A novel role of LRP5 in tubulointerstitial fibrosis through activating TGF-β/Smad signaling

Previous studies by us and others demonstrated that activation of Wnt/β-catenin signaling plays a pathogenic role in chronic kidney diseases(CKD).Wnt co-receptor LRP5 variants are reported to associate with autosomal dominant polycystic kidney disease;but their exact roles in this disease and renal fibrosis have not been explored.Here,we observed the upregulation of LRP5 in the renal tubules of both type 1 and type 2 diabetic models and of an obstructive nephropathy model.In the obstructed kidneys,Lrp5 knockout significantly ameliorated tubulointerstitial fibrosis and tubular injury without changing Wnt/β-catenin signaling.Instead,decreased levels of TGF-β1 and TGF-βreceptors(TβRs)were detected in Lrp5 knockout kidneys,followed by attenuated activation and nuclear translocation of Smad2/3 in the renal tubules,suggesting a regulatory effect of LRP5 on TGF-β/Smad signaling.In consistent with this hypothesis,LRP5 overexpression resulted in enhanced TGF-β/Smad signaling activation in renal tubule epithelial cells.Furthermore,LRP5 was co-immunoprecipitated with TβRI and TβRII,and its extracellular domain was essential for interacting with TβRs and for its pro-fibrotic activity.In addition to stabilizing TβRs,LRP5 increased the basal membrane presentation and TGF-β1-induced internalization of these receptors.Notably,TGF-β1 also induced LRP5 internalization.These findings indicate that LRP5 promotes tubulointerstitial fibrosis,at least partially,via direct modulation of TGF-β/Smad signaling,a novel,Wnt-independent function.

Exosome-mediated renal protection:Halting the progression of fibrosis

Renal fibrosis is a complex and multifactorial process that involves inflammation,cell proliferation,collagen,and fibronectin deposition in the kidney,ultimately leading to chronic kidney disease and even end-stage renal disease.The main goal of treatment is to slow down or halt the progression of fibrosis and to improve or preserve kidney function.Despite significant progress made in understanding the underlying mechanisms of renal fibrosis,cur-rent therapies have limited renal protection as the disease progresses.Exosomes derived from stem cells are a newer area of research for the treatment of renal fibrosis.Exosomes as nano-sized extracellular vesicles carry proteins,lipids,and nucleic acids,which can be taken up by local or distant cells,serving as mediators of intercellular communication and as drug delivery vehicles.Exosomes deliver molecules that reduce inflammation,renal fibrosis and extracel-lular matrix protein production,and promote tissue regeneration in animal models of kidney disease.Additionally,they have several advantages over stem cells,such as being non-immu-nogenic,having low risk of tumor formation,and being easier to produce and store.This re-view describes the use of natural and engineered exosomes containing therapeutic agents capable of mediating anti-inflammatory and anti-fibrotic processes during both acute kidney injury and chronic kidney disease.Exosome-based therapies will be compared with stem cell-based treatments for tissue regeneration,with a focus on renal protection.Finally,future directions and strategies for improving the therapeutic efficacy of exosomes are discussed.

Wnt pathway antagonists and angiogenesis

Dysregulation of the Wnt pathway has been extensively studied in multiple diseases,including some angiogenic disorders.Wnt signaling activation is a major stimulator in pathological angiogenesis and thus,Wnt antagonists are believed to have therapeutic potential for neovascular disorders.Actually,some Wnt antagonists have been identified directly from the anti-angiogenic factor family.This review summarizes the recent progress toward understanding of the roles of Wnt pathway antagonists in angiogenic regulation and their mechanism of action,and exploring their therapeutic potential.