Chronic renal failure in a mouse model of human adenine phosphoribosyltransferase deficiency
Chronic renal failure in a mouse model of human adenine phosphoribosyltransferase deficiency
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DOI：
10.1152/ajprenal.1998.275.1.f154
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发表时间：
1998-07-01
影响因子：
4.2
通讯作者：
Stambrook, PJ
中科院分区：
文献类型：
--
作者：
Stockelman, MG;Lorenz, JN;Stambrook, PJ
在人类中，腺嘌呤磷酸核糖基转移酶（APRT，EC 2.4.2.7）缺乏可表现为肾结石、间质性肾炎和慢性肾衰竭。APRT催化由腺嘌呤和5-磷酸核糖-1-焦磷酸合成AMP。在缺乏APRT的情况下，2，8-二羟基腺嘌呤（DHA）通过黄嘌呤脱氢酶（XDH）从腺嘌呤产生，并可在肾髓质中沉淀，导致肾脏疾病。别嘌呤醇治疗通过抑制XDH活性来控制DHA结石的形成。APRT缺陷小鼠的肾脏疾病与人类相似。到12周龄时，APRT缺陷的雄性小鼠平均轻度贫血，并且比正常雄性小鼠小。它们具有广泛的肾间质损伤（通过图像分析评估）和升高的血尿素氮（BUN），并且它们的肌酐清除率（其测量作为肾小球滤过率（GFR）的估计的输注肌酐的排泄）约为野生型雄性的一半。在饮用水中加入别嘌呤醇治疗的APRT缺陷男性患者BUN正常，可见肾损害范围较小，但肌酐清除率仍较低。在它们的整个生命周期中，纯合子无效雌性小鼠表现出比同龄纯合子无效雄性小鼠显著更少的肾损伤。APRT缺陷的女性在12周龄时GFR无明显损害。雄性小鼠APRT缺乏的后果比雌性小鼠更明显，可能是由于腺嘌呤或DHA合成速率的差异或肾脏的性别决定反应。
In humans, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency can manifest as nephrolithiasis, interstitial nephritis, and chronic renal failure. APRT catalyzes synthesis of AMP from adenine and 5-phosphoribosyl-1-pyrophosphate. In the absence of APRT, 2,8-dihydroxyadenine (DHA) is produced from adenine by xanthine dehydrogenase (XDH) and can precipitate in the renal interstitium, resulting in kidney disease. Treatment with allopurinol controls formation of DHA stones by inhibiting XDH activity. Kidney disease in APRT-deficient mice resembles that seen in humans. By age 12 wk, APRT-deficient male mice are, on average, mildly anemic and smaller than normal males. They have extensive renal interstitial damage (assessed by image analysis) and elevated blood urea nitrogen (BUN), and their creatinine clearance rates, which measure excretion of infused creatinine as an estimate of glomerular filtration rate (GFR), are about half that of wild-type males. APRT-deficient males treated with allopurinol in the drinking water had normal BUN and less extensive visible renal damage, but creatinine clearance remained low. Throughout their lifespans, homozygous null female mice manifested significantly less renal damage than homozygous null males of the same age. APRT-deficient females showed no significant impairment of GFR at age 12 wk. Consequences of APRT deficiency in male mice are more pronounced than in females, possibly due to differences in rates of adenine or DHA synthesis or to sex-determined responses of the kidneys.