Browsing by Subject "Diabetic nephropathy"
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- PublicationOpen Access1,25-Dihydroxyvitamin D3 mitigates high glucose-induced oxidative stress, inflammation, and extracellular matrix accumulation in glomerular mesangial cells via the ROS/TXNIP/NLRP3 pathway(2026) Bo Chen; Chunjiang Zhang; Lin Jia; Xingyu Yao; Gang Liu; Qingyue Meng; Biología Celular e Histología; Universidad de Murcia, Departamento de Biologia Celular e Histiologiaackground. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is a physiologically active form of vitamin D. Our study investigated the renoprotective functions of 1,25(OH)2D3 in diabetic nephropathy (DN) progression and its underlying mechanism targeting the ROS/TXNIP/NLRP3 inflammasome pathway. Methods. DN was induced in Wistar rats via high-fat diet (4 weeks) and streptozotocin injection (30 mg/kg, i.p.); hyperglycemic rats were randomized into DN and DN + 1,25(OH)2D3 (16 μg/kg, 12 weeks) groups. Rat mesangial HBZY-1 cells were maintained under normal glucose (5.5 mM), high glucose (25 mM), high glucose plus 1,25(OH)2D3 (1-50 nM), or high glucose plus N acetylcysteine (NAC, 10 mM). Cell viability was assessed by the CCK-8 assay. Oxidative stress parameters (ROS via DCFH-DA fluorescence, MDA content, SOD activity) and pyroptosis markers (LDH release, PI/Hoechst 33342 nuclear staining) were quantified. Renal histopathology was performed using PAS and Masson trichrome staining. Biochemical analyses included serum creatinine, urea nitrogen, and 24h urinary protein quantification. Molecular profiling encompassed ELISA (IL-1β, IL-6, TNF-α, IL-18, fibronectin, collagen IV), RT-qPCR (NOX2, NOX4, NLRP3, ASC), western blotting (TXNIP, NLRP3, ASC, caspase-1, IL-1β, IL-18, collagen IV, fibronectin, laminin), and TXNIP immunofluorescence. Results. 1,25(OH)2D3 significantly attenuated high glucose-induced pathological alterations in HBZY-1 cells, including ROS overproduction, TXNIP upregulation, NLRP3 inflammasome activation, oxidative stress, inflammation, extracellular matrix (ECM) deposition, and pyroptotic cell death. Consistently, 1,25(OH)2D3 suppressed ROS/TXNIP/ NLRP3/caspase-1 signaling, ameliorated renal dysfunction, and mitigated histopathological damage in DN rats. Conclusion. 1,25(OH)2D3 confers renoprotection in DN by inhibiting the ROS/TXNIP/NLRP3 inflamma some axis, thereby suppressing oxidative stress, inflammatory cytokine production, ECM accumulation, and pyroptotic cell death in glomerular mesangial cells and renal tissues.
- PublicationOpen AccessCyclin-dependent kinase 5 as a potential therapeutic target to alleviate high glucose-induced podocyte apoptosis and hyperglycemia-induced renal injury in mice(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Zhao, Li; Gu, Wenjuan; He, Wenfang; Yang, Kaibi; Yang, Nan; Jia, YanqingBackground. Hyperglycemia is a risk factor for impaired renal function, including cellular metabolic disturbance, apoptosis, inflammation, and histologic lesion. This study aims to investigate the potential therapeutic targeting of cyclin-dependent kinase 5 (Cdk5) in hyperglycemia-induced podocyte dysfunction and renal damage. Methods. Cell viability and apoptosis of podocytes were assessed through CCK-8 and TUNEL staining, respectively, following exposure to normal glucose (NG; 5 mM), high glucose (HG; 30 mM), or treatment with Cdk5 inhibitors (trans-resveratrol, myricetin, salvianolic acid A, and BML-259). Diabetic mice were established by intraperitoneal injection of freshly streptozotocin (STZ), which was given at a dose of 35 mg/kg in five successive injections. Additionally, histochemical staining was employed to evaluate the morphologic lesion of the kidney. Results. Cdk5 was found to be activated by HG stimulation both in vitro and in vivo. Notably, the inhibition of Cdk5 effectively mitigated the podocyte dysfunction induced by HG, including growth inhibition, membrane damage, and apoptosis. The compounds Trans-resveratrol, myricetin, salvianolic acid A, and BML-259 exhibited low binding energy values of -8.032 kcal/mol, -8.693 kcal/mol, -8.743 kcal/mol, and -10.952 kcal/mol, respectively, indicating strong and stable binding affinity between these candidates and Cdk5. The results of in vivo experimental analysis demonstrate that Cdk5 inhibitors, namely trans-resveratrol, myricetin, salvianolic acid A, and BML-259, confer protection against tubular and glomerular lesions induced by hyperglycemia. Conclusion. Both myricetin and BML-259 exhibit comparable protective effects on renal injury by inhibiting Cdk5
