scholarly journals The Role of TLR4 on PGC-1α-Mediated Oxidative Stress in Tubular Cell in Diabetic Kidney Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Shuguang Yuan ◽  
Xuemei Liu ◽  
Xuejing Zhu ◽  
Zhong Qu ◽  
Zailiang Gong ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cytochrome C ◽  
Oxidative Damage ◽  
Mitochondrial Dysfunction ◽  
Diabetic Kidney Disease ◽  
Caspase 3 ◽  
Tubular Cell ◽  
Renal Tubules ◽  
Diabetic Mice ◽  
Diabetic Kidney

The role and precise mechanism of TLR4 in mitochondria-related oxidative damage and apoptosis of renal tubules in diabetic kidney disease (DKD) remain unclear. We examined the expression of TLR4 in renal biopsy tissues. Db/db diabetic mice and HK-2 cells cultured under high glucose (HG) were used as in vivo and vitro models. Real-time RT-PCR, Western blot, and immunohistochemistry were performed to examine the mRNA and protein levels of TLR4, NF-κΒ, PGC-1α, cytochrome C, and cleaved caspase-3. ATP level, activity of electron transport chain complex III, and antioxidant enzymes were investigated for mitochondrial function. Electron microscopy (EM) and MitoTracker Red CMXRos were used for mitochondrial morphology alteration. DHE staining and TUNEL assay were detected for ROS accumulation and apoptosis. PGC-1α plasmids were used for the overexpression of PGC-1α in HK-2. TAK242 and parthenolide were used as TLR4 and NF-κB blockers, respectively. Results showed that TLR4 was extensively expressed in the renal tubules of DKD patients and db/db diabetic mice, which was positively related to the tubular interstitial damage score and urinary β-NAG levels. In diabetic mice, inhibition of TLR4 could reverse the decreased expression of PGC-1α, increased expression of cytochrome C and cleaved caspase-3, mitochondrial dysfunction and deformation, increased accumulation of ROS, and activation of tubular cell apoptosis. In vitro, inhibition of TLR4 or NF-κB showed consistent results. PGC-1α overexpression could reverse the mitochondrial dysfunction, increased cleaved caspase-3, and apoptosis in HK-2 cells treated with HG. Data indicated that the TLR4/NF-κB signaling pathway might be the upstream pathway of PGC-1α and promote the tubular damage of DKD by modulating the mitochondria-related oxidative damage and apoptosis.

Abstract 016: Profound and Sustained Amplification of Circulating ACE2 Activity Does Not Protect Diabetic Mice from Kidney Disease

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Jan Wysocki ◽  
Minghao Ye ◽  
Ahmed M Khattab ◽  
Yashpal Kanwar ◽  
Mark Osborn ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Over Expression ◽  
Akita Mice

ACE2 is a monocarboxypeptidase that by converting AngII to Ang1-7 should down-regulate the renin-angiotensin system and therefore provide a means to therapeutically target diabetic kidney disease, a condition where the kidney RAS is overactive. Previous work indicated that soluble human recombinant (r)ACE2 administration for 4 weeks attenuated kidney injury in diabetic Akita mice. Whether such effect of rACE2 can be confirmed and attributed to augmented ACE2 activity is uncertain because chronic use of human rACE2 in mice induces immunogenicity and the development of antibodies that neutralize serum ACE2 activity. To examine the effect of chronic amplification of circulating ACE2 on kidney injury caused by STZ-induced diabetes and to circumvent the immunogenicity arising from xenogeneic ACE2, ACE2 of mouse origin was administered to mice using either daily i.p. injections (1 mg/kg) of mrACE2 for 4 weeks or after 20 weeks of ACE2 mini-circle (MC) (10-30ug/mouse) administration. MC provides a form of gene delivery that is resistant to gene silencing and, in addition, greatly optimizes long-term in vivo overexpression of proteins of interest. ACE2MC resulted in a profound and sustained increase in serum ACE2 activity (2.4±0.3 vs. 497±135 RFU/ul/hr, p<0.01) but kidney ACE2 activity was unchanged (17.4±1.3 vs. 19.0±0.8 RFU/ug prot/hr). mACE2-treated mice injected with STZ developed diabetes similar to sham mice injected with STZ. Systolic BP was not different between non-diabetic mice, sham STZ-mice, and STZ-mice receiving mACE2 by either i.p. mrACE2 or ACE2MC. Urinary albumin was similarly increased in sham STZ-mice and in STZ-mice receiving mACE2. Glomerular mesangial score and glomerular cellularity were both increased to a similar extent in sham STZ-mice and in STZ-mice with mACE2 administration, as compared to non-diabetic controls. In conclusion, profound and long-term augmentation of ACE2 activity confined to the circulation is not sufficient to attenuate glomerular pathology and albuminuria in STZ-induced diabetic kidney disease probably because of lack of kidney delivery of ACE2. Strategies to achieve over-expression of ACE2 at the kidney level are needed to demonstrate a beneficial effect of this enzyme on diabetic kidney disease.

