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

Ferroptosis is critically involved in the pathophysiology of diabetic nephropathy (DN). As a bioactive peptide, salusin-beta is abundantly expressed in the kidneys. However, it is unclear whether salusin-beta 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-beta in a dose- and time-dependent manner. Genetic knockdown of salusin-beta retarded, whereas overexpression of salusin-beta aggravated, HG-triggered iron overload, antioxidant capability reduction, massive reactive oxygen species production and lipid peroxidation in HK-2 cells. Mechanistically, salusin-beta 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-beta 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-beta in HK-2 cells exposed to HG. Taken together, these results suggested that a positive feedback loop between salusin-beta and ferroptosis primes renal tubular cells for injury in diabetes.

Automated summary

The study revealed that salusin-beta plays a crucial role in diabetic kidney damage by regulating ferroptosis, with its activity exacerbating abnormal changes induced by high glucose. Furthermore, inactivation of the Nrf-2 signaling pathway by salusin-beta also influences the occurrence of ferroptosis.