de a partial therapeutic alternative in countries where cysteamine therapy is too expensive. Background Nephropathic cystinosis is a rare inherited lysosomal storage disorder caused by mutations in the CTNS gene that encodes for cystinosin, a lysosomal cystine/H+ symporter. From the standpoint of the kidneys, patients develop early-onset renal Fanconi syndrome and progressive CKD. Current therapy with cysteamine delays but does not prevent kidney failure and has significant side effects that limit adherence and reduce the quality of life of patients. Methods We have tested biochemically and histologically the effects of ketogenic diet on kidney disease of two animal models of nephropathic cystinosis. Results When Ctns−/− mice were fed with ketogenic diet from 3 to 12 months of age, we observed significant nearly complete prevention of Fanconi syndrome, including low molecular weight proteinuria, glycosuria, and polyuria. Compared with wild-type animals, BUN at 12 months was higher in cystinotic mice fed with standard diet (P < 0.001), but not with ketogenic diet. At sacrifice, kidneys of knockout mice fed with ketogenic diet appeared macroscopically similar to those of wild-type animals, which was reflected microscopically by a significant reduction of interstitial cell infiltration (CD3 and CD68 positive cells, P < 0.01), of interstitial fibrosis (Masson and α-smooth muscle actin staining, P < 0.001), and of apoptosis (cleaved caspase-3 levels; P < 0.001), and by indirect evidence of restoration of a normal autophagic flux (SQSTM1/p62 and LC3-II expression, P < 0.05). Beneficial effects of ketogenic diet on tubular function were also observed after mice were fed with this ketogenic diet from the age of 6 months to the age of 15 months, after they had developed proximal tubular dysfunction. Although slightly less pronounced, these results were replicated in Ctns−/− rats fed with ketogenic diet from 2 to 8 months of life. Conclusions These results indicate significant mitigation of the kidney phenotype in cystinotic animals fed with ketogenic diet....

中文翻译：

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肾病性胱氨酸病动物模型中的生酮饮食和肾脏疾病进展


DE 半胱胺治疗过于昂贵的国家的部分治疗选择。背景 肾病性胱氨酸病是一种罕见的遗传性溶酶体贮积症，由编码胱氨酸/H+ 同向转运蛋白的 CTNS 基因突变引起。从肾脏的角度来看，患者会出现早发性肾 Fanconi 综合征和进行性 CKD。目前的半胱胺疗法可延迟但不能预防肾功能衰竭，并且具有显着的副作用，会限制依从性并降低患者的生活质量。方法 我们从生化和组织学上测试了生酮饮食对两种肾病性胱氨酸病动物模型肾脏疾病的影响。结果 当 Ctns-/-小鼠在 3 至 12 月龄时用生酮饮食喂养时，我们观察到 Fanconi 综合征的显着预防几乎完全，包括低分子量蛋白尿、糖尿和多尿。与野生型动物相比，饲喂标准饮食的胱氨酸小鼠在 12 个月时的 BUN 较高 （P < 0.001），但生酮饮食则不然。在处死时，用生酮饮食喂养的基因敲除小鼠的肾脏在宏观上与野生型动物的肾脏相似，这在微观上反映为间质细胞浸润 （CD3 和 CD68 阳性细胞，P < 0.01），间质纤维化 （Masson 和 α - 平滑肌肌动蛋白染色，P < 0.001） 和细胞凋亡 （裂解的 caspase-3 水平;P < 0.001），以及恢复正常自噬通量的间接证据 （SQSTM1/p62 和 LC3-II 表达，P < 0.05）。 在 6 个月至 15 月龄期间用这种生酮饮食喂养小鼠后，在它们出现近端肾小管功能障碍后，也观察到生酮饮食对肾小管功能的有益影响。虽然略显不明显，但这些结果在出生后 2 至 8 个月用生酮饮食喂养的 Ctns - / - 大鼠中得到了复制。结论 这些结果表明，用生酮饮食喂养胱氨酸动物的肾脏表型显着减轻。