The effects of the inactivation of Hydroxyproline dehydrogenase on urinary oxalate and glycolate excretion in mouse models of primary hyperoxaluria
The effects of the inactivation of Hydroxyproline dehydrogenase on urinary oxalate and glycolate excretion in mouse models of primary hyperoxaluria
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DOI：
10.1016/j.bbadis.2019.165633
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发表时间：
2020-03-01
影响因子：
6.2
通讯作者：
Knight, John
中科院分区：
文献类型：
--
作者：
Buchalski, Brianna;Wood, Kyle D.;Knight, John
原发性高草酸血症（PH）的主要临床表现是草酸的产生增加，这是基因突变导致异常的乙醛酸和羟脯氨酸代谢的结果。高草酸尿可导致草酸钙肾结石、肾钙质沉着症和肾功能衰竭。目前的治疗方法依赖于器官移植和最近使用siRNA疗法修改草酸盐合成途径。我们最近报道了反式-4-羟基- l -脯氨酸（Hyp）的代谢，一种主要来源于胶原代谢的氨基酸，是PH2和PH3患者草酸盐产生的重要来源。因此，Hyp降解途径中的第一个酶羟脯氨酸脱氢酶（HYPDH）代表了减少这些个体内源性草酸生成的有希望的治疗靶点。这是由观察到的，在HYPDH （PRODH2基因）遗传突变的个体没有病理后果支持。建立不表达HYPDH的小鼠模型将有助于评估HYPDH作为靶点的研究。我们描述了Prodh2敲除小鼠模型的表型，并表明PH小鼠模型中缺乏HYPDH导致尿草酸排泄水平降低，这与我们之前的代谢示踪剂和基于sirna的敲除研究一致。双敲除小鼠Grhpr KO （PH2模型）和Prodh2 KO在给予1% Hyp饮食时，可阻止肾脏中草酸钙晶体沉积。这些观察结果支持使用Grhpr KO小鼠在体内筛选HYPDH抑制剂。总之，这些数据支持HYPDH作为PH2和PH3患者有吸引力的治疗靶点。
The major clinical manifestation of the Primary Hyperoxalurias (PH) is increased production of oxalate, as a consequence of genetic mutations that lead to aberrant glyoxylate and hydroxyproline metabolism. Hyperoxaluria can lead to the formation of calcium-oxalate kidney stones, nephrocalcinosis and renal failure. Current therapeutic approaches rely on organ transplants and more recently modifying the pathway of oxalate synthesis using siRNA therapy. We have recently reported that the metabolism of trans-4-hydroxy-L-proline (Hyp), an amino acid derived predominantly from collagen metabolism, is a significant source of oxalate production in individuals with PH2 and PH3. Thus, the first enzyme in the Hyp degradation pathway, hydroxyproline dehydrogenase (HYPDH), represents a promising therapeutic target for reducing endogenous oxalate production in these individuals. This is supported by the observation that individuals with inherited mutations in HYPDH (PRODH2 gene) have no pathological consequences. The creation of mouse models that do not express HYPDH will facilitate research evaluating HYPDH as a target. We describe the phenotype of the Prodh2 knock out mouse model and show that the lack of HYPDH in PH mouse models results in lower levels of urinary oxalate excretion, consistent with our previous metabolic tracer and siRNA-based knockdown studies. The double knockout mouse, Grhpr KO (PH2 model) and Prodh2 KO, prevented calcium-oxalate crystal deposition in the kidney, when placed on a 1% Hyp diet. These observations support the use of the Grhpr KO mice to screen HYPDH inhibitors in vivo. Altogether these data support HYPDH as an attractive therapeutic target for PH2 and PH3 patients.