Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy

Abstract

BackgroundHereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.MethodsUsing animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies.ResultsAdenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy.ConclusionsRodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

“…Tumor growth factor-β (TGF-β), produced at least in part by epithelial cells, and infiltrated macrophages then activate interstitial fibroblasts to produce extra cellular matrix. Recently, it was shown that TNFR-1 (TNF receptor 1) knockout mice were protected from 2,8-DHA nephropathy, suggesting that TNFR1 antagonism could be a potential future target for APRT deficiency in human [44]. Here, we demonstrate that AhR knockout mice are also protected from 2,8-DHA nephropathy.…”

Inhibition of transforming growth factor β1 signaling in resident interstitial cells attenuates profibrotic gene expression and preserves erythropoietin production during experimental kidney fibrosis in mice

“…Nonetheless the growing consensus is that resident fibroblasts, pericytes and bone marrow derived cells are the main precursors of myofibroblasts in the kidney and contribute to renal fibrosis in a similar proportion. 4,10,29,[33][34][35] Resident fibroblasts and pericytes express the platelet derived growth factor receptor β (PDGFR-β) and are one of the most numerous cell types in the kidney. 4,9,31,36 A recent study also confirmed PDGFR-β + cells as the main precursors for myofibroblasts in human kidneys.…”

“…Adenine nephropathy is a chronic damage model with strong parallels to human crystal induced pathologies, whilst UUO is an acute damage model for mechanical stress. 29,33,[42][43][44] Using the highly specific RNAscope® in-situ hybridization method allowed the colocalization of target and marker mRNAs down to a single cell resolution. In these pathological models the effects of TGFβ-R2 deletion in PDGFR-β + cells on the expression of α-SMA as a marker for myofibroblast formation was examined.…”

Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage

“…Adenine-induced kidney disease in mice is frequently used as an experimental animal model of CKD [ 4 , 9 , 25 , 26 ]. Mechanistically, orally administered adenine (a purine base) is converted into an insoluble nephrotoxic byproduct 2,8-dihydroxyadenine (2,8-DHA) that forms tubulointerstitial crystals and causes renal inflammation and fibrosis [ 27 ]. We have previously reported that germ-free (GF) mice showed more severe adenine-induced kidney damage than specific-pathogen-free (SPF) mice with normal microbiota [ 15 ]; however, the underlying mechanism for this has not yet been elucidated.…”