Ursolic acid alleviates inflammation and against diabetes‑induced nephropathy through TLR4‑mediated inflammatory pathway

Abstract

Ursolic acid (UA) is a triterpenoid isolated from Chinese herbal medicine. It is extensively distributed in the plant kingdom in at least 63 Chinese herbal medicines of 26 families. UA has multiple bioactivities, including anti‑viral hepatitis, antitumor, anti‑oxidation, anti‑bacterium and anti‑inflammation. The aim of this in vitro study was to examine the effects of UA on diabetes‑induced nephropathy and its possible mechanism. In mice with diabetes‑induced nephropathy, UA increased the body weight, reduced kidney/body weight index, protected kidney cells, alleviated inflammation [tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, IL‑6 and IL‑18 levels] and kidney cell damage. It was also indicated that UA suppressed Toll‑like receptor 4 (TLR4), myeloid differentiation factor 88 and nuclear factor‑κB protein expression in mice with diabetes‑induced nephropathy. The inhibition of TLR4 increased the anti‑inflammation of UA on inflammation in rat with diabetes‑induced nephropathy through the TLR4 signaling pathway. In conclusion, UA alleviates inflammation and inhibits diabetes‑induced nephropathy through a TLR4‑mediated inflammatory pathway. The present findings indicated that UA may be a possible therapeutic agent against diabetic nephropathy.

Antioxidant and Anti-inflammatory Mechanisms of Neuroprotection by Ursolic Acid: Addressing Brain Injury, Cerebral Ischemia, Cognition Deficit, Anxiety, and Depression

“…In this context, the therapeutic potential of UA as a prototype lead is shown in various CNS diseases primarily through antioxidant and anti-inflammatory mechanisms and also specific actions in various receptor/enzyme systems outlined in the preceding sections. Similarly, the antioxidant-anti-inflammatory axis has been shown to play a role in the antidiabetic effect of UA as demonstrated in the streptozotocin-induced rats [113, 114] in the db/db diabetic mouse model [115], other models of diabetes nephropathies [116, 117], diabetic-induced monocyte dysfunction and atherosclerosis in mice [118], aortic injury in STZ-induced diabetic rats [119], or clinical trial in human [120]. The anti-inflammatory effect of UA in HFD-induced obese rats [121, 122], inhibition of lipoxygenase-1- (LOX-1-) mediated ROS generation and NF- κ B activation as well as atherosclerosis development in mice [123], inhibition of matric metalloproteases in the aortic smooth muscle cells [124], cytokine-induced glioma cell invasion in the transwell cell migration assay [125], or cytokine expression in a macrophage and inhibition of atherosclerosis in mice [126] have also been shown.…”

Ursolic acid induces the production of IL6 and chemokines in both adipocytes and adipose tissue

“…UA has been proved to ameliorate hepatic steatosis, suppress adipogenesis of pre-adipocytes, and stimulate lipolysis in cultured adipocytes [10][11][12][13]. Besides, UA was also reported to regulate inflammation in macrophages, mammary epithelial cells, liver, skin, lung, kidney and intestine, with both anti-and proinflammatory effects in different cell types and tissues [9,[14][15][16][17][18]. However, the effect of UA on adipose tissue inflammation has not been reported.…”

Metformin attenuates diabetic renal injury via the AMPK‑autophagy axis

“…Furthermore, it was recently demonstrated that diabetic kidney fibrosis is responsible for chronic inflammatory responses (6,7). DN is therefore considered to induce a renal inflammatory response, which is characterized by inflammatory cell infiltration and inflammatory cytokine upregulation (8)(9)(10). For example, T cells and macrophages have been demonstrated to accumulate in the kidney interstitium and glomeruli in human DN, even at the initial stage of the disease.…”

“…For example, T cells and macrophages have been demonstrated to accumulate in the kidney interstitium and glomeruli in human DN, even at the initial stage of the disease. Furthermore, hyperglycemia and glycated hemoglobin, which are hallmarks of diabetes, have been indicated to be associated with renal inflammatory responses (10). As demonstrated in diabetic models, enhanced production of chemokines and cytokines aggravate the inflammatory response (11,12).…”