- PublicationOpen AccessDiabetic nephropathy inflammation, hyaluronan and interstitial fibrosis(Murcia : F. Hernández, 2008) Lewis, Aled; Steadman, Robert; Manley, Paul; Craig, Kathrine; Motte, Carol de la; Hascall, Vicent; Phillips, Aled O.Hyaluronan (HA) is a ubiquitous connective tissue glycosaminoglycan component of most extracellular matrices and alterations in its synthesis have been suggested to be involved in the glomerular changes of diabetic nephropathy. Similarly it has been suggested that macrophages are involved in the initiation of diabetic glomerular injury. Much less is known regarding the role of the prognostic value of changes in interstitial HA and interstitial inflammatory infiltrate. The aim of this study was to examine the potential association of inflammatory infiltrate, deposition of the matrix component hyaluronan and inter-alpha inhibitor (which is involved in HA assembly) and clinical outcome in diabetic nephropathy. Histological specimens of 40 patients with biopsy proven diabetic nephropathy were examined. Based on the rate of change in estimated GFR (eGFR, abbreviated MDRD formula), patients were defined as late presenters, progressors or non-progressors. The degree of interstitial fibrosis was associated with progression of disease and late presentation. There was a significant greater number of CD68-positive cells in the interstitium of patients who subsequently developed progressive renal disease, or those who presented with advanced disease compared to nonprogressors. In contrast, there was significant staining for interstitial HA in all the patient groups. Furthermore there was no correlation between the accumulation of HA and CD68-positive macrophages. In addition all patients with biopsy-proven diabetic nephropathy had significantly greater interstitial IaI compared to the normal controls and there was a significant correlation between interstitial HA and IaI. Increased HA is seen at all stages of diabetic change in the kidney but is not predictive of progression. Macrophage influx, however, is directly related to the progression of diabetic nephropathy and is not associated with HA accumulation.
- PublicationOpen AccessDiabetic nephropathy: The central role of renal proximal tubular cells in tubulointerstitial injury(Murcia : F. Hernández, 2002) Phillips, A.O.; Steadman, R.Diabetic nephropathy is now the commonest cause of end stage renal disease and accounts for 30- 40% of all patients requiring renal replacement therapy. Furthermore, the incidence of diabetic nephropathy continues to increase, in part due to the improved survival of type 2 diabetic patients as the cardiovascular mortality in this group declines (Ritz and Stefanski, 1996). Clinically incipient nephropathy is first manifest by the onset of persistent microalbuminuria, after which, overt diabetic nephropathy is heralded by the appearance of persistent proteinuria. Subsequently, there is a progressive decline in glomerular filtration rate (GFR) resulting, within 5 years, in end stage renal disease in 50% of patients (Hasslacher et al., 1989). The pathology of the renal lesions are similar in type I and II diabetes ( Taft et al., 1994), although it has been suggested that there is more heterogeneity in type II diabetes (Chihara et al., 1986). Studies analysing structural-functional relationships have demonstrated that the development of proteinuria correlates with the degree of mesangial expansion (Mauer et al., 1984; White and Bilous, 2000). Although diabetic nephropathy was traditionally considered a primarily glomerular disease, it is now widely accepted that the rate of deterioration of function correlates best with the degree of renal tubulointerstitial fibrosis (Mauer et al., 1984, Bohle et al., 1991). This suggests that although in the majority of patients the primary event is a condition manifest by glomerular changes resulting in proteinuria, the long-term outcome is determined by events in the renal interstitium. Wi t h the increasing awareness of the importance of these pathological interstitial changes, interest has focused on the role of cells, such as the epithelial cells of the proximal tubule (PTC) or the interstitial myofibroblast, in the initiation of fibrosis. The aim of the present review is to analyse the available data supporting the role for the PTC in orchestrating renal interstitial fibrosis in diabetic nephropathy as a result of glucose-dependent alterations in PTC function. The potential for subsequent e ffects on PTC-fibroblast cross-talk will also be considered.
