Genetic deficiency of aldose reductase counteracts the development of diabetic nephropathy in C57BL/6 mice
Genetic deficiency of aldose reductase counteracts the development of diabetic nephropathy in C57BL/6 mice
复制标题
醛糖还原酶的遗传缺陷阻碍了 C57BL/6 小鼠糖尿病肾病的发展
DOI：
10.1007/s00125-011-2045-4
复制
发表时间：
2011-05-01
期刊：
影响因子：
8.2
通讯作者：
Yang, J. Y.
中科院分区：
文献类型：
--
作者：
Liu, H.;Luo, Y.;Yang, J. Y.
目的/假说本研究的目的是探讨醛糖还原酶基因缺陷在糖尿病肾病关键终点发生中的作用。方法选用AFAR(又称Akr1b3)基因敲除(KO)小鼠、双转基因小鼠和对照C57BL/6小鼠。KO和双转基因小鼠在肾小球和所有其他组织中缺乏ArC，但在双转基因小鼠中，除了引导集合管上皮细胞特异性表达的人ARcDNA敲击转基因外，其他组织中都缺乏ArC。用链脲佐菌素诱导8周龄雄性小鼠糖尿病。小鼠被进一步维持17周，然后被处死。对这些25周龄的小鼠进行了一些血清和尿液变量的测定。结果糖尿病Ar-KO组和双转基因小鼠肾组织细胞外基质堆积和IV型胶原过度生成均被完全阻止。缺铁性缺铁还可完全或部分阻止糖尿病引起的肾皮质β、转化生长因子-β1和肾小球肥大的激活。Ar-KO糖尿病小鼠的尿白蛋白排泄减少了43%，双转基因糖尿病小鼠的(p<； 0.01).Conclusions/interpretationGenetic缺失减少了48%，ARA的缺失显著改善了体内与早期糖尿病肾病有关的关键终点的发育。强效、特异地抑制醛糖还原酶可能是防治糖尿病肾病的有效策略。
Aims/hypothesisThe aim of the study was to investigate the effects of genetic deficiency of aldose reductase in mice on the development of key endpoints of diabetic nephropathy.MethodsA line ofAr(also known asAkr1b3)-knockout (KO) mice, a line ofAr-bitransgenic mice and control C57BL/6 mice were used in the study. The KO and bitransgenic mice were deficient forArin the renal glomeruli and all other tissues, with the exception of, in the bitransgenic mice, a humanARcDNA knockin-transgene that directed collecting-tubule epithelial-cell-specificARexpression. Diabetes was induced in 8-week-old male mice with streptozotocin. Mice were further maintained for 17 weeks then killed. A number of serum and urinary variables were determined for these 25-week-old mice. Periodic acid–Schiff staining, western blots, immunohistochemistry and protein kinase C (PKC) activity assays were performed for histological analyses, and to determine the levels of collagen IV and TGF-β1 and PKC activities in renal cortical tissues.ResultsDiabetes-induced extracellular matrix accumulation and collagen IV overproduction were completely prevented in diabeticAr-KO and bitransgenic mice.Ardeficiency also completely or partially prevented diabetes-induced activation of renal cortical PKC, TGF-β1 and glomerular hypertrophy. Loss ofArresults in a 43% reduction in urine albumin excretion in the diabeticAr-KO mice and a 48% reduction in the diabetic bitransgenic mice (p< 0.01).Conclusions/interpretationGenetic deficiency ofArsignificantly ameliorated development of key endpoints linked with early diabetic nephropathy in vivo. Robust and specific inhibition of aldose reductase might be an effective strategy for the prevention and treatment of diabetic nephropathy.