Department of Internal Medicine 4-Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany.
Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
Kidney Int. 2019 Aug;96(2):378-396. doi: 10.1016/j.kint.2019.02.016. Epub 2019 Mar 5.
Prolyl hydroxylase domain enzyme inhibitors (PHDIs) stabilize hypoxia-inducible factors (HIFs), and are protective in models of acute ischemic and inflammatory kidney disease. Whether PHDIs also confer protection in chronic inflammatory kidney disease models remains unknown. Here we investigated long-term effects of PHDI treatment in adenine-induced nephropathy as a model for chronic tubulointerstitial nephritis. After three weeks, renal dysfunction and tubulointerstitial damage, including proximal and distal tubular injury, tubular dilation and renal crystal deposition were significantly attenuated in PHDI-treated (the isoquinoline derivative ICA and Roxadustat) compared to vehicle-treated mice with adenine-induced nephropathy. Crystal-induced renal fibrosis was only partially diminished by treatment with ICA. Renoprotective effects of ICA treatment could not be attributed to changes in adenine metabolism or urinary excretion of the metabolite 2,8-dihydroxyadenine. ICA treatment reduced inflammatory infiltrates of F4/80+ mononuclear phagocytes in the kidneys and supported a regulatory, anti-inflammatory immune response. Furthermore, interstitial deposition of complement C1q was decreased in ICA-treated mice fed an adenine-enriched diet. Tubular cell-specific HIF-1α and myeloid cell-specific HIF-1α and HIF-2α expression were not required for the renoprotective effects of ICA. In contrast, depletion of mononuclear phagocytes with clodronate largely abolished the nephroprotective effects of PHD inhibition. Thus, our findings indicate novel and potent systemic anti-inflammatory properties of PHDIs that confer preservation of kidney function and structure in chronic tubulointerstitial inflammation and might counteract kidney disease progression.
脯氨酰羟化酶结构域酶抑制剂（PHDIs）稳定缺氧诱导因子（HIFs），并在急性缺血性和炎症性肾病模型中具有保护作用。PHDIs 是否在慢性炎症性肾病模型中也具有保护作用尚不清楚。在这里，我们研究了 PHDI 治疗在腺嘌呤诱导的肾病（一种慢性肾小管间质性肾炎模型）中的长期作用。在 3 周后，与用腺嘌呤诱导肾病的载体处理的小鼠相比，用 PHDI 处理（异喹啉衍生物 ICA 和罗沙司他）的小鼠肾功能障碍和肾小管间质损伤，包括近端和远端肾小管损伤、肾小管扩张和肾脏晶体沉积明显减轻。ICA 治疗仅部分减轻了晶体诱导的肾纤维化。ICA 治疗的肾保护作用不能归因于腺嘌呤代谢的变化或代谢物 2,8-二羟腺嘌呤的尿排泄。ICA 治疗减少了肾脏中 F4/80+单核吞噬细胞的炎症浸润，并支持调节性、抗炎免疫反应。此外，富含腺嘌呤的饮食中 ICA 治疗小鼠的间质补体 C1q 沉积减少。肾小管细胞特异性 HIF-1α和髓样细胞特异性 HIF-1α和 HIF-2α表达不是 ICA 发挥肾保护作用所必需的。相反，用 clodronate 耗尽单核吞噬细胞在很大程度上消除了 PHDI 抑制的肾保护作用。因此，我们的研究结果表明 PHDIs 具有新型和有效的全身抗炎特性，可在慢性肾小管间质性炎症中保留肾功能和结构，并可能阻止肾脏疾病进展。
