Calcium oxalate crystals and oxalate induce an epithelial-to-mesenchymal transition in the proximal tubular epithelial cells: Contribution to oxalate kidney injury

Abstract

TGF-β1 is the main mediator of epithelial-to-mesenchymal transition (EMT). Hyperoxaluria induces crystalluria, interstitial fibrosis, and progressive renal failure. This study analyzed whether hyperoxaluria is associated with TGF-β1 production and kidney fibrosis in mice and if oxalate or calcium oxalate (CaOx) could induce EMT in proximal tubule cells (HK2) and therefore contribute to the fibrotic process. Hyperoxaluria was induced by adding hydroxyproline and ethylene glycol to the mice’s drinking water for up to 60 days. Renal function and oxalate and urinary crystals were evaluated. Kidney collagen production and TGF-β1 expression were assessed. EMT was analyzed in vitro according to TGF-β1 production, phenotypic characterization, invasion, cell migration, gene and protein expression of epithelial and mesenchymal markers. Hyperoxaluric mice showed a decrease in renal function and an increase in CaOx crystals and Ox urinary excretion. The deposition of collagen in the renal interstitium was observed. HK2 cells stimulated with Ox and CaOx exhibited a decreased expression of epithelial as well as increased expression mesenchymal markers; these cells presented mesenchymal phenotypic changes, migration, invasiveness capability and TGF-β1 production, characterizing EMT. Treatment with BMP-7 or its overexpression in HK2 cells was effective at preventing it. This mechanism may contribute to the fibrosis observed in hyperoxaluria.

Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies

“…TNF receptor and TGF beta signaling pathways are assumed to play a role in the induction of an immune response in CaOx nephropathies. [ 35,36 ] Indeed, we found elevated expression of TNF alpha and TGF beta signaling pathway genes, such as TNF receptor superfamily member 10a, TNF alpha induced protein 3, and TGF beta receptor 3, in the CaOx group compared to all other groups (Figure 5C). Further, cell surface glycoproteins, in particular annexin II, were reported to be upregulated in hyperoxaluric animal models and suggested to facilitate CaOx adhesion.…”

Exploring the Therapeutic Mechanism of Desmodium styracifolium on Oxalate Crystal-Induced Kidney Injuries Using Comprehensive Approaches Based on Proteomics and Network Pharmacology

“…The occurrence of the epithelial mesenchymal transition of tubular cells and renal fibrogenesis induced by oxalate crystals has been demonstrated by multiple studies in mouse, rat, and cell models (Toblli et al, 2002 ; Convento et al, 2017 ). As our previous study showed, the expression of kidney interstitial markers (α-SMA and Vim) increased gradually in response to the glyoxylate-induced CaOx crystal formation and deposition (Hu et al, 2015 ).…”

Metabolism oxalic acid: failure causes and consequences of molecular-biochemical factors for the formation of oxalate-induced diseases

“…Вони набувають характеристики, які притаманні мезенхімальним клітинам, а саме -негативну регуляцію кадгерином, цитокератином, що призводить до втрати клітинних контактів. Навпаки, позитивну регуляцію мезенхімальних клітин під час епітеліально-мезенхімального переходу здійснюють віментин і α-актин [62].…”

“…Експресія BMP-7 виявлена в первинних клітинах ураження: епітеліальних клітинах та подоцитах. Вона істотно зменшується під час гострого ураження нирок, а введення екзогенного аналога прискорює відновлення ренальних пошкоджень [62].…”