Calcineurin A-α But Not A-β Is Required for Normal Kidney Development and Function

Abstract

Calcineurin is an important signaling molecule in the kidney and may be involved in a variety of processes. The phosphatase subunit of calcineurin (CnA) has three isoforms, alpha, beta, and gamma. In this study, we investigated the effect of loss of calcineurin A-alpha (CnA-alpha) or calcineurin A-beta (CnA-beta) on the development and function of the kidney. Total calcineurin expression and activity was significantly reduced in whole kidney homogenates from both CnA-alpha -/- and CnA-beta -/- mice. Kidneys of CnA-beta -/- mice appear normal and the mice develop with no phenotypic abnormalities. In contrast, kidneys of CnA-alpha -/- animals fail to fully develop. In particular, postnatal maturation of the nephrogenic zone (NZ) is defective. Within the NZ, glomeruli also fail to mature and lack mesangial cells. In addition to alterations in development, there is an absence of proliferation and an increase of cell death in the NZ with loss of CnA-alpha. Finally, increased collagen deposition is observed and serum creatinine levels are significantly increased in CnA-alpha -/- animals compared to wild-type littermates, indicating that kidney function is impaired. In summary, absence of CnA-alpha but not CnA-beta leads to a defect in normal maturation of the NZ and glomeruli, alterations in the cell cycle, and impaired kidney function.