scholarly journals Relationship between lysosomal dyshomeostasis and progression of diabetic kidney disease

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Man Wu ◽  
Minjie Zhang ◽  
Yaozhi Zhang ◽  
Zixian Li ◽  
Xingyu Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Cell Metabolism ◽  
Renal Diseases ◽  
Future Research ◽  
Lysosomal Function ◽  
Diabetic Kidney ◽  
Effective Interventions ◽  
Proximal Tubular Epithelial Cells ◽  
And Function

AbstractLysosomes are organelles involved in cell metabolism, waste degradation, and cellular material circulation. They play a key role in the maintenance of cellular physiological homeostasis. Compared with the lysosomal content of other organs, that of the kidney is abundant, and lysosomal abnormalities are associated with the occurrence and development of certain renal diseases. Lysosomal structure and function in intrinsic renal cells are impaired in diabetic kidney disease (DKD). Promoting lysosomal biosynthesis and/or restoring lysosomal function can repair damaged podocytes and proximal tubular epithelial cells, and delay the progression of DKD. Lysosomal homeostasis maintenance may be advantageous in alleviating DKD. Here, we systematically reviewed the latest advances in the relationship between lysosomal dyshomeostasis and progression of DKD based on recent literature to further elucidate the mechanism of renal injury in diabetes mellitus and to highlight the application potential of lysosomal homeostasis maintenance as a new prevention and treatment strategy for DKD. However, research on screening effective interventions for lysosomal dyshomeostasis is still in its infancy, and thus should be the focus of future research studies. The screening out of cell-specific lysosomal function regulation targets according to the different stages of DKD, so as to realize the controllable targeted regulation of cell lysosomal function during DKD, is the key to the successful clinical development of this therapeutic strategy.

scholarly journals Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

2021 ◽  
Vol 10 (10) ◽  
pp. 2046
Author(s):  
Goren Saenz-Pipaon ◽  
Saioa Echeverria ◽  
Josune Orbe ◽  
Carmen Roncal
Keyword(s):  
Kidney Disease ◽  
Extracellular Vesicles ◽  
Diabetic Kidney Disease ◽  
Current Knowledge ◽  
Developed Countries ◽  
Disease Diagnosis ◽  
Renal Diseases ◽  
Diabetic Kidney ◽  
Glucose Levels ◽  
Stage Renal Disease

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in developed countries, affecting more than 40% of diabetes mellitus (DM) patients. DKD pathogenesis is multifactorial leading to a clinical presentation characterized by proteinuria, hypertension, and a gradual reduction in kidney function, accompanied by a high incidence of cardiovascular (CV) events and mortality. Unlike other diabetes-related complications, DKD prevalence has failed to decline over the past 30 years, becoming a growing socioeconomic burden. Treatments controlling glucose levels, albuminuria and blood pressure may slow down DKD evolution and reduce CV events, but are not able to completely halt its progression. Moreover, one in five patients with diabetes develop DKD in the absence of albuminuria, and in others nephropathy goes unrecognized at the time of diagnosis, urging to find novel noninvasive and more precise early diagnosis and prognosis biomarkers and therapeutic targets for these patient subgroups. Extracellular vesicles (EVs), especially urinary (u)EVs, have emerged as an alternative for this purpose, as changes in their numbers and composition have been reported in clinical conditions involving DM and renal diseases. In this review, we will summarize the current knowledge on the role of (u)EVs in DKD.

scholarly journals Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Dong-Yuan Chang ◽  
Xiao-Qian Li ◽  
Min Chen ◽  
Ming-Hui Zhao
Keyword(s):  
Kidney Disease ◽  
Protective Effect ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Membrane Attack Complex ◽  
Sglt2 Inhibitors ◽  
Tubulointerstitial Injury ◽  
Diabetic Kidney ◽  
Proximal Tubular Epithelial Cells ◽  
Complement Regulator

Sodium-glucose cotransporter 2(SGLT2) inhibitors show prominent renal protective effect in diabetic kidney disease (DKD), anti-inflammatory effect being one of its key mechanisms. Over-activation of the complement system, a crucial part of innate immunity, plays an important role in DKD. We aimed to investigate the effect of SGLT2 inhibitors on alleviating complement over-activation in DKD. Db/db mice were randomly divided into two groups, with 7 mice in each group treated with dapagliflozin and vehicle respectively, and 7 mice in m/m mice group. Laboratory and renal pathological parameters were evaluated. Mouse proximal tubular epithelial cells (MPTECs) were cultured and treated with high glucose. Dapagliflozin and dimethyloxallyl glycine (DMOG) were added as conditional treatment. Dapagliflozin-treated db/db mice showed significantly lower urinary albumin than vehicle-treated ones. Besides typical glomerular and tubulointerstitial injury, both C3b and membrane attack complex (MAC) depositions were significantly attenuated in dapagliflozin-treated db/db mice. The expression of complement receptor type 1-related protein y (Crry), a key complement regulator which inhibits complement over-activation, was significantly upregulated by dapagliflozin. Dapagliflozin-mediated Crry upregulation was associated with inhibition of HIF-1α accumulation under high glucose. When HIF-1α expression was stabilized by DMOG, the protective effect of dapagliflozin via upregulating Crry was blocked. In conclusion, dapagliflozin could attenuate complement over-activation in diabetic mice via upregulating Crry, which is associated with the suppression of HIF-1α accumulation in MPTECs.

