Minimal Kidney Disease Phenotype in Heterozygous Null Mice.

BACKGROUND

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.

OBJECTIVE

Characterize the phenotypic abnormalities associated with reduced expression in postnatal day 3-, 1-month and 3-month-old mice.

METHODS

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.

RESULTS

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.

CONCLUSION

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.