Catalpol ameliorates endothelial dysfunction and inflammation in diabetic nephropathy via suppression of RAGE/RhoA/ROCK signaling pathway

Shu, Anmei; Du, Quan; Chen, Jing; Gao, Yuyan; Zhu, Yihui; Lv, Gaohong; Lu, Jianhua; Chen, Yuping; Xu, Hao

doi:10.1016/j.cbi.2021.109625

“…Chronic hyperglycemia can damage the kidney and induce diabetic nephropathy, which is one of the severe complications and one of the main causes of death in diabetic patients [ 5 ]. The duration of the disease is long, and the kidney damage is relatively insidious.…”

Section: Discussionmentioning

confidence: 99%

Correlation between Glucose/C-Peptide Ratio and the Risk of Disease Progression in Diabetic Nephropathy Patients: A Clinical Retrospective Analysis

Tong

¹

,

Wang

²

,

Fang

³

2022

Journal of Healthcare Engineering

2

0

1

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The aim of this study is to analyze the correlation between the glucose/C-peptide ratio and the risk of disease progression in patients with diabetic nephropathy. Ninety-three patients with diabetic nephropathy, who were treated in the Chun’an Branch of Zhejiang Provincial People’s Hospital, China, from January 2016 to January 2019, were recruited as subjects. In accordance with the disease progression, the patients were divided into a progression group (n = 59) and a nonprogression group (n = 34). Clinical data were compared between the two groups. Pearson’s correlation was applied to analyze the correlation of age, postprandial glucose/C-peptide, glycosylated hemoglobin, insulin resistance index, serum cystatin C, uric acid, 24 h urinary albumin excretion rate (24 hUAER), and estimated glomerular filtration rate (eGFR). Univariate and multivariate logistic regression models were utilized to analyze the influencing factors for the risk of disease progression in patients with diabetic nephropathy. The receiver operating characteristic (ROC) curve was employed to assess the predictive value of postprandial glucose/C-peptide on the risk of disease progression in patients with diabetic nephropathy. Results. The age differences, postprandial glucose/C-peptide, glycosylated hemoglobin, insulin resistance index, serum cystatin C, uric acid, 24 hUAER, and eGFR were significantly different between the two groups P < 0.05 . Pearson’s linear correlation analysis exhibited that postprandial glucose/C-peptide, insulin resistance index, serum cystatin C, and uric acid were positively correlated with 24 hUAER (r = 0.514, 0.345, 0.311, 0.279, P < 0.05 ). Age, postprandial glucose/C-peptide, insulin resistance index, serum cystatin C, and uric acid were negatively correlated with eGFR (r = −0.210, −0.610, −0.351, −0.347, and −0.274, P < 0.05 ). Univariate logistic regression analysis displayed that age (OR = 0.938; P = 0.043 ), postprandial glucose/C-peptide (OR = 0.851; p ≤ 0.001 ), insulin resistance index (OR = 0.219; p ≤ 0.001 ), serum cystatin C (OR = 0.113; p ≤ 0.001 ), and uric acid (OR = 0.989; P = 0.001 ) were risk factors for the risk of disease progression in patients with diabetic nephropathy. Multivariate logistic regression analysis exhibited that postprandial glucose/C-peptide (OR = 0.747; P = 0.004 ), insulin resistance index (OR = 0.072; P = 0.012 ), serum cystatin C (OR = 0.023; P = 0.020 ), and uric acid (OR = 0.967; P = 0.039 ) were independent risk factors for the risk of disease progression in patients with diabetic nephropathy. The ROC curve results demonstrated that the AUC of postprandial glucose/C-peptide predicting the risk of disease progression in patients with diabetic nephropathy was 0.931. Postprandial glucose/C-peptide, insulin resistance index, serum cystatin C, and uric acid are correlated with 24hUAER and eGFR. Postprandial glucose/C-peptide, insulin resistance index, serum cystatin C, and uric acid are independent risk factors for the risk of disease progression in patients with diabetic nephropathy. Among them, postprandial glucose/C-peptide can be employed as a crucial indicator to predict the risk of disease progression in diabetic nephropathy patients.

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“…The KEGG results suggested that the significant pathways mainly included AGE‐RAGE signaling pathway in diabetic complications, ROS, and apoptosis pathways (Figure 1B). Study indicated that overexpression of RAGE could exacerbate mouse glomerular endothelial cells dysfunction and inflammation response, exacerbating the progression of diabetic nephropathy 29 . Similarly, methylglyoxal could induce apoptosis in human embryonic kidney cells and aggravate the development of diabetic nephropathy 24 .…”

Section: Resultsmentioning

confidence: 99%

“…Diabetic nephropathy is also a chronic inflammatory disease 29 . Activation of the NF‐κB pathway has been shown to be a major trigger of inflammation in kidney damage 42 .…”

Section: Resultsmentioning

confidence: 99%

Investigating the molecular mechanisms of glyoxal‐induced cytotoxicity in human embryonic kidney cells: Insights from network toxicology and cell biology experiments

