Loganetin protects against rhabdomyolysis‐induced acute kidney injury by modulating the toll‐like receptor 4 signalling pathway

Abstract

Background and Purpose: Acute kidney injury (AKI) is a rapid renal dysfunctional disease, for which no effective drugs or therapies are available to improve prognosis.Loganetin is a natural product with unknown bioactivities. Here, we identified a new protective effect and mechanism of Loganetin in a mouse model of AKI induced by rhabdomyolysis.Experimental Approach: AKI was induced using glycerol by i.m. injection in mice models. Thirty minutes and 24 and 48 hr after injection of glycerol, the mice received 2 and 18 mg·kg −1 of Loganetin i.p. respectively. Then mice blood and kidney were collected for various biochemical and histopathological studies. Mechanistic studies on modulation of AKI by Loganetin were performed using HK-2 cells and Toll-like receptor 4 (TLR4) knockout mice.Key Results: In the Loganetin treated group, kidney damage and mortality rate were declined, and blood urea nitrogen and serum creatinine were much lower. Loganetin prevented damage to the tubular structures induced by glycerol and decreased apoptotic cells at the corticomedullary junction. In HK-2 cells, Loganetin could inhibit NF-κB pathway and pro-apoptotic genes expression. However, TLR4 was silenced by a specific shRNA, and the inhibitory effect of Loganetin in HK-2 cells vanished. Loganetin also down-regulated the expression of inflammation factors by suppressing TLR4 activity.Conclusion and Implications: All the results suggested that TLR4 plays a critical role in AKI development, and Loganetin ameliorates AKI by inhibiting TLR4 activity and blocking the JNK/p38 pathway, which provides a new strategy for AKI treatment.

Toll-Like Receptors in Acute Kidney Injury

“…In other study, rhabdomyolysis was induced by exerting 3 kg of pressure for 8 h in rats, and treatment with TAK-242 reduced renal injury and decreased systemic inflammatory cytokines (IL-6 or TNF-α) [ 164 ]. In line with this data, other studies also reported that direct inhibition of the TLR-4/JNK/p38/NFκB pathway with curcumin and loganetin [ 165 , 166 ], reduced kidney injury and inflammation, as well as improved renal function in pre-clinical models of rhabdomyolysis [ 45 , 165 ]. However, there are contradictory results in the literature, since TLR4 antagonism with TAK-242 did not protect from rhabdomyolysis-mediated renal damage in other study [ 162 ].…”

Renoprotective effects of levosimendan on acute kidney injury following cardiac arrest via anti‐inflammation, anti‐apoptosis, and ERK activation

“…[ 39 ] reported gentamycin‐induced AKI was associated with the activation of renal p38. In addition, JNK activation was increased in rhabdomyolysis‐induced AKI [ 40 ]. However, the activation of p38 and JNK pathway was not involved in our model.…”

Loganetin and 5‐fluorouracil synergistically inhibit the carcinogenesis of gastric cancer cells via down‐regulation of the Wnt/β‐catenin pathway

“…Loganetin ( Figure 1A) is a natural product derived from C. officinalis. 20 We found that at the same concentration, the inhibition of cell viability of loganetin ( Figure 1B) on GC cells was about three times higher than that of loganin. Therefore, we focused on loganetin, investigating its potential synergy with 5FU on proliferation of human GC cell lines including HGC27 and MGC803.…”

“…31 Recent work has revealed that loganetin protects against kidney injury in a TLR4-dependent manner. 20 However, the role of loganetin that plays in cancer was not previously known. Our data revealed that loganetin exhibits clear anti-tumour efficacy ( Figure 1B).…”

“…While the biological activity of loganetin is poorly understood, loganin has been widely used 31 . Recent work has revealed that loganetin protects against kidney injury in a TLR4‐dependent manner 20 . However, the role of loganetin that plays in cancer was not previously known.…”