FK506 reduces albuminuria through improving podocyte nephrin and podocin expression in diabetic rats

Abstract

Objective and designSeveral works in the setting of early experimental diabetic nephropathy using anti-inflammatory drugs, such as the calcineurin inhibitor FK506, have shown prevention of the development or amelioration of renal injury including proteinuria. The exact mechanisms by which anti-inflammatory drugs lower the albuminuria have not been still clarified well.MaterialsThe diabetic rats were induced by using streptozotocin.TreatmentThe diabetic rats were subjected to oral FK506 treatment at a dose of 0.5 or 1.0 mg/kg daily for 4 weeks.MethodsRenal histology for the ultrastructural evaluation was determined by electron microscope, followed by analyses of renal nephrin and podocin and detection of renal iNOS+ macrophages and NF-κB-p-p65+.ResultsElevated 24-h urinary albumin excretion rate was markedly attenuated by FK506 treatment. In diabetic model rats, FK506 treatment at a dose of 0.5 or 1.0 mg/kg significantly increased the expression of nephrin and podocin when compared to control. As expected, rats in control diabetic group had an increase in GBM thickening and foot process effacement when compared to normal rats; increased GBM thickening and foot process effacement were ameliorated by FK506 treatment with 0.5 and 1.0 mg/kg. Histologically, there was marked accumulation of ED-1+cells (macrophages) in diabetic kidneys, and FK506 treatment failed to inhibit it. In contrast, FK506 treatment at 0.5 and 1.0 mg/kg doses significantly inhibited the elevated ED-1+/iNOS+ cells in the kidneys of diabetic rats. ED-1+/NF-κB-p-p65+ cells were significantly increased in positive diabetic kidneys compared to those of normal rats. FK506 treatment at 0.5 and 1.0 mg/kg significantly attenuated the elevated ED-1+/NF-κB-p-p65+ cells in diabetic kidneys. Additionally, a positive correlation was observed between ED-1+/iNOS+ cells and albuminuria (r = 0.87, p < 0.05). Likewise, ED-1+/iNOS+ cells were correlated negatively with both nephrin and podocin protein (r = −0.70, p < 0.05; r = −0.68, p < 0.05, respectively).ConclusionOur results show that FK506 not only upregulates expression of nephrin and podocin but also inhibits macrophage activation to protect against podocyte injury.

Short-term anti-proteinuric effect of tacrolimus is not related to preservation of the glomerular filtration rate in IgA nephropathy: A 5-year follow-up study

“…Along with the results of these studies, several studies have investigated the mechanisms of tacrolimus in reducing proteinuria. Tacrolimus was considered to have multifocal mechanisms for reducing proteinuria, such as immunosuppressive mechanisms by suppression of the nuclear factor of activated T cell activity in podocytes [ 17 , 18 ], intraglomerular hemodynamic changes [ 19 – 21 ], inhibition of the vascular permeability factor [ 22 ], and a direct effect on podocytes [ 8 – 10 , 23 , 24 ]. Among these mechanisms, we suggested that the early anti-proteinuria effect of tacrolimus was due to reversible hemodynamic changes rather than to other structural changes.…”

“…The lower UPCR in the Tac group compared to the non-Tac group during the trial phase despite the later cr has recovery, is difficult to explain solely by hemodynamic changes. Therefore, the rapid decrease of proteinuria in the early stage may be due to hemodynamic changes, but the overall decrease may be the combination of the various mechanisms mentioned above [ 16 – 23 ]. Time-averaged proteinuria is the most reliable predictor of kidney survival [ 1 ].…”

“…The first aspect is tacrolimus dosage. Several studies evaluating the direct effects of tacrolimus on podocytes have shown that structural changes occur in podocytes when tacrolimus is administered, hence suggesting long duration effects of tacrolimus [ 8 , 23 , 24 ]. In these aforementioned studies, a tacrolimus dose of approximately 0.2–1 mg/kg/day was given; however, these particular studies were performed on animals.…”

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

“…In recent years, studies have found that the mutation, deletion and abnormal expression of podocyte proteins, especially nephrin and podocin, play an important role in glomerulopathy and proteinuria . Tacrolimus's mechanism that protects glomerular podocytes and reduces urinary protein may be associated with up‐regulation of nephrin and podocin expression . However, the expression changes of these podocyte proteins in different pathological types of glomerular diseases are inconsistent .…”

“…[102][103][104] Tacrolimus's mechanism that protects glomerular podocytes and reduces urinary protein may be associated with up-regulation of nephrin and podocin expression. 105,106 However, the expression changes of these podocyte proteins in different pathological types of glomerular diseases are inconsistent. 107,108 Another possible reason for different remission rates in different studies is whether the relapses of glomerular disease has been observed.…”