Establishment of an experimental rat model of tacrolimus-induced kidney injury accompanied by interstitial fibrosis. (1st May 2021)

• Record Type: Journal Article
• Authors: Fu, Rao; Tajima, Soichiro; Shigematsu, Tomohiro; Zhang, Mengyu; Tsuchimoto, Akihiro; Egashira, Nobuaki; Ieiri, Ichiro; Masuda, Satohiro
• Is Part Of: Toxicology letters. Volume 341(2021)
• Page Start: 43
• Page End: 50
• Publication Date: 2021-05-01
• Subjects: AKI acute kidney injury -- BUN blood urea nitrogen -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- HE hematoxylin and eosin -- K potassium -- KIM-1 kidney injury molecule 1 -- MCP-1 monocyte chemotactic protein 1 -- Mg magnesium -- I/R ischemia reperfusion -- PAS periodic acid-Schiff -- Scr serum creatinine -- TAC tacrolimus -- TGF-β transforming growth factor-β -- α-SMA α-smooth muscle actin; Tacrolimus -- Nephrotoxicity -- Renal interstitial fibrosis -- Kidney transplantation; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2021.01.020
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: This study reports the development of a rat model of tacrolimus-induced nephropathy with renal interstitial fibrosis via 2 weeks administration of tacrolimus following renal ischemia reperfusion. The TAC + IRI group, which received tacrolimus daily for 2 weeks, had significantly lower renal function and higher levels of Scr, BUN compared to the other groups. The TAC + IRI group exhibited noticeable kidney injury, such as vacuolization and glomerulosclerosis, as well as increased α-SMA, TGF-β, and KIM-1 expression in their renal tubulointerstitium compared with the Sham, IRI, and TAC groups. Abstract: Nephrotoxicity is the major adverse reaction to tacrolimus; however, the underlying mechanisms remain to be fully elucidated. Although several tacrolimus-induced nephrotoxicity animal models have been reported, most renal injury rat models contain factors other than tacrolimus. Here, we report the development of a new nephrotoxicity with interstitial fibrosis rat model induced by tacrolimus administration. Thirty Wistar rats were randomly divided into four groups: sham-operated (Sham), vehicle-treated ischemia reperfusion (I/R) injury (IRI), tacrolimus treated (TAC) and tacrolimus treated I/R injury (TAC + IRI). Rats subjected to IR injury and treated with tacrolimus for 2 weeks showed higher serum creatinine (Scr), blood urea nitrogen (BUN), serum magnesium (Mg) and serum potassium (K), indicating decreased renal function. In addition, tacrolimus treatment combined with IR injury increased histological injury (tubular vacuolation, glomerulosclerosis and interstitial fibrosis), as well as α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), and kidney injury molecule-1 (KIM-1) expression in the renal cortex. In summary, we have developed a tacrolimus-induced kidney injury rat model with interstitial fibrosis within 2 weeks by creating conditions mimicking renal transplantation via tacrolimus administration following ischemia-reperfusion.