BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is characterized by mutations in either the Pkd1 or Pkd2 genes leading to progressive cyst growth and often kidney failure. We have previously demonstrated that tubules can enlarge following loss of Pkd1 without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. RNA sequencing of Pkd1 null kidneys revealed increased expression of 17 metalloproteinases, of which A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1) is the most highly expressed and upregulated. METHODS Mice were generated with inducible tubule-specific knockout of Adamts1 alone (AtsTKO), Pkd1 alone (PkdTKO), or both (P/ATKO) following doxycycline induction from 4-6 weeks age. Uninduced mice were used as controls. AtsTKO mice had no detectable phenotype through 12 weeks age. RESULTS Upregulation of Adamts1 in PkdTKO kidneys correlated with a significant increase in the 70 kDa cleavage product of the V1 isoform of versican, which localized to the tubular basement membrane and adjacent interstitial mononuclear cells. Simultaneous deletion of both Adamts1 and Pkd1 (P/ATKO) reduced Adamts1 expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/ATKO mice demonstrated reduced cystic enlargement, improved BUN and creatinine and better survival than did PkdTKO mice. CONCLUSIONS Preventing Adamts1 upregulation following loss of tubular Pkd1 effectively reduced cyst growth and preserved kidney function.

中文翻译：

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Adamts1 和多囊肾病中的囊肿扩大。


背景常染色体显性遗传性多囊肾病 （ADPKD） 的特征是 Pkd1 或 Pkd2 基因突变，导致进行性囊肿生长，经常导致肾功能衰竭。我们之前已经证明，Pkd1 丢失后小管可以扩大，而肾小管细胞数量没有增加，这表明小管基底膜重塑对于囊性扩张很重要。Pkd1 缺失肾脏的 RNA 测序显示 17 种金属蛋白酶的表达增加，其中 A 解整合素和具有血小板反应蛋白基序 1 的金属蛋白酶 （Adamts1） 表达最高，上调最高。方法 小鼠在 4-6 周龄多西环素诱导后，单独使用 Adamts1 （AtsTKO） 、单独 Pkd1 （PkdTKO） 或两者 （P/ATKO） 诱导肾小管特异性敲除。未诱导的小鼠用作对照。AtsTKO 小鼠在 12 周龄内没有可检测到的表型。结果 PkdTKO 肾脏中 Adamts1 的上调与 versican 的 V1 亚型的 70 kDa 切割产物的显着增加相关，该亚型定位于肾小管基底膜和相邻的间质单核细胞。Adamts1 和 Pkd1 （P/ATKO） 同时缺失使 Adamts1 表达水平降低了 >90%，阻止了 V1 杂细胞裂解，并减少了间质巨噬细胞的积累和活化。P/ATKO 小鼠表现出比 PkdTKO 小鼠减少的囊肿大，改善 BUN 和肌酐，并且存活率更高。结论 防止肾小管 Pkd1 丢失后 Adamts1 上调可有效减少囊肿生长并保留肾功能。