Liu

¹

,

Chen

²

,

Xie

³

et al. 2022

Environmental Toxicology

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Glyoxal, a reactive carbonyl species, can be generated both endogenously (glucose metabolism) and exogenously (cigarette smoke and food system). Increasing evidence demonstrates that glyoxal exacerbates the development and progression of diabetic nephropathy, but the underlying mechanisms of glyoxal toxicity to human embryonic kidney (HEK293) cells remain unclear. In this work, the molecular mechanisms of glyoxal-induced cytotoxicity in HEK293 cells were explored with network toxicology and cell biology experiments. Network toxicology results showed that oxidative stress and advanced glycation end products (AGEs)/RAGE signaling pathways played a crucial role in glyoxal toxicity. Next, further validation was performed at the cellular level. Glyoxal activated the AGEs-RAGE signaling pathway, caused the increase of cellular ROS, and activated the p38MAPK and JNK signaling pathways, causing cellular oxidative stress. Furthermore, glyoxal caused the activation of the NF-κB signaling pathway and increased the expression of TGF-β1, indicating that glyoxal caused cellular inflammation. Moreover, glyoxal caused cellular DNA damage accompanied by the activation of DNA damage response pathways. Finally, the mitochondrial apoptosis pathway was activated. The results that obtained in cell biology were consistent with network toxicology, which corroborated each other and together indicated that glyoxal induced HEK293 cells damage via the process of oxidative stress, the AGEs-RAGE pathway, and their associated signaling pathways. This study provides the experimental basis for the cytotoxicity of glyoxal on HEK293 cells.

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“…The multivariate Cox regression analyses also showed that DKD is one of the risk factors for 50% eGFR decline and KRT endpoints but not for all-cause death and CVD events after adjusting for other potential confounding factors. It has been established that there is an enhanced inflammation and oxidative stress [ 12 ], activated renin-angiotensin system [ 13 ], and endothelial dysfunction [ 14 ] in DKD status. And these factors are highly associated with CKD progression and adverse complications such as increased mortality and CVD events.…”

Section: Discussionmentioning

confidence: 99%

Prognosis and risk factors of chronic kidney disease progression in patients with diabetic kidney disease and non-diabetic kidney disease: a prospective cohort CKD-ROUTE study

Chen

¹

,

Chen

²

,

Jiang

³

2022

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Diabetic kidney disease (DKD) is emerging rapidly as the leading cause of chronic kidney disease (CKD) worldwide. In this 3-year prospective, multicenter cohort study, a total of 1138 pre-dialysis CKD patients were recruited. Patients were categorized into two groups according to the etiologies of DKD and non-diabetic kidney disease (NDKD). Propensity score matching was performed to adjust for confounding factors, resulting in 197 patients being assigned to DKD and NDKD groups, respectively. The primary endpoints were 50% estimated glomerular filtration rate (eGFR) decline and initiation of kidney replacement therapy (KRT). The secondary endpoints were all-cause death and the development of cardiovascular disease (CVD) events. We found that DKD patients have a higher risk to develop 50% eGFR decline endpoint (HR:2.30, 95%CI [1.48–3.58], p < 0.001) and KRT endpoint (HR:1.64, 95%CI [1.13–2.37], p < 0.05) than NDKD patients. The 3-year cumulative incidence of 50% eGFR decline and KRT endpoint was significantly higher in DKD patients (26.90% vs. 13.71% and 35.03% vs. 22.34%, respectively). The Cox regression analyses showed that the increased systolic blood pressure (SBP), DKD, decreased serum albumin (Alb), and higher CKD stages were risk factors for the 50% eGFR decline endpoint; the increased SBP, DKD, decreased serum Alb, serum creatinine (Scr), higher CKD stages, presence of proteinuria and CVD were risk factors for KRT endpoint; the increased age, decreased hemoglobin (Hb), decreased serum Alb were risk factors for all-cause death endpoint; the increased age, decreased serum Alb were risk factors for CVD events endpoint. Appropriate preventive or therapeutic interventions should be taken to control these predictive factors to delay the development of CKD complications, thereby improving the prognosis and reducing the disease burden of the high-risk populations.

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Catalpol ameliorates endothelial dysfunction and inflammation in diabetic nephropathy via suppression of RAGE/RhoA/ROCK signaling pathway

Cited by 49 publications

References 29 publications

Correlation between Glucose/C-Peptide Ratio and the Risk of Disease Progression in Diabetic Nephropathy Patients: A Clinical Retrospective Analysis

Correlation between Glucose/C-Peptide Ratio and the Risk of Disease Progression in Diabetic Nephropathy Patients: A Clinical Retrospective Analysis

Investigating the molecular mechanisms of glyoxal‐induced cytotoxicity in human embryonic kidney cells: Insights from network toxicology and cell biology experiments

Prognosis and risk factors of chronic kidney disease progression in patients with diabetic kidney disease and non-diabetic kidney disease: a prospective cohort CKD-ROUTE study

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