scholarly journals IL33/ST2 Axis in Diabetic Kidney Disease: A Literature Review

Medicina ◽  
2019 ◽  
Vol 55 (2) ◽  
pp. 50 ◽  
Author(s):  
Alessandro Tonacci ◽  
Paolina Quattrocchi ◽  
Sebastiano Gangemi
Keyword(s):  
Kidney Disease ◽  
Literature Review ◽  
Diabetic Kidney Disease ◽  
Inflammatory Diseases ◽  
Th2 Cells ◽  
Renal Diseases ◽  
Diabetic Kidney ◽  
Interleukin 33 ◽  
Endothelial Barriers ◽  
Barrier Tissues

Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, playing a role in inflammatory, infectious and autoimmune diseases and expressed in the cellular nucleus in several tissues. High levels of IL-33 are expressed in epithelial barrier tissues and endothelial barriers. ST2 is a receptor for IL-33, expressed selectively on a subset of Th2 cells, mediating some of their functions. The IL-33/ST2 axis plays an important role in several acute and chronic inflammatory diseases, including asthma and rheumatoid arthritis. Different disorders are related to the activity of IL-33, ST2, or their axis, including cardiovascular disease or renal disturbances. Therefore, in the present work, a literature review was conducted, covering the period from 1 January 2000 to 30 November 2018, in PubMed, ScienceDirect, and Google Scholar database, to assess the involvement of the IL-33/ST2 axis in diabetic kidney disease. 6 articles directly dealing with the argument were identified, highlighting a clear link between IL-33/ST2 axis and diabetic kidney disease or related nephropathy. Overall, the involvement of ST2 seems to be more predictive than IL-33, especially in investigating the deterioration of kidney function; however, both compounds are pivotal in the field of renal diseases. Future studies are required to confirm the scientific evidences on larger and more heterogeneous cohorts.

scholarly journals Tgm2-p62-p53 Complex May Function as an Autophagic Regulator Through Fyn and Involve in Diabetic Kidney Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A442-A443
Author(s):  
Ryota Uehara ◽  
Eijiro Yamada ◽  
Masaya Uehara ◽  
Yasuyo Nakajima ◽  
Kazuhiko Horiguchi ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Energy Levels ◽  
Transglutaminase 2 ◽  
Energy Status ◽  
P53 Expression ◽  
Diabetic Kidney ◽  
Proximal Tubular Epithelial Cells ◽  
Microscopic Studies ◽  
Hk2 Cells

Abstract Diabetic kidney disease (DKD) is one of the major diabetic complications and the leading cause of the end stage renal disease. Recently autophagy was shown to regulate DKD. Previously we reported that Fyn regulates muscle mass by suppressing autophagy through Fyn-STAT3-VPS34 signaling pathway. More recently, we demonstrated that Fyn also down-regulates autophagy in HK2 cells, an in vitrocell model of renal proximal tubular epithelial cells (RPTC). Phospho-proteomic analysis revealed that Fyn phosphorylates Transglutaminase 2 (Tgm2), a known autophagic inhibitor, at Y369 and Y617. Moreover, we found that Fyn-dependent phosphorylation of Tgm2 regulates autophagy. It has been reported that Tgm2 forms complexes with p53 and p62 (a known autophagy regulator) to mediate degradation of p53 at autophagosome in cancer cells and p53 functions as a DKD inducer. We found that p53 expression was decreased in Tgm2 knock-downed HK2 cells suggesting that Tgm2-p62-p53 complex also modulates autophagy in RPTC. We previously showed that Fyn and autophagy is regulated by energy status, therefore we next examined whether energy levels changed the subcellular localization of p53, p62 and Tgm2 in HK2 cells in vivousing the marker, Aquaporin 1. Confocal microscopic studies revealed that ad libitum-fed mice showed increased punctate of p62 in RPTC suggesting that autophagy was reduced. Fyn, Tgm2 and p53 shaped the dotted form mainly in the basement membrane of the cells. Interestingly, all these molecules moved to the cytoplasm in fasted state, where decreased p62 punctations were observed indicating increased autophagy. More importantly, in HFD fed mice, diet-induced rodent models of metabolic disorders, we found that protein expression of p53 was increased due to decreased levels of degradation with inhibition of autophagy implicated by decreased p62 punctations in RPTC. Taken together, these data suggest that the metabolic status may regulate Fyn to not only phosphorylate Tgm2 and modulates Tgm2-p62-p53 complex but also change their co-localizations of Fyn, p53 and Tgm2 in RPTC to regulate autophagy leading to pathogenesis of DKD.

