Lawlor Allison, Cunanan Kristina, Cunanan Joanna, Paul Amy, Khalili Hadiseh, Ko Doyun, Khan Ahsan, Gros Robert, Drysdale Thomas, Bridgewater Darren
Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
Toronto General Hospital Research Institute, University Health Network, Ontario, Canada.
Can J Kidney Health Dis. 2023 Jun 7;10:20543581231165716. doi: 10.1177/20543581231165716. eCollection 2023.
Shroom family member 3 (SHROOM3) encodes an actin-associated protein that regulates epithelial morphology during development. Several genome-wide association studies (GWAS) have identified genetic variances primarily in the 5' region of SHROOM3, associated with chronic kidney disease (CKD) and poor transplant outcomes. These genetic variants are associated with alterations in Shroom3 expression.
Characterize the phenotypic abnormalities associated with reduced expression in postnatal day 3-, 1-month and 3-month-old mice.
The Shroom3 protein expression pattern was determined by immunofluorescence. We generated heterozygous null mice () and performed comparative analyses with littermates based on somatic and kidney growth, gross renal anatomy, renal histology, renal function at postnatal day 3, 1 month, and 3 months.
The Shroom3 protein expression localized to the apical regions of medullary and cortical tubular epithelium in postnatal kidneys. Co-immunofluorescence studies confirmed protein expression localized to the apical side of the tubular epithelium in proximal convoluted tubules, distal convoluted tubules, and collecting ducts. While heterozygous null mice exhibited reduced Shroom3 protein expression, no differences in somatic and kidney growth were observed when compared to mice. Although, rare cases of unilateral hypoplasia of the right kidney were observed at postnatal 1 month in heterozygotes. Yet renal histological analysis did not reveal any overt abnormalities in overall kidney structure or in glomerular and tubular organization in heterozygous null mice when compared to mice. Analysis of the apical-basolateral orientation of the tubule epithelium demonstrated alterations in the proximal convoluted tubules and modest disorganization in the distal convoluted tubules at 3 months in heterozygotes. Additionally, these modest abnormalities were not accompanied by tubular injury or physiological defects in renal and cardiovascular function.
Taken together, our results describe a mild kidney disease phenotype in adult heterozygous null mice, suggesting that Shroom3 expression and function may be required for proper structure and maintenance of the various tubular epithelial parenchyma of the kidney.
Shroom家族成员3（SHROOM3）编码一种与肌动蛋白相关的蛋白质，该蛋白质在发育过程中调节上皮形态。多项全基因组关联研究（GWAS）已确定主要在SHROOM3的5'区域存在与慢性肾病（CKD）和不良移植结果相关的遗传变异。这些遗传变异与Shroom3表达的改变有关。
描述出生后3天、1个月和3个月大的小鼠中Shroom3表达降低所相关的表型异常。
通过免疫荧光确定Shroom3蛋白表达模式。我们构建了杂合缺失小鼠（），并基于出生后3天、1个月和3个月时的体细胞和肾脏生长、肾脏大体解剖结构、肾脏组织学、肾功能，与同窝小鼠进行比较分析。
Shroom3蛋白表达定位于出生后肾脏髓质和皮质肾小管上皮的顶端区域。共免疫荧光研究证实该蛋白表达定位于近端曲管、远端曲管和集合管中肾小管上皮的顶端侧。虽然杂合缺失小鼠表现出Shroom3蛋白表达降低，但与小鼠相比，未观察到体细胞和肾脏生长的差异。不过，在出生后1个月时，杂合子中罕见右肾单侧发育不全的情况。然而，与小鼠相比，肾脏组织学分析未发现杂合缺失小鼠的整体肾脏结构或肾小球和肾小管组织有任何明显异常。对肾小管上皮顶端 - 基底侧方向的分析表明，杂合子在3个月时近端曲管出现改变，远端曲管有适度的结构紊乱。此外，这些轻微异常并未伴有肾小管损伤或肾脏和心血管功能的生理缺陷。
综上所述，我们的结果描述了成年杂合缺失小鼠中的一种轻度肾病表型，表明Shroom3的表达和功能可能是肾脏各种肾小管上皮实质正常结构和维持所必需的。
