Hydroxypropyl-β-cyclodextrin protects from kidney disease in experimental Alport syndrome and focal segmental glomerulosclerosis.
Hydroxypropyl-β-cyclodextrin protects from kidney disease in experimental Alport syndrome and focal segmental glomerulosclerosis.
复制标题
DOI：
10.1016/j.kint.2018.06.031
复制
发表时间：
2018-12
影响因子：
19.6
通讯作者：
Fornoni A
中科院分区：
文献类型：
--
作者：
Mitrofanova A;Molina J;Varona Santos J;Guzman J;Morales XA;Ducasa GM;Bryn J;Sloan A;Volosenco I;Kim JJ;Ge M;Mallela SK;Kretzler M;Eddy S;Martini S;Wahl P;Pastori S;Mendez AJ;Burke GW;Merscher S;Fornoni A
研究表明，肾脏脂质代谢改变在糖尿病肾病的发病机制中起作用，胆固醇流出的遗传或药理学诱导可防止糖尿病肾病和局灶节段性肾小球硬化症（FSGS）的发展。在这里，我们测试了改变的脂质代谢是否会导致Alport综合征的Col 4a 3基因敲除小鼠模型中的肾衰竭。患有奥尔波特综合症的小鼠肾皮质中的胆固醇含量增加了八倍。这与肾小球脂滴和胆固醇结晶增加有关。用羟丙基-β-环糊精（HPβCD）治疗Alport综合征小鼠可降低Alport综合征小鼠肾脏中的胆固醇含量，并防止蛋白尿、肾衰竭、炎症和肾小管间质纤维化的发生。胆固醇流出和运输相关基因主要在Alport综合征小鼠中受到影响，并在肾皮质和分离的肾小球中受到差异调节。HPβCD还在第二种非代谢性肾病模型（阿霉素诱导的肾病）中保护蛋白尿和系膜扩张。与我们的实验结果一致，微阵列分析证实了从参与NEPTUNE研究的原发性FSGS患者的肾活检中分离的肾小球中几种脂质相关基因的失调。因此，脂质代谢异常发生在非代谢性肾小球疾病如Alport综合征和FSGS中，HPβCD改善实验性Alport综合征和FSGS中的肾功能。
Studies suggest that altered renal lipid metabolism plays a role in the pathogenesis of diabetic kidney disease and that genetic or pharmacological induction of cholesterol efflux protects from the development of diabetic kidney disease and focal segmental glomerulosclerosis (FSGS). Here we tested whether altered lipid metabolism contributes to renal failure in the Col4a3 knockout mouse model for Alport Syndrome. There was an eight fold increase in the cholesterol content in renal cortexes of mice with Alport Syndrome. This was associated with increased glomerular lipid droplets and cholesterol crystals. Treatment of mice with Alport Syndrome with hydroxypropyl-β-cyclodextrin (HPβCD) reduced cholesterol content in the kidneys of mice with Alport Syndrome and protected from the development of albuminuria, renal failure, inflammation and tubulointerstitial fibrosis. Cholesterol efflux and trafficking related genes were primarily affected in mice with Alport Syndrome and were differentially regulated in the kidney cortex and isolated glomeruli. HPβCD also protected from proteinuria and mesangial expansion in a second model of non-metabolic kidney disease; adriamycin-induced nephropathy. Consistent with our experimental findings, microarray analysis confirmed dysregulation of several lipid related genes in glomeruli isolated from kidney biopsies of patients with primary FSGS enrolled in the NEPTUNE study. Thus, lipid dysmetabolism occurs in non-metabolic glomerular disorders such as Alport Syndrome and FSGS, and HPβCD improves renal function in experimental Alport Syndrome and FSGS.
登录
查看更多内容
影响因子：
7.7
作者：
Merscher-Gomez S;Guzman J;Pedigo CE;Lehto M;Aguillon-Prada R;Mendez A;Lassenius MI;Forsblom C;Yoo T;Villarreal R;Maiguel D;Johnson K;Goldberg R;Nair V;Randolph A;Kretzler M;Nelson RG;Burke GW 3rd;Groop PH;Fornoni A;FinnDiane Study Group
通讯作者：
FinnDiane Study Group
影响因子：
15.9
作者：
Pedigo, Christopher E.;Ducasa, Gloria Michelle;Fornoni, Alessia
通讯作者：
Fornoni, Alessia
影响因子：
3.9
作者：
Montes, GS
通讯作者：
Montes, GS
影响因子：
10.5
作者：
Cosgrove, D;Meehan, DT;Samuelson, GC
通讯作者：
Samuelson, GC
影响因子：
6.5
作者：
Herman-Edelstein, Michal;Scherzer, Pnina;Gafter, Uzi
通讯作者：
Gafter, Uzi