Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update.

Molecular mechanisms in the pathogenesis of diabetic nephropathy: an update.

Diabetic nephropathy (DN) is one of the microvascular complications of the kidney arising commonly from type 1 diabetes mellitus (T1DM), and occasionally from type 2 diabetes mellitus (T2DM). Microalbuminuria serves as an early indicator of DN risk and a predictor of its progression as well as cardiovascular disease risk in both T1DM and T2DM. Although microalbuminuria remains the gold standard for early detection of DN, it is not a sufficiently accurate predictor of DN risk due to some limitations. Thus, there is a paradigm shift to novel biomarkers which would help to predict DN risk early enough and possibly prevent the occurrence of end-stage kidney disease. These new biomarkers have been broadly classified into glomerular biomarkers, tubular biomarkers, biomarkers of inflammation, biomarkers of oxidative stress, and miscellaneous biomarkers which also include podocyte biomarkers, some of which are also considered as tubular and glomerular biomarkers. Although they are potentially useful for the evaluation of DN, current data still preclude the routine clinical use of majority of them. However, their validation using high-quality and large longitudinal studies is of paramount importance, as well as the subsequent development of a biomarker panel which can reliably predict and evaluate this renal microvascular disease. This paper aims to review the predictive role of these biomarkers in the evaluation of DN.

https://www.dovepress.com/getfile.php?fileID=37980

The role of novel biomarkers in predicting diabetic nephropathy: a review

Diabetic nephropathy is a major cause of end-stage renal failure and the mortality rate due to this disease is continuously progressing worldwide. The multifaceted signalling mechanisms have been identified to be involved in the pathogenesis of diabetic nephropathy. Despite the modern therapies like antidiabetics, antihypertensives, and antioxidants available to treat diabetic nephropathy; most of patients continue to show progressive renal damage. It suggests that the key pathogenic mechanism involved in the induction and progression of diabetic nephropathy is still remaining active and unmodified by the present therapies. The purpose of this review is to bring together the current information concerning the signalling systems involved in the pathogenesis of diabetic nephropathy.

Pathophysiology of diabetic nephropathy: involvement of multifaceted signalling mechanism.

Mesaconitine (MA), one of the main diterpenoid alkaloids in Aconitum, has a variety of pharmacological effects, such as analgesia, anti-inflammation and relaxation of rat aorta. However, MA is a highly toxic ingredient. At present, studies on its toxicity are mainly focused on the heart and central nervous system, and there are few reports on the hepatotoxic mechanism of MA. Therefore, we evaluated the effects of MA administration on liver. SD rats were randomly divided into a normal saline (NS) group, a low-dose MA group (0.8 mg/kg/day) and a high-dose MA group (1.2 mg/kg/day). After 6 days of administration, the toxicity of MA on the liver was observed. Metabolomic and network toxicology methods were combined to explore the effect of MA on the liver of SD rats and the mechanism of hepatotoxicity in this study. Through metabonomics study, the differential metabolites of MA, such as L-phenylalanine, retinyl ester, L-proline and 5-hydroxyindole acetaldehyde, were obtained, which involved amino acid metabolism, vitamin metabolism, glucose metabolism and lipid metabolism. Based on network toxicological analysis, MA can affect HIF-1 signal pathway, MAPK signal pathway, PI3K-Akt signal pathway and FoxO signal pathway by regulating ALB, AKT1, CASP3, IL2 and other targets. Western blot results showed that protein expression of HMOX1, IL2 and caspase-3 in liver significantly increased after MA administration (p &lt; 0.05). Combined with the results of metabonomics and network toxicology, it is suggested that MA may induce hepatotoxicity by activating oxidative stress, initiating inflammatory reaction and inducing apoptosis. 

/pdf/study-on-the-mechanism-of-mesaconitine-induced-146o9o3j.pdf

Study on the Mechanism of Mesaconitine-Induced Hepatotoxicity in Rats Based on Metabonomics and Toxicology Network

Citrinin (CTN) is a mycotoxin found in crops and agricultural products and poses a serious threat to human and animal health. The aim of this study is to investigate the hepatotoxicity of CTN in mice and analyze its mechanisms from Ca2+-dependent endoplasmic reticulum (ER) stress perspective. We showed that CTN induced histopathological damage, caused ultrastructural changes in liver cells, and induced abnormal values of biochemical laboratory tests of some liver functions in mice. Treatment with CTN could induce nitric oxide (NO), malondialdehyde (MDA), and reactive oxygen species (ROS) accumulation in mice, accompanied with losses of activities of superoxide dismutase (SOD) and catalase (CAT), levels of glutathione (GSH), and capacities of total antioxidant (T-AOC), resulting in oxidative stress in mice. Furthermore, CTN treatment significantly increased Ca2+ accumulation, upregulated protein expressions of ER stress-mediated apoptosis signal protein (glucose regulated protein 78 (GRP78/BIP), C/EBP-homologous protein (CHOP), Caspase-12, and Caspase-3), and induced hepatocyte apoptosis. These adverse effects were counteracted by 4-phenylbutyric acid (4-PBA), an ER stress inhibitor. In summary, our results showed a possible underlying molecular mechanism for CTN that induced hepatocyte apoptosis in mice by the regulation of the Ca2+/ER stress signaling pathway.

/pdf/citrinin-induced-hepatotoxicity-in-mice-is-regulated-by-the-eapyrun2.pdf

Citrinin-Induced Hepatotoxicity in Mice Is Regulated by the Ca2+/Endoplasmic Reticulum Stress Signaling Pathway

In current study, the expressions of protein kinase C (PKC)-α, βI and βII as well as their correlation to the expression of transforming growth factor-βI (TGF-βI) and vascular endothelial growth factor (VEGF) were investigated in glomeruli of normal renal tissues taken from human kidney tumors and kidney tissues from patients with diabetic nephropathy (DN). The accumulation of glomerular extracelluar matrix (ECM) was determined by PAS staining, the expressions of PKC-α, PKC-βI, PKC-βII, TGF-βI and VEGF were measured by semi-quantitative immunohistochemistry. Our results showed that in glomeruli of normal renal tissues, PKC-α and βII had a strong expression whereas the expression of PKC-βI was weak; in glomeruli of DN patients, the expressions of PKC-α, PKC-βI, VEGF and TGF-βI and the accumulation of ECM increased significantly, but the expression of PKC-βII decreased markedly. Meanwhile, the expressions of PKC-α and βI had a positive correlation to the expressions of VEGF and TGF-βI respectively, whereas PKC-βII showed no correlation to VEGF and TGF-βI. It is concluded that the expressions of PKC-α, βI and βII in glomeruli of normal subjects and DN patients are different. PKC-α seems to play a critical role in human DN by up-regulating VEGF expression, whereas PKC-βI is relatively important for the up-regulation of TGF-βI and the accumulation of ECM under diabetic conditions.

Different expressions of protein kinase C-alpha, beta I and beta II in glomeruli of diabetic nephropathy patients.

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Citrinin-Induced Hepatotoxicity in Mice Is Regulated by the Ca2+/Endoplasmic Reticulum Stress Signaling Pathway

Different expressions of protein kinase C-alpha, beta I and beta II in glomeruli of diabetic nephropathy patients.