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.

中文翻译：

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羟脯氨酸脱氢酶失活对原发性高草酸尿小鼠模型尿草酸盐和乙醇酸盐排泄的影响。

原发性高草酸尿症 (PH) 的主要临床表现是草酸盐的产生增加，这是导致乙醛酸盐和羟脯氨酸代谢异常的基因突变的结果。高草酸尿可导致草酸钙肾结石、肾钙质沉着症和肾衰竭的形成。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，反式 4-羟基-L-脯氨酸 (Hyp) 的代谢是一种主要来自胶原代谢的氨基酸，是 PH2 和 PH3 患者产生草酸盐的重要来源。因此，Hyp 降解途径中的第一种酶，羟脯氨酸脱氢酶 (HYPDH)，代表了减少这些个体内源性草酸盐产生的有希望的治疗靶点。HYPDH（PRODH2 基因）具有遗传性突变的个体没有病理后果，这一观察结果支持了这一点。创建不表达 HYPDH 的小鼠模型将有助于将 HYPDH 作为目标进行评估的研究。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 导致尿液草酸盐排泄水平较低，这与我们之前的代谢示踪剂和基于 siRNA 的敲低研究一致。双基因敲除小鼠 Grhpr KO（PH2 模型）和 Prodh2 KO 在给予 1% Hyp 饮食时可防止肾脏草酸钙晶体沉积。这些观察结果支持使用 Grhpr KO 小鼠在体内筛选 HYPDH 抑制剂。