The Calcineurin Inhibitor Tacrolimus Reduces Proteinuria in Membranous Nephropathy Accompanied by a Decrease in Angiopoietin-Like-4

Abstract

Tacrolimus is an anticalcineurinic agent with potent immunosuppressive activity that has recently been shown to have the added benefit of reducing proteinuria in membranous nephropathy (MN) patients. However, its potential mechanisms remain unknown. To reveal the mechanism, rat cohorts were administered tacrolimus or vehicle from days 7 to 28 after the induction of passive Heymann nephritis (PHN). PHN induction resulted in heavy proteinuria and increased expression of desmin, a marker of injured podocytes. We also showed that the glomerular expression of angiopoietin-like-4 (Angptl4) was markedly upregulated in PHN rats and human MN followed by an increase in urine Angptl4 excretion. In addition, increased Angptl4 expression may be related to podocyte injury and proteinuria. Furthermore, upregulated Angptl4 expression primarily colocalized with podocytes rather than endothelial or mesangial cells, indicating that podocytes may be the source of Angptl4, which then gradually migrated to the glomerular basement membrane over time. However, tacrolimus treatment markedly reduced glomerular and urinary Angptl4, accompanied by a reduction in the established proteinuria and the promotion of podocyte repair. Additionally, glomerular immune deposits and circulating IgG levels induced by PHN clearly decreased following tacrolimus treatment. In conclusion, this is the first demonstration that the calcineurin inhibitor tacrolimus can reduce Angptl4 in podocytes accompanied by a decrease in established proteinuria and promotion of podocyte repair in MN.

Calcineurin inhibitors cyclosporin A and tacrolimus protect against podocyte injury induced by puromycin aminonucleoside in rodent models

“…Moreover, podocyte functional assay also showed increased cell viability and decreased cell motility in CsA and FK506 preincubated podocytes. The protective effects of CaN inhibitors (CsA and FK506) were also observed in other podocyte injury models such as adriamycin induced MCD29, membranous nephropathy4, Lupus Nephritis27 and IgA nephropathy6.…”

Upregulation of podocyte-secreted angiopoietin-like-4 in diabetic nephropathy

“…Simultaneously, PHN rats were chosen as positive control as shown in Supplemental Fig. S1, since significant enhanced Angptl4 expression was observed in PHN rats according to our very recent study [22].…”

“…Rat and human kidney tissues were fixed in PLP solution for 2 h, followed by an overnight incubation in 18 % sucrose as our previously described [21,22]. The tissues were then embedded in a Tissue-Tek OCT compound, flash-frozen, and stored at -80°C.…”

“…To exclude the non-specificity of this Angptl4 antibody for immunofluorescence, we did negative controls using normal rats and secondary antibody only. Simultaneously, passive Heymann nephritis (PHN) rats were chosen as positive control, since significant enhanced Angptl4 expression was observed in PHN rats according to our very recent study [22].…”

Epigallocatechin-3-Gallate Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis via Suppression of Oxidant Stress and Apoptosis by Targeting Hypoxia-Inducible Factor-1α/ Angiopoietin-Like 4 Pathway

“…Most importantly, according to a study conducted by Pengcheng Zhu et al [21] ANGPTL4 could elevate O 2 -production and O 2 -:H 2 O 2 ratio through stimulating NADPH oxidase 1 (Nox1), which indicates the possible relationship between ANGPTL4 and ROS production. Also, reducing the expression of ANGPTL4 in podocytes could decrease the podocyte apoptosis and promote podocyte repair [22]. These studies indicated that the up-regulated ANGPTL4 was highly related with the ROS production and podocyte apoptosis.…”