期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 31, 期 4, 页码 799-816出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2019080827
关键词
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资金
- German Research Foundation (Deutsche Forschungsgemeinschaft (DFG)) [SFB/TRR57, SFB/TRR219, BO3755/3-1, BO3755/6-1, AN372/16-2, 24-1]
- German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung (BMBF)) [STOP-FSGS-01GM1901A]
- RWTH Interdisciplinary Centre for Clinical Research (Interdisziplinares Zentrum fur Klinische Forschung (IZKF)) [O3-2]
- Medical Faculty of the RWTH Aachen University [START 09/15]
- Rare Kidney Stone Consortium, National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network [U54DK083908]
- NCATS
- National Institute of Diabetes and Digestive and Kidney Diseases
Background Hereditary 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. Methods Using 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. Results Adenine-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 Tnfrl 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. Conclusions Rodent 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.
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