Salusin‑β participates in high glucose‑induced HK‑2 cell ferroptosis in a Nrf‑2‑dependent manner

Abstract

Ferroptosis is critically involved in the pathophysiology of diabetic nephropathy (DN). As a bioactive peptide, salusin-β is abundantly expressed in the kidneys. However, it is unclear whether salusin-β participates in the pathologies of diabetic kidney damage by regulating ferroptosis. The present study found that high glucose (HG) treatment upregulated the protein expressions of salusin-β in a dose-and time-dependent manner. Genetic knockdown of salusin-β retarded, whereas overexpression of salusin-β aggravated, HG-triggered iron overload, antioxidant capability reduction, massive reactive oxygen species production and lipid peroxidation in HK-2 cells. Mechanistically, salusin-β inactivated nuclear factor erythroid-derived 2-like 2 (Nrf-2) signaling, thus contributing to HG-induced ferroptosis-related changes in HK-2 cells. Notably, the protein expression of salusin-β was upregulated by ferroptosis activators, such as erastin, RSL3, FIN56 and buthionine sulfoximine. Pretreatment with ferrostatin-1 (a ferroptosis inhibitor) prevented the upregulated protein expression of salusin-β in HK-2 cells exposed to HG. Taken together, these results suggested that a positive feedback loop between salusin-β and ferroptosis primes renal tubular cells for injury in diabetes.

Ferroptosis and ferritinophagy in diabetes complications

“…Different from the previously mentioned role of the NRF2 pathway, W. J. Wang et al. found salusin-β is involved in high glucose-induced ferroptosis of renal tubular cells HK-2 in an NRF2 dependent manner, indicating that salusin-β and ferroptosis form a positive feedback loop, which promotes high glucose-induced renal tubular cell injury [ 95 ]. However, this effect is only explored in cell experiments, and animal experiments are still needed for further research.…”

Ferroptosis as a Novel Therapeutic Target for Diabetes and Its Complications

“…Renal tubular injury is a critical factor in DKD. High glucose (HG) triggered iron overload, antioxidant capability reduction, massive ROS production, and lipid peroxidation in renal tubular cell death ( 23 , 88 ). Salusin−β, a bioactive peptide of 20 amino acids, participates in HG−induced HK−2 cell ferroptosis in an Nrf−2−dependent manner ( 88 ).…”

Identification of Genes Reveals the Mechanism of Cell Ferroptosis in Diabetic Nephropathy

“…It is worth noting that "ferroptosis" named in 2012 (Dixon et al, 2012) is appreciated as one of the most widespread and ancient forms of cell death, because of the similarity to ferroptosis-like cell death observed in evolutionarily remote species, such as plants protozoa and so on (Distefano et al, 2017;Bogacz and Krauth-Siegel, 2018). Previous studies have observed the existence of ferroptosis in renal tubules in DN Wang et al, 2021), but which in glomerulus and its mechanism still need to be further explored.…”