Abstract
ObjectiveSeveral studies have reported that tacrolimus (TAC) significantly reduced proteinuria in lupus nephritis (LN) patients and mouse models. However, the mechanism for this effect remains undetermined. This study explored the mechanism of how TAC protects podocytes from injury to identify new targets for protecting renal function.MethodsMRL/lpr mice were given TAC at a dosage of 0.1 mg/kg per day by intragastric administration for 8 weeks. Urine and blood samples were collected. Kidney sections (2μm) were stained with hematoxylin-eosin (HE), periodic acid-Schiff base (PAS) and Masson's trichrome stain. Mouse podocyte cells (MPC5) were treated with TAC and/or TGF-β1 for 48h. The mRNA levels and protein expression of synaptopodin and Wilms’ tumor 1 (WT1) were determined by real-time PCR, Western blotting and/or immunofluorescence, respectively. Flow cytometry was used to detect cell apoptosis with annexin V. Podocyte foot processes were observed under transmission electron microscopy. IgG and C3 deposition were assessed with immunofluorescence assays and confocal microscopy.ResultsSynaptopodin expression significantly decreased in MRL/lpr disease control mice, accompanied by increases in 24-h proteinuria, blood urea nitrogen, and serum creatinine. TAC, however, reduced proteinuria, improved renal function, attenuated renal pathology, restored synaptopodin expression and preserved podocyte numbers. In MPC5 cells, TGF-β1 enhanced F-actin damage in podocytes and TAC stabilized it. TAC also decreased TGF-β1-induced podocyte apoptosis in vitro and inhibited foot process fusion in MRL/lpr mice. In addition, our results also showed TAC inhibited glomerular deposition of IgG and C3.ConclusionThis study demonstrated that TAC reduced proteinuria and preserved renal function in LN through protecting podocytes from injury partly by stabilizing podocyte actin cytoskeleton and inhibiting podocyte apoptosis.
Highlights
Lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE)
Synaptopodin expression significantly decreased in MRL/lpr disease control mice, accompanied by increases in 24-h proteinuria, blood urea nitrogen, and serum creatinine
This study demonstrated that TAC reduced proteinuria and preserved renal function in LN through protecting podocytes from injury partly by stabilizing podocyte actin cytoskeleton and inhibiting podocyte apoptosis
Summary
Lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Proteinuria is an important risk factor for the progression of renal diseases in patients with LN [1]. A recent review reported that tacrolimus (TAC), a calcineurin inhibitor (CNI), was able to reduce proteinuria and prevent the progression of the nephropathy in lupus mice or LN patients [2]. A previous study showed that cyclosporin A (CsA), another CNI, blocks the calcineurin-mediated dephosphorylation of synaptopodin, which in turn, protects synaptopodin from cathepsin L-mediated degradation, thereby maintaining the integrity of the glomerular filtration barrier and safeguarding against proteinuria [4]. The aim of this study was to investigate the mechanisms of TAC effects on anti-albuminuria and protection of renal function, which may provide a potential new way to treat LN
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