FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury

Abstract

Cisplatin, a widely used cancer therapy drug, induces nephrotoxicity or acute kidney injury (AKI), but the underlying mechanism remains unclear, and renal protective approaches are not available. Fibroblast growth factor (FGF)21 is an endocrine factor that regulates glucose uptake, metabolism, and energy expenditure. However, recent work has also implicated FGF21 in cellular stress response under pathogenic conditions. The role and regulation of FGF21 in AKI are unclear. Here, we show that FGF21 was dramatically induced during cisplatin treatment of renal tubular cells in vitro and mouse kidneys in vivo. The inductive response was suppressed by pifithrin (a pharmacological inhibitor of P53), suggesting a role of P53 in FGF21 induction. In cultured renal tubular cells, knockdown of FGF21 aggravated cisplatin-induced apoptosis, whereas supplementation of recombinant FGF21 was protective. Consistently, recombinant FGF21 alleviated cisplatin-induced kidney dysfunction, tissue damage, and tubular apoptosis in mice. Mechanistically, FGF21 suppressed P53 induction and activation during cisplatin treatment. Together, these results indicate that FGF21 is induced during cisplatin nephrotoxicity to protect renal tubules, and recombinant FGF21 may have therapeutic potential.-Li, F., Liu, Z., Tang, C., Cai, J., Dong, Z. FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury.

Fibroblast growth factor 21 in chronic kidney disease

“…Fenofibrate protects against type 1 DN by FGF21-mediated upregulation of the nuclear factor E2-related factor 2 (Nrf2) antioxidant pathway [92]. In cisplatin-induced acute kidney injury (AKI), silencing of FGF21 aggravated tubular cell injury, whereas supplementation of rFGF21 protected against cisplatin nephrotoxicity [7, 8, 93]. …”

Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule

“…Acute kidney injury (AKI) is characterized by a rapid deterioration of renal functions, and it presents as one of the major causes of morbidity in hospitalized patients (1,2). It is estimated that more than 2 million deaths a year are related to AKI around the world.…”

SIRT1 Mediates Effects of FGF21 to Ameliorate Cisplatin-Induced Acute Kidney Injury

“…It was significantly upregulated as an effective catabolic factor in order to antagonize metabolism and energy imbalance (Gómez-Sámano et al, 2017;Luo et al, 2017). In addition, it has been indicated that upregulation of serum FGF21 levels may delay the progression of diabetic nephropathy and chronic kidney disease (Li F. et al, 2018;Suassuna et al, 2019). Many studies have previously shown that loss of FGF21 causes pathologic damage in multiple animal models, including decreased productivity of pancreatic beta cells and insulin sensitivity (Lee et al, 2018;Wanders et al, 2017), promotion of the development of fatty liver in mice followed by aggravation of liver fibrosis (Singhal et al, 2018), and even aggravation of cisplatin-induced AKI (Holditch et al, 2019).…”

“…The experimental mice were randomly divided into three subgroups at each time point, i.e., the control group (NC), cisplatin model group (CIS), and treatment group (FGF21 + CIS) (n = 5 in each subgroup). Based on the procedure described by Li F. et al (2018), we used a high dose (30 mg/kg) of cisplatin in a single intraperitoneal injection to establish the AKI mouse model. The control group was injected with the same volume of normal saline.…”

“…FGF21 activity depends on its binding to β-Klotho protein and FGF receptors (FGFRs) and the formation of a stable FGF21/β-Klotho/FGFR complex, which regulates the biological effects of downstream signaling molecules (Kuro, 2019). Previous studies showed that serum levels of FGF21 are significantly increased in both AKI and CKD, and FGF21 concentration is correlated with the severity of kidney injury (Li F. et al, 2018;Suassuna et al, 2019). However, numerous studies have demonstrated that FGF21 functions in alleviating inflammation and in the regulation of oxidative stress and autophagy-induced apoptosis (Lu et al, 2019;Suassuna et al, 2019).…”