Date Published: February 28, 2019
Publisher: Sociedade Brasileira para o Desenvolvimento da Pesquisa em
Author(s): Yang Zhao, Qian Wang, Bin Zang.
To explore the effect of milk fat globule-epidermal growth factor 8 (MFG-E8)
on sepsis-induced acute kidney injury (SAKI).
Male C57BL/6 mice were randomized to control, sham, CLP, CLP+PBS, and
CLP+rmMFG-E8 groups. SAKI was induced by cecal ligation and puncture (CLP).
Recombinant mouse MFG-E8 (rmMFG-E8) (20 μg/kg) or PBS (vehicle) was
administered intraperitoneally. Blood, urine and renal tissue were collected
at 24 h after CLP. Blood samples were tested for serum kidney injury
biomarker and cytokines. Urine samples were collected to detect KIM-1, and
NGAL. Real-time PCR was tested for Bax and Bcl-2. TUNEL staining was used to
determine renal apoptosis. Western blot was used to detect the expression of
Bax, Bcl-2, and proteins in the NF-κB pathway.
MFG-E8 alleviated SAKI by decreasing serum Cre, BUN, urine KIM-1 and NGAL
and by mitigating renal pathological changes significant (p < 0.05). IL-1β, IL-6, TNF-α were significantly inhibited by MFG-E8 (p < 0.05). Apoptosis induced by SAKI was markedly suppressed by MFG-E8. Finally, MFG-E8 attenuated the activation of the NF- B signaling pathway in SAKI. MFG-E8 has beneficial effects on SAKI, which may be achieved by inhibiting the NF-κB pathway.
Acute kidney injury (AKI) is one of the most common and severe complications of
sepsis1; 40-50% of patients with sepsis develop AKI with a 6 to 8 folds increase in
mortality2. About 3-50% of inpatients experience AKI3. Sepsis-induced AKI not only leads to the accumulation of various
metabolites but also further causes severe clinical consequences. AKI is common and
is associated with many adverse perioperative outcomes in surgical patients4. AKI carries a two-fold increased risk of end-stage chronic kidney disease
within five years5. Despite continuous advances in treatment, including continuous renal
replacement therapy, the prognosis of sepsis-induced AKI has not been fundamentally
changed, and the mortality rate remains high6. Sepsis-induced AKI causes a substantial financial burden7. Furthermore, AKI increases the durations of mechanical ventilation and
hospital stays8. These urgently require us to understand the pathogenesis of AKI in sepsis
and to carry out early treatment.
Sepsis is a life-threatening disease that arises from the body’s response to
systemic inflammatory response syndrome (SIRS), which causes injury to tissues and
organs. It often leads to pathophysiological processes such as septic shock and
multiple organ dysfunction syndrome (MODS)14. The kidney is one of the most vulnerable organs in sepsis. Sepsis-induced
AKI occurs early, and its mortality rate is high. Therefore, it is urgent to find
effective therapy to treat sepsis-induced AKI. In this study, we demonstrated that
rmMFG-E8 improved renal function, inhibited pro-inflammatory factors, and achieved a
protective effect on sepsis-induced AKI.
We have demonstrated that treatment with MFG-E8 having a protective role against
sepsis-induced AKI. The underlying mechanism of MFG-E8 on sepsis-induced AKI may be
related to inhibiting the release of pro-inflammatory cytokines and mediators,
suppressing renal cell apoptosis, and inactivating NF-κB signaling pathway. This
evidence suggests that exogenous MFG-E8 may be a potential approach for the
treatment of sepsis-induced AKI.