Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease

Abstract

Intrarenal crystals trigger inflammation and renal cell necroptosis, processes that involve TNF receptor (TNFR) signaling. Here, we tested the hypothesis that TNFRs also have a direct role in tubular crystal deposition and progression of hyperoxaluria-related CKD. Immunohistochemical analysis revealed upregulated tubular expression of TNFR1 and TNFR2 in human and murine kidneys with calcium oxalate (CaOx) nephrocalcinosis-related CKD compared with controls. Western blot and mRNA expression analyses in mice yielded consistent data. When fed an oxalate-rich diet, wild-type mice developed progressive CKD, whereas , anddeficient mice did not. Despite identical levels of hyperoxaluria, , and-deficient mice also lacked the intrarenal CaOx deposition and tubular damage observed in wild-type mice. Inhibition of TNFR signaling prevented the induced expression of the crystal adhesion molecules, CD44 and annexin II, in tubular epithelial cells and, and treatment with the small molecule TNFR inhibitor R-7050 partially protected hyperoxaluric mice from nephrocalcinosis and CKD. We conclude that TNFR signaling is essential for CaOx crystal adhesion to the luminal membrane of renal tubules as a fundamental initiating mechanism of oxalate nephropathy. Furthermore, therapeutic blockade of TNFR might delay progressive forms of nephrocalcinosis in oxalate nephropathy, such as primary hyperoxaluria.

Novel Insights into Crystal-Induced Kidney Injury

“…Moreover, crystal plugs adhere to the tubular lumen and cause obstruction, leading to declined renal function. Crystal adhesion to tubular epithelium is regulated by several surface molecules such as CD44, annexin II, osteopontin, phosphatidylserine, hyaluronan, as well as TNF receptor signaling [45-47]. …”

“…Indeed, epithelial injury or absence of crystallization inhibitors enhances crystal adhesion to the tubular epithelium [38, 46]. For example, own experiments suggest that the receptors of TNFα mediate the adhesion of calcium oxalate crystals to the tubular epithelium by inducing the expression of crystal adhesion molecules at the luminal surface [47]. However, the process of adhesion and growth of calcium oxalate stones at Randall plaques and plugs obstructing the ducts of Bellini remains poorly understood.…”

Sodium glucose transporter-2 inhibition has no renoprotective effects on non-diabetic chronic kidney disease

“…Calcium oxalate crystal adhesion depends on the luminal expression of several crystal adhesion molecules, such as CD44, annexin II, and osteopontin (Asselman et al. ) which are induced by TNF receptor signaling in tubular epithelial cells (Mulay ). Crystal adhesion promotes further crystal growth to crystal plugs that obstruct the tubular lumen leading to intrarenal nephron obstruction (Mulay ).…”

“…) which are induced by TNF receptor signaling in tubular epithelial cells (Mulay ). Crystal adhesion promotes further crystal growth to crystal plugs that obstruct the tubular lumen leading to intrarenal nephron obstruction (Mulay ). Tubule obstruction is then followed by tubular atrophy and replacement with fibrous tissue.…”

<i>Glechoma longituba</i> (Lamiaceae) alleviates apoptosis in calcium oxalate-induced oxidative stress in kidney proximal tubule epithelial cell line, HK-2

“…Calcium oxalate (CaOx) stones are considered to constitute the majority of calculi in kidney stones, which are characterized by hypercalciuria, attached CaOx stones, and interstitial calcium phosphate deposits [7]. CaOx not only obstructs ureters, but also induces reactive oxygen species (ROS), which results in renal cellular injury and inflammation [8,9].…”