Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1
Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1
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DOI：
10.1111/j.1523-1755.2004.00788.x
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发表时间：
2004-09-01
影响因子：
19.6
通讯作者：
van den Berg, IET
中科院分区：
文献类型：
--
作者：
Luijerink, MC;van Beurden, EACM;van den Berg, IET
背景遗传性酪氨酸血症1型（HT 1）是由酪氨酸分解级联反应的最后一种酶富马酰乙酰乙酸水解酶（FAH）缺乏引起的，与严重的肝脏和肾脏损害有关。HT 1相关的肝和肾衰竭可以通过用2-（2-硝基-4-三氟甲基苯甲酰基）-1，3-环己二酮（NTBC）阻断酪氨酸分解途径中FAH上游的酶来预防。当NTBC治疗停止时，FAH敲除小鼠发展为HT 1表型。在Fah（-/-）小鼠的肾脏中研究了细胞死亡的发生，无论是未激发的还是注射800 mg/kg的尿黑酸（HGA），一种酪氨酸分解的中间体。在NTBC的Fah（-/-）小鼠的肾脏中未检测到细胞死亡。裂解的半胱天冬酶-3的轻微增加是在未使用NTBC的Fah（-/-）小鼠的肾脏中可以检测到的唯一的糖尿病相关特征。Fah（-/-）小鼠在NTBC上用HGA激发导致肾近端小管细胞大量死亡，具有阳性末端脱氧核苷酸转移酶介导的脱氧尿苷二磷酸（dUDP）缺口末端标记（TUNEL）和DNA片段化测定，但几乎没有半胱天冬酶-9和半胱天冬酶-3的任何裂解。Fah（-/-）小鼠对HGA诱导的肾细胞死亡具有抵抗性，HGA诱导的肾细胞凋亡较少，caspase-9和caspase-3表达增加。从NTBC中撤出15天的成年Fah（-/-）小鼠的肾脏显示出有限的细胞凋亡特征，并且对由HGA引起的半胱天冬酶-9和半胱天冬酶-3非依赖性形式的细胞死亡具有获得性抗性。
Background. Hereditary tyrosinemia type 1 (HT1), which is associated with severe liver and kidney damage, is caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of the tyrosine breakdown cascade. HT1-associated liver and kidney failure can be prevented by blocking an enzyme upstream of FAH in the tyrosine breakdown pathway with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). FAH knockout mice develop the HT1 phenotype when NTBC treatment is discontinued.Methods. The occurrence of cell death was investigated in kidneys of Fah(-/-) mice on and off NTBC either unchallenged or injected with 800 mg/kg of homogentisic acid (HGA), an intermediate of tyrosine breakdown.Results. No cell death could be detected in kidneys of Fah(-/-) mice on NTBC. A slight increase of cleaved caspase-3 was the only apoptosis-related feature that could be detected in kidneys of Fah(-/-) mice off NTBC. Challenge of Fah(-/-) mice on NTBC with HGA led to massive death of renal proximal tubular cells, with positive terminal deoxynucleotidyl transferase-mediated deoxyuridine diphosphate (dUDP) nick-end labeling (TUNEL) and DNA fragmentation assays, but hardly any cleavage of caspase-9 and caspase-3. Fah(-/-) mice off NTBC acquired resistance to HGA-induced renal cell death and the kidneys exhibited relatively few features of apoptosis upon challenge with HGA, with a small increase in expression of cleaved caspase-9 and caspase-3.Conclusion. Kidneys of adult Fah(-/-) mice, withdrawn from NTBC for 15 days, reveal limited characteristics of apoptosis, and have acquired resistance to a caspase-9- and caspase-3-independent form of cell death provoked by HGA.