The renoprotective effects of tadalafil on ischemia-reperfusion injury during partial nephrectomy in an animal model

Abstract

Background: Although 25 min is the reported safe partial nephrectomy time for warm ischemia, acute kidney injury occurs even with arterial ligation within 25 min, causing serious complications in patients with chronic renal disease. Various drugs have been studied but evidence of their effectiveness and safety is insufficient. This study investigated the renoprotective function of tadalafil.

Methods: A rat model of partial nephrectomy was treated orally with tadalafil for 14 days before ischemic-reperfusion (IR) injury. Blood and kidney samples were collected for biochemical and molecular analyses 24 h after IR injury. The levels of serum blood urea nitrogen, creatinine, and urine kidney injury molecule-1 were analyzed, while kidney tissues were used for qPCR and histological analysis.

Results: Although effects on blood urea nitrogen and creatine levels were not observed, tadalafil preserved renal function by suppressing the decrease of viable glomeruli, indicating it protected kidneys from IR injury-induced glomeruli loss. Tadalafil effectively reduced the expression of the oxidative stress markers, inducible NOS, endothelial NOS, and myeloperoxidase, and significantly suppressed the expression of inflammation-related genes like TNF-α, IL-1β, IL-6, CD4, and CD8.

Conclusions: Tadalafil inhibits oxidative stress and inflammation, and protects from glomeruli loss during ischemic-reperfusion damage in a rat model of partial nephrectomy.

Clinical trial number: Not applicable.

Keywords: Ischemic–reperfusion injury; Partial nephrectomy; Tadalafil.

Fig. 1

Gross image and serum and tissue analysis. (A) Kidney gross image, weight, and volume. (B) Serum and urine chemistry analysis. (C) Representative H&E staining image, glomeruli number, and tubule injury scoring. Data represent the mean ± SD of three independent experiments (*, **, and *** indicate p < 0.05, < 0.01, and < 0.001, respectively, between the sham and IR groups. #, ##, and ### indicate p < 0.05, < 0.01, and < 0.001, respectively, between the IR and IR + T groups. N = 4–6 per group

Fig. 2

Tadalafil’s effect on oxidative stress. (A) iNOS and kidney MPO expression levels. (B) eNOS immunofluorescence staining. Data represent the mean ± SD of three independent experiments. *, **, and *** indicate p < 0.05, < 0.01, and < 0.001, respectively, between the sham and IR groups. #, ##, and ### indicate p < 0.05, < 0.01, and < 0.001, respectively, between the IR and IR + T groups. N = 4–6 per group

Fig. 3

Tadalafil’s effects on inflammation and lymphocyte recruitment. (A) Quantitative real-time PCR analysis of inflammation-related gene expression. (B) Immunofluorescence detection of CD4- and CD8-positive lymphocytes. (C) Immunofluorescence detection of neutrophils (MPO), macrophages (F4/80), and monocytes (HLA-DR). Data represent the mean ± SD of three independent experiments. *, **, and *** indicate p < 0.05, < 0.01, and < 0.001, respectively, between the sham and IR groups. #, ##, and ###, indicate p < 0.05, < 0.01, and < 0.001, respectively, between the IR and IR + T groups. N = 4–6 per group

Fig. 3

Tadalafil’s effects on inflammation and lymphocyte recruitment. (A) Quantitative real-time PCR analysis of inflammation-related gene expression. (B) Immunofluorescence detection of CD4- and CD8-positive lymphocytes. (C) Immunofluorescence detection of neutrophils (MPO), macrophages (F4/80), and monocytes (HLA-DR). Data represent the mean ± SD of three independent experiments. *, **, and *** indicate p < 0.05, < 0.01, and < 0.001, respectively, between the sham and IR groups. #, ##, and ###, indicate p < 0.05, < 0.01, and < 0.001, respectively, between the IR and IR + T groups. N = 4–6 per group