scholarly journals MMP-10 is Increased in Early Stage Diabetic Kidney Disease and can be Reduced by Renin-Angiotensin System Blockade

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
José María Mora-Gutiérrez ◽  
José Antonio Rodríguez ◽  
María A. Fernández-Seara ◽  
Josune Orbe ◽  
Francisco Javier Escalada ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Early Stage ◽  
Renin Angiotensin System ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Angiotensin System ◽  
Diabetic Kidney ◽  
Renin Angiotensin

AbstractMatrix metalloproteinases have been implicated in diabetic microvascular complications. However, little is known about the pathophysiological links between MMP-10 and the renin-angiotensin system (RAS) in diabetic kidney disease (DKD). We tested the hypothesis that MMP-10 may be up-regulated in early stage DKD, and could be down-regulated by angiotensin II receptor blockade (telmisartan). Serum MMP-10 and TIMP-1 levels were measured in 268 type 2 diabetic subjects and 111 controls. Furthermore, histological and molecular analyses were performed to evaluate the renal expression of Mmp10 and Timp1 in a murine model of early type 2 DKD (db/db) after telmisartan treatment. MMP-10 (473 ± 274 pg/ml vs. 332 ± 151; p = 0.02) and TIMP-1 (573 ± 296 ng/ml vs. 375 ± 317; p < 0.001) levels were significantly increased in diabetic patients as compared to controls. An early increase in MMP-10 and TIMP-1 was observed and a further progressive elevation was found as DKD progressed to end-stage renal disease. Diabetic mice had 4-fold greater glomerular Mmp10 expression and significant albuminuria compared to wild-type, which was prevented by telmisartan. MMP-10 and TIMP-1 are increased from the early stages of type 2 diabetes. Prevention of MMP-10 upregulation observed in diabetic mice could be another protective mechanism of RAS blockade in DKD.

scholarly journals Effects of Pentoxifylline on Soluble Klotho Concentrations and Renal Tubular Cell Expression in Diabetic Kidney Disease

Diabetes Care ◽  
2018 ◽  
Vol 41 (8) ◽  
pp. 1817-1820 ◽  
Author(s):  
Juan F. Navarro-González ◽  
María Dolores Sánchez-Niño ◽  
Javier Donate-Correa ◽  
Ernesto Martín-Núñez ◽  
Carla Ferri ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Diabetic Kidney ◽  
Renal Tubular ◽  
Cell Expression

scholarly journals Glomerular Endothelial Mitochondrial Dysfunction Is Essential and Characteristic of Diabetic Kidney Disease Susceptibility

Diabetes ◽  
2016 ◽  
Vol 66 (3) ◽  
pp. 763-778 ◽  
Author(s):  
Haiying Qi ◽  
Gabriella Casalena ◽  
Shaolin Shi ◽  
Liping Yu ◽  
Kerstin Ebefors ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Diabetic Kidney Disease ◽  
Disease Susceptibility ◽  
Diabetic Kidney

scholarly journals Mitochondrial Regulation of Diabetic Kidney Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Daniel L. Galvan ◽  
Koki Mise ◽  
Farhad R. Danesh
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Diabetic Kidney Disease ◽  
Mitochondrial Morphology ◽  
Mitochondria Dysfunction ◽  
Diabetic Kidney ◽  
Mitochondrial Regulation ◽  
Mitochondrial Remodeling ◽  
Remarkable Progress

The role and nature of mitochondrial dysfunction in diabetic kidney disease (DKD) has been extensively studied. Yet, the molecular drivers of mitochondrial remodeling in DKD are poorly understood. Diabetic kidney cells exhibit a cascade of mitochondrial dysfunction ranging from changes in mitochondrial morphology to significant alterations in mitochondrial biogenesis, biosynthetic, bioenergetics and production of reactive oxygen species (ROS). How these changes individually or in aggregate contribute to progression of DKD remain to be fully elucidated. Nevertheless, because of the remarkable progress in our basic understanding of the role of mitochondrial biology and its dysfunction in DKD, there is great excitement on future targeted therapies based on improving mitochondrial function in DKD. This review will highlight the latest advances in understanding the nature of mitochondria dysfunction and its role in progression of DKD, and the development of mitochondrial targets that could be potentially used to prevent its progression.

