Division of Nephrology & Hypertension, Department of Medicine, University of California San Diego & VA San Diego Healthcare System, San Diego, California, USA.
Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California, USA.
Nephron. 2020;144(8):400-412. doi: 10.1159/000508636. Epub 2020 Jul 6.
Alström syndrome is a rare recessive genetic disease caused by mutations in ALMS1, which encodes a protein that is related to cilia function and intracellular endosome trafficking. The syndrome has been linked to impaired glucose metabolism and CKD. Polymorphisms in Alms1 have likewise been linked to CKD, but little is known about the modification of the phenotype by environmental factors.
To gain further insights, the fat aussie (foz) mouse strain, a genetic murine model of Alström syndrome, was exposed to a normal chow (NC) or to a Western diet (WD, 20% fat, 34% sucrose by weight, and 0.2% cholesterol) and renal outcomes were measured.
Body weight and albuminuria were higher in foz than in wild-type (WT) mice on both diets but WD significantly increased the difference. Measurement of plasma creatinine and cystatin C indicated that glomerular filtration rate was preserved in foz versus WT independent of diet. Renal markers of injury, inflammation, and fibrosis were similar in both genotypes on NC but significantly greater in foz than in WT mice on WD. A glucose tolerance test performed in foz and WT mice on WD revealed similar basal blood glucose levels and subsequent blood glucose profiles.
WD sensitizes a murine model of Alström syndrome to kidney injury, inflammation, and fibrosis, an effect that may not be solely due to effects on glucose metabolism. Polymorphisms in Alms1 may induce CKD in part by modulating the deleterious effects of high dietary fat and sucrose on kidney outcome.
Alström 综合征是一种罕见的常染色体隐性遗传疾病，由 ALMS1 基因突变引起，该基因编码一种与纤毛功能和细胞内内体运输有关的蛋白质。该综合征与葡萄糖代谢受损和 CKD 有关。Alms1 的多态性同样与 CKD 有关，但环境因素对表型的修饰知之甚少。
为了进一步深入了解，脂肪澳斯（foz）小鼠品系，一种 Alström 综合征的遗传小鼠模型，暴露于正常饲料（NC）或西方饮食（WD，20%脂肪，34%蔗糖重量比和 0.2%胆固醇），并测量肾脏结果。
在两种饮食中，foz 的体重和白蛋白尿均高于野生型（WT）小鼠，但 WD 显著增加了差异。血浆肌酐和胱抑素 C 的测量表明，肾小球滤过率在 foz 与 WT 之间独立于饮食而得以维持。在 NC 中，两种基因型的肾损伤、炎症和纤维化标志物相似，但在 WD 中，foz 比 WT 小鼠的标志物显著更大。在 WD 中进行的 foz 和 WT 小鼠的葡萄糖耐量试验显示，基础血糖水平相似，随后的血糖曲线也相似。
WD 使 Alström 综合征的小鼠模型易发生肾损伤、炎症和纤维化，其作用可能不仅仅是由于对葡萄糖代谢的影响。Alms1 的多态性可能通过调节高膳食脂肪和蔗糖对肾脏结果的有害影响，在一定程度上导致 CKD。
