Therapeutic effect and mechanism of combination therapy with ursolic acid and insulin on diabetic nephropathy in a type I diabetic rat model

Abstract

This work aims to investigate the therapeutic effect of ursolic acid (UA) plus insulin (In) on diabetic nephropathy (DN) in streptozotocin (STZ)-induced T1DM rats. The experimental groups and operational details are as follows: A total of thirty-two SD rats were divided into four groups: the DN model group (DN, n = 8), DN + In treatment group (DN + In, n = 8), DN + In + UA administration group (DN + In + UA, n = 8), and negative control group (control, n = 8). After 8 weeks, changes in renal function indices and pathological damage were assessed. Additionally, oxidative stress-, apoptosis-, and fibrosis-related proteins in kidney tissue were measured. Compared with the control group, the vehicle group showed higher levels of creatine, blood urea nitrogen, urinary protein, apoptosis, and lipid peroxidation; lower superoxide dismutase levels; more severe levels of pathological kidney damage and renal fibrosis; and a deepened degree of EMT and EndMT. Better outcomes were achieved with the combined treatment than with insulin-only treatment. The improvement of TGF-β1, phosphorylated p38 MAPK, FGFR1, SIRT3 and DPP-4 expression levels in renal tissues after combination therapy was greater than that after insulin-only treatment. This study shows that the combination of insulin and UA significantly improved the pathological changes in the renal tissue of T1DM rats, and the underlying mechanism may be related to improving apoptosis and oxidative stress by regulating p38 MAPK, SIRT3, DPP-4 and FGFR1 levels, thereby blocking TGF-β signaling pathway activation and inhibiting EMT and EndMT processes.

Study on effects and relevant mechanisms of Mudan granules on renal fibrosis in streptozotocin-induced diabetes rats

“…Based on previous experience and pre-experiments, the Type I Diabetes mellitus (T1DM) model was induced by a single intraperitoneal injection of strepotozotocin (STZ, 65 mg/kg, in 0.1 mol/L sodium citrate buffer, pH 4.4; Sigma, United States) in SD rats, and the normal control group was injected with an equal volume of citrate buffer at the same time. After 72 h of STZ injection, animals with random blood glucose levels ≥16.7 mmol/L were considered successful in modeling [ 12 , 13 ].…”

Oleanolic acid and its analogues: promising therapeutics for kidney disease

“…T helper cell (Th17) plays an important role in the pathogenesis of lupus nephritis [108]. Research has demonstrated that, in mice with pristane-induced lupus nephritis, treatment with OA reduces dsDNA levels, IL-17A expression and interferon γ (IFN-γ), and alleviate (↑) and (↓) signs show positive and negative effects of oleanolic acid and its analogues on its target molecules, respectively In vivo CP-induced nephrotoxicity in Wistar rats UA (5, 10 mg/kg) GSH↑, SOD↑, CAT↑, MDA↓, IL-1β↓, IL-6↓, TNF-α↓, Caspase-3↓, Caspase-9↓ [141] In vivo STZ-induced DN in SD rats UA (50 mg/kg) TNF-α↓, IL-1β↓, IL-6↓, SOD↑, MDA↓, GSH↑, CAT↑, NO↓, FN↓, E-cad↑, MMP-9↑,TIMP-1↓, α-SMA↓, TGF-β1↓,SMA3↓, SMA7↓, P38↓ [167] In vivo RIRI in SD rats OA (50 mg/kg) PI3K↓, p-AKT↓, PDK1↑, p27↑, TRAP1↑, CypD↓ [168] In vitro HK-2 cells stimulated with OTA OA (2 μM) Bax↓, Bcl-2↑, Cyt-C↓, Caspase-9↓,Caspase-3↓, GRP78↓, CHOP↓ [169] In vivo STZ-induced DN in SD rats OA (50, 100 mg/kg) nephrin↑, CD68↓, COL-IV↓, p-AMPK/ AMPK↑, PGC-1α↑, TLR4↓, NF-κB↓, TGF-β1↓ [103] In vivo STZ-induced DN in SD rats OA (50 mg/kg) Caspase-3↓, Bax↓, CD31, E-cadherin↑, α-SMA↓, Vimentin↓, TGF-β1↓, p-P38↓, FGFR1↑, SIRT3↑, DPP-4↓ [170] In vivo UUO in SD rats UA (40 mg/kg) TGF-β1↓, Keap1↓, Nrf2↑, HO-1↑, 8-oxo-dG↓, Caspase-3↓, Caspase-8↓ [171] In vivo TAA-induced AKI in BALB/c mice OA (45, 90 mg/kg) MDA ↓, NOx ↓, GSH↑, SOD↑, NF-κB↓, TNF-α↓, Bax↓, Bcl2 ↑, Caspase-3↓ Nrf2↑, HO-1↑ [143] In vitro HK-2 cells stimulated with OTA UA (4 μM) Lonp1↑, Sig-1R↑, GRP78↓, p-ERK↓, p-eIF2α↓, CHOP↓, IRE1α↓, Bcl2↑, Bax↓ [142] renal injury by decreasing the deposition of IgG and IgM in the glomeruli [20]. Further studies have revealed that OA inhibits the differentiation of Th17 cells in vitro.…”

YME1L-mediated mitophagy protects renal tubular cells against cellular senescence under diabetic conditions

“…Diabetic kidney disease (DKD) stands as one of the most severe complications of diabetes and has emerged as the primary cause of end-stage renal disease (ESRD) globally [ 1 ]. Recent research has found that the pathogenesis of DKD involves several factors, including the downregulation of endothelial cell glucocorticoid receptor leading to epithelial-mesenchymal transition (EMT) [ 2 ], abnormal activation of the Wnt signaling pathway [ 3 ], the TGF-β signaling pathway [ 4 ], and dipeptidyl peptidase-4 (DPP-4)-mediated signaling mechanism [ 5 , 6 ], while some drugs such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blocker (ARB), and sodium-glucose co-transporter-2 (SGLT2) inhibitors, as well as mineralocorticoid receptor antagonist finerenone [ 7 ], have been used in efforts to slow the progression of DKD or improve renal function, but existing therapies have not effectively halted the advancement of DKD. This lack of progress leaves 20%-40% of individuals in need of renal transplantation [ 8 ].…”