling in chronic kidney disease activates a noncanonical pathway through increased Sonic hedgehog which has been demonstrated to promote LEC proliferation. 66 LEC interactions with T-cells and their cytokines define a role for LECs as antigen-presenting cells and provide a potential mechanism through which T cell systemic peripheral tolerance is mediated. 45 It is clear lymphatics communicate directly to the renal immune environment and systemically through interactions with antigens and immune cells.…”