Role of calcineurin (CN) in kidney glomerular podocyte: CN inhibitor ameliorated proteinuria by inhibiting the redistribution of CN at the slit diaphragm

Abstract

Although calcineurin (CN) is distributed in many cell types and functions in regulating cell functions, the precise roles of CN remained in each type of the cells are not well understood yet. A CN inhibitor (CNI) has been used for steroid‐resistant nephrotic syndrome. A CNI is assumed to ameliorate proteinuria by preventing the overproduction of T‐cell cytokines. However, recent reports suggest that CNI has a direct effect on podocyte. It is accepted that a slit diaphragm (SD), a unique cell–cell junction of podocytes, is a critical barrier preventing a leak of plasma protein into urine. Therefore, we hypothesized that CNI has an effect on the SD. In this study, we analyzed the expression of CN in physiological and in the nephrotic model caused by the antibody against nephrin, a critical component of the SD. We observed that CN is expressed at the SD in normal rat and human kidney sections and has an interaction with nephrin. The staining of CN at the SD was reduced in the nephrotic model, while CN activity in glomeruli was increased. We also observed that the treatment with tacrolimus, a CNI, in this nephrotic model suppressed the redistribution of CN, nephrin, and other SD components and ameliorated proteinuria. These observations suggested that the redistribution and the activation of CN may participate in the development of the SD injury.

Membranous Nephropathy: Approaches to Treatment

“…Preclinical studies have shown that under conditions of increased intracellular calcium, calcineurin stimulates the degradation of synaptopodin, a cell cytoskeletal protein that is central to footplate formation [36]. Moreover, recent studies have indicated that calcineurin regulates expression and function of the slit pore, including nephrin and ZO-1, a slit-diaphragm marker [37]. This effect, however, appears to be of little clinical significance, otherwise clinical recurrence of MN post-transplant with massive proteinuria would not occur in patients on calcineurin inhibitors as maintenance therapy post kidney transplantation [38].…”

Endoplasmic Reticulum Stress Predicts Clinical Response to Cyclosporine Treatment in Primary Membranous Nephropathy

“…Calcineurin is a Ca 2+ -/calmodulin-dependent serine/threonine protein phosphatase and serves as a target of calcineurin inhibitors (CNIs), cyclosporine and tacrolimus [5]. CNIs induce complete or PR through immunologic and non-immunologic ways.…”

Off‐label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics

“…Tacrolimus' pivotal mechanism of action involves inhibition of the redistribution of calcineurin at the slit diaphragm. 18 In recent years, podocyte injury has been recognized as a central event in the occurrence and progression of glomerular diseases. 19 Podocytes are highly differentiated cells with limited proliferative and divisive abilities, which are difficult to regenerate and repair after injury.…”

“…Both cellular and humoral immunities are inhibited to reduce the damage to the kidney caused by the inflammatory response. Tacrolimus' pivotal mechanism of action involves inhibition of the redistribution of calcineurin at the slit diaphragm …”