Tacrolimus restores podocyte injury and stabilizes the expression of Cabin1 in 5/6 nephrectomized rats

Abstract

Podocyte injury is a vital factor, which induces massive proteinuria. Studies have shown that tacrolimus (TAC) protected podocyte via stabilizing cytoskeleton. Our latest study indicates that calcineurin binding protein 1 (Cabin1) undergoes nuclear translocation during podocytes injury. Whether TAC targets on Cabin1 during podocyte injury is still not clear. This study establishes non-immunological proteinuric model. To observe the effect of the treatment of TAC on Cabin1 expression in 5/6 nephrectomized rats. Sprague-Dawley rats were injected with TAC (0.2 mg/kg/day) for 4-8 weeks after 5/6 nephrectomy. Then, rats were sacrificed in the eighth week after operation, renal tissues were processed for morphological studies under light and electrical microscope. Cabin1 expression and distribution were detected by western blot and indirect immunofluorescence staining. In 5/6 nephrectomized rats, urinary protein excretion reached 90.2 ± 30.1 mg/24 h, glomerular sclerosis index and tubulointerstitial fibrosis score were significantly increased, and widespread of podocyte foot processes fusion was found. Moreover, Cabin1 protein expression was markedly increased, and its distribution became much more obviously in podocytes nuclei. In TAC treated rats, urinary protein excretion significantly decreased (44.9 ± 22.5 mg/24 h), glomerular sclerosis and tubulointerstitial fibrosis were alleviated, and podocyte foot processes fusion was inhibited. Furthermore, TAC alleviated the increased protein expression and abnormal distribution of Cabin1. In conclusion, TAC restores podocyte injury and stabilizes the expression of Cabin1. Cabin1 may become a new target to demonstrate the mechanism of TAC in podocyte injury.

Effect of Vitamin D and Tacrolimus Combination Therapy on IgA Nephropathy

“…As IgAN is an immune-complex-mediated glomerulonephritis, immunosuppressants are commonly used for the treatment of the disease. TAC treatment can significantly reduce the dysregulation of Scr, BUN, ALB, and UAE levels [13,14]; studies also found that both TAC and vitamin D have good effect with regards to kidney injury recovery [15,16]. In our study, TAC+VD therapy demonstrated higher potency in normalizing these levels.…”

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 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.…”

“…Two reports from a study carried out in China stated that up-regulation of the core I B3-Gal-T-specific molecular chaperone gene expression can treat IgAN [ 6 , 7 ]. Wen et al demonstrated that tacrolimus restored podocyte damage by stabilizing the expression of the Cabin 1 gene, which is a selective inhibitor of calcineurin [ 8 ]. In other studies, tacrolimus has been shown to reduce angiopoietin-like-4 in podocytes, and thereby reduce proteinuria [ 9 , 10 ].…”

Chlormethine Hydrochloride is Not Inferior to Tacrolimus in Treating Steroid-Resistant Nephrotic Syndrome

“…Mechanically, one possible reason is the depletion of B-and T-lymphocytes or the inhibition of podocyte injury induced by macrolide immunosuppressants or alkylating agents. This was demonstrated in a previous study [1,27,28]. The activation of B-or T-lymphocytes triggers antibody-independent autoimmune damage, which is considered to be the most common cause of nephrotic syndrome [29].…”