Lansoprazole promotes cisplatin‐induced acute kidney injury via enhancing tubular necroptosis

Abstract

Acute kidney injury (AKI) is the main obstacle that limits the use of cisplatin in cancer treatment. Proton pump inhibitors (PPIs), the most commonly used class of medications for gastrointestinal complications in cancer patients, have been reported to cause adverse renal events. However, the effect of PPIs on cisplatin‐induced AKI remains unclear. Herein, the effect and mechanism of lansoprazole (LPZ), one of the most frequently prescribed PPIs, on cisplatin‐induced AKI were investigated in vivo and in vitro. C57BL/6 mice received a single intraperitoneal (i.p.) injection of cisplatin (18 mg/kg) to induce AKI, and LPZ (12.5 or 25 mg/kg) was administered 2 hours prior to cisplatin administration and then once daily for another 2 days via i.p. injection. The results showed that LPZ significantly aggravated the tubular damage and further increased the elevated levels of serum creatinine and blood urea nitrogen induced by cisplatin. However, LPZ did not enhance cisplatin‐induced tubular apoptosis, as evidenced by a lack of significant change in mRNA and protein expression of Bax/Bcl‐2 ratio and TUNEL staining. Notably, LPZ increased the number of necrotic renal tubular cells compared to that by cisplatin treatment alone, which was further confirmed by the elevated necroptosis‐associated protein expression of RIPK1, p‐RIPK3 and p‐MLKL. Furthermore, LPZ deteriorated cisplatin‐induced inflammation, as revealed by the increased mRNA expression of pro‐inflammatory factors including, NLRP3, IL‐1β, TNF‐α and caspase 1, as well as neutrophil infiltration. Consistently, in in vitro study, LPZ increased HK‐2 cell death and enhanced inflammation, compared with cisplatin treatment alone. Collectively, our results demonstrate that LPZ aggravates cisplatin‐induced AKI, and necroptosis may be involved in the exacerbation of kidney damage.

Protective Effects of 6-Shogaol, an Active Compound of Ginger, in a Murine Model of Cisplatin-Induced Acute Kidney Injury

“…A pharmacological suppression of RIPK1 activity ameliorated tubular cell necroptosis and renal injury in cisplatin-treated mice [ 46 , 47 ]. Previous studies have reported that the renal expression of RIPK1, RIPK3, and p-MLKL was increased after cisplatin treatment [ 48 , 49 ]. Interestingly, these changes were significantly attenuated by 6-shogaol.…”

Regulated cell death pathways in kidney disease

“…However, findings from experimental models and systems are contradictory. For example, omeprazole induced tubular cell death in healthy mice in vivo 216 and another PPI, lansoprazole, increased the severity of experimental cisplatin-induced AKI 217 . By contrast, one in vitro study found that omeprazole could scavenge lipid peroxyl radicals, and demonstrated short-term (48 h) anti-ferroptotic effects in cultured cells following cystine deprivation; however, omeprazole was toxic at higher doses 218 .…”

Macrophage‐derived exosomal miR ‐195a‐5p impairs tubular epithelial cells mitochondria in acute kidney injury mice

“…Subsequently, the sections were stained with hematoxylin–eosin (HE) and periodic acid‐Schiff (PAS), and observed by light microscopy (Zeiss, Germany). Tubular cell necrosis, loss of brush border, cast formation, and tubule dilation were scored 0–4 as a percentage of the whole cortical area of the kidney slices:1, <10% damage; 2, 10%–25% damage; 3, 26%–75% damage; 4, >75% damage 33 …”

“…Tubular cell necrosis, loss of brush border, cast formation, and tubule dilation were scored 0-4 as a percentage of the whole cortical area of the kidney slices:1, <10% damage; 2, 10%-25% damage; 3, 26%-75% damage; 4, >75% damage. 33 For immunohistochemistry (IHC) staining, after quenching with endogenous peroxidase, achieving antigen retrieval, and blocking nonspecific binding sites, the sections were incubated with primary antibodies, including anti-UQCRC2 (Abclonal, Cat. No.…”