Renoprotective Effects of Alpha-1 Antitrypsin against Tacrolimus-Induced Renal Injury

Abstract

The protective effects of alpha-1 antitrypsin (AAT) in tacrolimus (TAC)-induced renal injury was evaluated in a rat model. The TAC group rats were subcutaneously injected with 2 mg/kg TAC every day for four weeks. The TAC with AAT group was cotreated with daily subcutaneous injections of TAC and intraperitoneal injections of AAT (80 mg/kg) for four weeks. The effects of AAT on TAC-induced renal injury were evaluated using serum biochemistry, histopathology, and Western blotting. The TAC injection significantly increased renal interstitial fibrosis, inflammation, and apoptosis as compared to the control treatment. The histopathological examination showed that cotreatment of TAC and AAT attenuated interstitial fibrosis (collagen, fibronectin, and α-SMA staining), and α-SMA expression in Western blotting was also decreased. Immunohistochemical staining for inflammation (osteopontin and ED-1 staining) revealed improved interstitial inflammation in the TAC with AAT group compared to that in the TAC group. The TAC treatment increased renal apoptosis compared to the control treatment, based on the results of increased immunohistochemical staining of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), increased caspase-3 activity, and lower Bcl-2 to Bad expression ratio. However, AAT cotreatment significantly changed these markers and consequently showed decreased apoptosis. AAT protects against TAC-induced renal injury via antifibrotic, anti-inflammatory, and antiapoptotic effects.

Linagliptin ameliorates tacrolimus-induced renal injury: role of Nrf2/HO-1 and HIF-1α/CTGF/PAI-1

“…Our results have revealed that the renal content of TGFβ-1, as well as the protein expression of α-SMA and collagen type1, increased following TAC treatment. These align with the results published by Lim et al [ 1 ], where the immunostaining of fibrotic markers collagen, fibronectin, and α-SMA increased in the TAC group. In addition, the study of Ume and colleagues [ 31 ] showed that tacrolimus-treated renal fibroblasts displayed fibroblast-to-myofibroblast transition phenotyping, which was demonstrated by α-smooth muscle actin, and collagen type IV overexpression accompanied by concomitant induction of TGF-β1 ligand secretion, and receptor activation.…”

“…Bcl-2 is a protein that blocks programmed cell death by controlling mitochondrial apoptosis while The Bax protein, a member of the Bcl-2 family, promotes apoptosis. The ratio of Bax/ Bcl-2 is an indicator of the susceptibility of a cell to undergo apoptosis [ 1 , 35 ]. In our results, TAC increased the renal contents of caspase-3 and Bax proteins and decreased that of Bcl-2.…”

“…Tacrolimus is the most frequently utilized immunosuppressive calcineurin inhibitor in solid organ transplantation; it increases grafted organ survival and is used as a treatment option for various autoimmune disorders [ 1 ]. However, prolonged use causes nephrotoxicity [ 2 ].…”

Linagliptin Mitigates TGF-β1 Mediated Epithelial–Mesenchymal Transition in Tacrolimus-Induced Renal Interstitial Fibrosis <i>via</i> Smad/ERK/P38 and HIF-1α/LOXL2 Signaling Pathways

“…This deposition results from fibroblast differentiation into myofibroblasts that can be promoted by TGF-β 51) and have been regulated by metalloproteinases, lysyl oxidase enzymes, and the EMT process. 52) Consistent with that published by Lim et al 53) our immunohistochemical results have shown a significant increase in tubular expression of ECM proteins including collagen type І, and fibronectin following TAC treatment. One more finding in our study which has not been published elsewhere is that TAC treatment has resulted in an increased tubular expression of TIMP1.…”

The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice

“…Tac administration induces an increase in blood pressure and plasma creatinine in post-renal transplant patients [ 9 , 10 , 11 ]. Although the precise mechanisms of Tac-induced nephrotoxicity are not entirely comprehended, studies on murine models have revealed that it is linked to acute hemodynamic impairment [ 12 , 13 ]; reduced natriuresis [ 14 ]; elevated proinflammatory lymphocytes [ 15 ]; heightened levels of proinflammatory cytokines; such as IL-6 [ 14 , 15 ]; and the induction of a fibrotic phenotype [ 16 , 17 ].…”