Polyethylene glycol loxenatide protects diabetic kidneys by inhibiting GRP78/PERK/eIF2α pathway, and improves cardiac injury by suppressing TLR4/NF-κB inflammatory pathway.

Background: Cardiovascular and renal complications of type 2 diabetes are the main causes of death in diabetic patients. Clinical studies have found that polyethylene glycol loxenatide (PEG-Loxe), a GLP-1 analog widely used to treat type 2 diabetes, boosts renal and cardiac functions in diabetic patients. However, its mechanism of action remains to be elucidated.

Methods: Using injury models of HK-2 human renal proximal tubular epithelial cells and H9C2 rat myocardial cells, as well as db/db mouse models of type 2 diabetes, this study assessed the protective effects of PEG-Loxe on T2DM mice kidneys and hearts and revealed their mechanisms of action.

Results: PEG-Loxe treatment significantly reduced the contents of serum creatinine, urea nitrogen, and 24 h urine protein, alleviated glomerular injury and inflammatory reaction, markedly elevated cardiac left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) levels, diminished pathological injuries in cardiac tissues, and improved renal and cardiac functions in db/db mice. In addition, PEG-Loxe considerably decreased the GRP78 mRNA and protein expressions of GRP78, p-eIF2α, ATF4, and CHOP in the kidneys of T2DM mice, inhibited GRP78/PERK/eIF2α pathway-related proteins in HK-2 cells cultured in high glucose concentrations, subdued renal endoplasmic reticulum stress, and eased renal injury in T2DM mice. PEG-Loxe also obstructed the TLR4/NF-κB inflammatory pathway and myocardial apoptosis and mitigated cardiac trauma in T2DM by reducing TLR4, MyD88, and p-NF-κBp65 protein expressions in cardiac tissues. The H9C2 cell experiment further confirmed PEG-Loxe's ability to protect the cardiovascular system of T2DM patients by inhibiting the TLR4/NF-κB inflammatory pathway and lessening LDH and CK-MB levels.

Conclusion: We showed that PEG-Loxe could decrease renal stress response and improve renal injury in T2DM by inhibiting endoplasmic reticulum stress via the GRP78/PERK/eIF2α pathway. Additionally, PEG-Loxe could hinder the TLR4/NF-κB inflammatory pathway and myocardial apoptosis and boost cardiac function, thus exerting protective effects on the cardiovascular system in T2DM.