PEG-Loxe treatment significantly improved renal and cardiac functions in db/db mice with type 2 diabetes.
Treatment with PEG-Loxe reduced serum levels of creatinine and urea nitrogen, indicating improved kidney function.
PEG-Loxe alleviated glomerular injury and inflammation in the kidneys of diabetic mice.
Cardiac function was markedly enhanced, with increased left ventricular ejection fraction and fractional shortening levels.
The treatment decreased expressions of stress-related proteins in the kidneys, suggesting reduced endoplasmic reticulum stress.
PEG-Loxe inhibited the /NF-κB inflammatory pathway, which is associated with myocardial apoptosis and cardiac damage.
Simplified
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 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 /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.
Key numbers
134.7 μmol/L
Decrease in Serum Creatinine
Serum creatinine levels in high-dose group
LVEF increase
Increase in
Improvement in cardiac function post- treatment
2.44 mmol/L
Decrease in Urea Nitrogen
Urea nitrogen levels in high-dose group
Full Text
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Declarations. Ethics approval and consent to participate: All animal experiments were approved (No. 20220102–05) by the Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. The animal care and experimental procedures were carried out in accordance with the Guidelines of the Institutional Animal Care and Use Committee of Tongji Medical College and the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
PubMed
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