- PublicationOpen AccessMoringa isothiocyanate-1 mitigates the damage of oxidative stress and apoptosis in diabetic nephropathy mice(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Hua, Zhou; Deng, Jiuhong; Wang, GuiyingObjective. Diabetic nephropathy (DN) is a prevalent cause of end-stage kidney disease worldwide. Moringa isothiocyanate-1 (MIC-1) has shown potential for DN management, however, the exact mechanisms remain unclear. This research intended to evaluate the impact and mechanism of MIC-1 on DN. Methods. Six C57BLKS/J-db/m mice served as controls. Eighteen C57BLKS/J-db/db mice were randomly separated into three groups: db/db, db/db + irbesartan (IBS), and db/db + MIC-1. Three weeks post-drug administration, the body weight and kidney weight of mice in each group were measured. Concurrently, serum creatinine (Scr), urine albumin, insulin, glycosylated hemoglobin (GHb), oxidative stress-, and inflammatory-related factors were determined. Additionally, the pathological injury, apoptosis, apoptosis-related markers, NLRP3, and ASC levels in the kidney tissues were examined utilizing H&E, Masson, PAS, TUNEL staining, and Western blot. Results. MIC-1 decreased the body weight, kidney weight, the levels of Glu, Scr, and urine albumin in db/db mice. Moreover, MIC-1 significantly suppressed the levels of MDA, insulin, GHb, TNF-α, IL-1β, and IL-6, while increased the activities of SOD, CAT, and GPX in the serum of db/db mice. MIC-1 also mitigated the kidney tissue injury in db/db mice. Western blot assay showed that MIC-1 enhanced the Bcl-2 level and suppressed the Bax, cleaved caspase-3, cleaved caspase-9, NLRP3, ASC, and caspase-1 levels of the kidney tissues in db/db mice. Conclusions. MIC-1 ameliorated the kidney injury in DN mice, and its mechanism may be associated with the suppression of renal cell apoptosis, oxidative stress, and inflammatory responses.
- PublicationOpen AccessRole of Smad1 in diabetic nephropathy: Molecular mechanisms and implications as a diagnostic marker(Murcia: F. Hernández, 2011) Abe, H.; Matsubara, Takeshi; Arai, Hidenori; Doi, ToshioDiabetic nephropathy (DN) is the leading cause of chronic kidney failure. Moreover, DN is associated with elevated cardiovascular morbidity and mortality. DN is characterized by progressive expansion of the mesangial matrix and thickening of the glomerular basement membrane, resulting in the obliteration of glomerular capillaries. Advanced glycation endproducts (AGEs) produced as the result of hyperglycemia are known to stimulate the production of extracellular matrix (ECM) proteins, resulting in glomerulosclerosis. Exposure of cultured mesangial cells to AGEs results in a receptor-mediated upregulation of mRNA and protein secretion of type IV collagen (Col4), which is a major component of ECM. Here we review recent novel insights into the pathogenesis and diagnosis of DN, with a special emphasis on the emerging concept that diabetic glomerulosclerosis can result from activation of the signaling cascade leading to irreversible ECM overproduction. Finally, we describe signaling pathways involved in the initial change of DN and how these pathways can be manipulated for therapeutic benefit.
- PublicationOpen AccessSignaling pathways in diabetic nephropathy(Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Kawanami, Daiji; Matoba, Keiichiro; Utsunomiya, KazunoriDiabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), however, specific treatment for DN has not yet been elucidated. Therefore, it is critically important to understand the molecular mechanism underlying DN to develop cause-related therapeutic strategy. To date, various factors such as hemodynamic changes and metabolic pathways have been shown to be involved in the pathogenesis of DN. Excessive glucose influx activates cellular signaling pathways, including the diacylglycerol (DAG)-protein kinase C (PKC) pathway, advanced glycation endproducts (AGE), polyol pathway, hexosamine pathway and oxidative stress. These factors interact with one another, thereby facilitating inflammatory processes, leading to the development of glomerulosclerosis under diabetic conditions. In addition to metabolic pathways, Rho-kinase, an effector of small-GTPase binding protein Rho, has been implicated as an important factor in the pathogenesis of DN. A number of studies have demonstrated that Rho-kinase plays key roles in the development of DN by inducing endothelial dysfunction, mesangial excessive extracellular matrix (ECM) production, podocyte abnormality, and tubulointerstitial fibrosis. In this review article, we describe our current understanding of the signaling pathways in DN.
- PublicationOpen AccessTreatment of berberine alleviates diabetic nephropathy by reducing iron overload and inhibiting oxidative stress(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Wang, Yujing; Yue, Shuling; Cai, Feng; Zhu, Wen; Zhong, Yuxiang; Chen, Juanjuan; Li, ChunyunDiabetic nephropathy (DN) has become one of the major fatal factors in diabetic patients. The aim of this study was to elucidate the function and mechanism by which berberine exerts renoprotective effects in DN. In this work, we first demonstrated that urinary iron concentration, serum ferritin and hepcidin levels were increased and total antioxidant capacity was significantly decreased in DN rats, while these changes could be partially reversed by berberine treatment. Berberine treatment also alleviated DN-induced changes in the expression of proteins involved in iron transport or iron uptake. In addition, berberine treatment also partially blocked the expression of renal fibrosis markers induced by DN, including MMP2, MMP9, TIMP3, β-arrestin-1, and TGF-β1. In conclusion, the results of this study suggest that berberine may exert renoprotective effects by ameliorating iron overload and oxidative stress and reducing DN