scholarly journals S-Nitrosylation of RhoGAP Myosin9A Is Altered in Advanced Diabetic Kidney Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Qi Li ◽  
Delma Veron ◽  
Alda Tufro
Keyword(s):  
Kidney Disease ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Diabetic Mice ◽  
Post Translational Modification ◽  
No Donor ◽  
Diabetic Kidney ◽  
Rhoa Activity

The molecular pathogenesis of diabetic kidney disease progression is complex and remains unresolved. Rho-GAP MYO9A was recently identified as a novel podocyte protein and a candidate gene for monogenic FSGS. Myo9A involvement in diabetic kidney disease has been suggested. Here, we examined the effect of diabetic milieu on Myo9A expression in vivo and in vitro. We determined that Myo9A undergoes S-nitrosylation, a post-translational modification dependent on nitric oxide (NO) availability. Diabetic mice with nodular glomerulosclerosis and severe proteinuria associated with doxycycline-induced, podocyte-specific VEGF164 gain-of-function showed markedly decreased glomerular Myo9A expression and S-nitrosylation, as compared to uninduced diabetic mice. Immortalized mouse podocytes exposed to high glucose revealed decreased Myo9A expression, assessed by qPCR, immunoblot and immunocytochemistry, and reduced Myo9A S-nitrosylation (SNO-Myo9A), assessed by proximity link assay and biotin switch test, functionally resulting in abnormal podocyte migration. These defects were abrogated by exposure to a NO donor and were not due to hyperosmolarity. Our data demonstrate that high-glucose induced decrease of both Myo9A expression and SNO-Myo9A is regulated by NO availability. We detected S-nitrosylation of Myo9A interacting proteins RhoA and actin, which was also altered by high glucose and NO dependent. RhoA activity inversely related to SNO-RhoA. Collectively, data suggest that dysregulation of SNO-Myo9A, SNO-RhoA and SNO-actin may contribute to the pathogenesis of advanced diabetic kidney disease and may be amenable to therapeutic targeting.

scholarly journals LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

2019 ◽  
Vol 30 (4) ◽  
pp. 546-562 ◽  
Author(s):  
Quan Hong ◽  
Lu Zhang ◽  
Jia Fu ◽  
Divya A. Verghese ◽  
Kinsuk Chauhan ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Cells ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Renal Outcome ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Genetic Ablation ◽  
Glomerular Endothelial Cells

BackgroundGlomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich α-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-β/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1’s role in the kidney, particularly in the setting of DKD, has been unclear.MethodsWe analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.ResultsLRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.ConclusionsThese findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.

scholarly journals Mitochondrial DNA: A New Predictor of Diabetic Kidney Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Yajing Huang ◽  
Jingwei Chi ◽  
Fanxiang Wei ◽  
Yue Zhou ◽  
Yihai Cao ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Large Scale ◽  
Diabetic Kidney Disease ◽  
Endothelial Damage ◽  
Inflammatory Factors ◽  
Mtdna Copy Number ◽  
Diabetic Kidney ◽  
Patients With Diabetes ◽  
Stage Renal Disease

Diabetic kidney disease (DKD) is a common cause of end-stage renal disease, and diagnosis and treatment in time can help delay its progress. At present, there are more and more studies on the pathogenesis of DKD; mitochondrial dysfunction plays an important role in DKD. The occurrence and development of DKD is closely related to epigenetic changes and the interaction between mtDNA, ROS, inflammatory factors, and endothelial damage, which continuously aggravates kidney. The change of mtDNA is both the cause of DKD and the result of DKD. It is of great significance to incorporate the change of mtDNA into the monitoring of patients with diabetes. Existing evidence indicates that changes in mtDNA copy number in blood and urine reflect mitochondrial dysfunction and the severity of DKD. However, large-scale, long-term follow-up clinical trials are still needed to determine the threshold range. By the time, mitochondrial-targeted antioxidants will become a new method for the treatment of DKD and other diabetic complications; mtDNA also can be a therapeutic target for them.

Sign in / Sign up

Export Citation Format

Share Document