Elevated Serum Levels of Carbohydrate Antigen 72–4 in Diabetic Kidney Disease

2021 ◽  
Author(s):  
Lei Shi ◽  
Jiali Meng ◽  
Bin Zhang ◽  
Jiandong Chen ◽  
Jianzhong Chen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Elevated Serum ◽  
Serum Levels ◽  
Carbohydrate Antigen ◽  
Urinary Albumin ◽  
Renal Diseases ◽  
Diabetic Patients ◽  
Healthy Controls ◽  
Diabetic Kidney

AbstractThe aim of this study was to determine whether carbohydrate antigen 72–4 (CA72–4) is elevated in diabetic kidney disease (DKD), and examine the association between urinary albumin-to-creatinine ratio (UACR) and CA72–4 in patients with type 2 diabetes mellitus (T2DM). Non-dialysis patients with T2DM (n=296) and 90 healthy controls were recruited in this study. CA72–4 level was measured by electrochemiluminescence immunoassay. DKD was defined as UACR≥ 30 mg/g in the absence of a urinary infection or other renal diseases. We found that patients with DKD had significantly higher serum CA72–4 levels compared to those with normoalbuminuria and healthy controls. Positive rates of CA72–4 increased gradually and markedly from normoalbuminuria to microalbuminuria and to macroalbuminuria in diabetic patients (7.5, 11.2, and 17.4%, respectively; P for trend< 0.05). CA72–4 also showed a positive correlation with UACR (r=0.288, P< 0.01). Logistic regression analysis revealed the association of increased UACR with an increased odds ratio of elevation of CA72–4 levels (P for trend< 0.05) after multivariable adjustment. In conclusion, serum levels of CA72–4 increase abnormally with the increase in urinary albumin excretion, which affects the specificity of diagnosis of malignancies. An appropriate interpretation of CA72–4 is essential to prevent unnecessary and even hazardous diagnostic procedures in patients with T2DM.

scholarly journals Therapeutic Targeting of SGLT2: A New Era in the Treatment of Diabetes and Diabetic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
James Shaffner ◽  
Bohan Chen ◽  
Deepak K. Malhotra ◽  
Lance D. Dworkin ◽  
Rujun Gong
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Therapeutic Potential ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Metabolic Reprogramming ◽  
Therapeutic Modality ◽  
Future Research ◽  
Bodyweight Loss ◽  
Diabetic Kidney

As the prevalence of diabetic kidney disease (DKD) continues to rise, so does the need for a novel therapeutic modality that can control and slow its progression to end-stage renal disease. The advent of sodium-glucose cotransporter-2 (SGLT2) inhibitors has provided a major advancement for the treatment of DKD. However, there still remains insufficient understanding of the mechanism of action and effectiveness of this drug, and as a result, its use has been very limited. Burgeoning evidence suggests that the SGLT2 inhibitors possess renal protective activities that are able to lower glycemic levels, improve blood pressure/hemodynamics, cause bodyweight loss, mitigate oxidative stress, exert anti-inflammatory and anti-fibrotic effects, reduce urinary albumin excretion, lower uric acid levels, diminish the activity of intrarenal renin-angiotensin-aldosterone system, and reduce natriuretic peptide levels. SGLT2 inhibitors have been shown to be safe and beneficial for use in patients with a GFR ≥30mL/min/1.73m2, associated with a constellation of signs of metabolic reprogramming, including enhanced ketogenesis, which may be responsible for the correction of metabolic reprogramming that underlies DKD. This article aims to provide a comprehensive overview and better understanding of the SGLT2 inhibitor and its benefits as it pertains to renal pathophysiology. It summarizes our recent understanding on the mechanisms of action of SGLT2 inhibitors, discusses the effects of SGLT2 inhibitors on diabetes and DKD, and presents future research directions and therapeutic potential.

scholarly journals Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Riccardo Pofi ◽  
Daniela Fiore ◽  
Rita De Gaetano ◽  
Giuseppe Panio ◽  
Daniele Gianfrilli ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Renal Hemodynamics ◽  
Diabetic Kidney ◽  
And Function ◽  
Phosphodiesterase 5

scholarly journals Lysosome restoration to activate podocyte autophagy: a new therapeutic strategy for diabetic kidney disease

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Wei Jing Liu ◽  
Yu Gan ◽  
Wei Fang Huang ◽  
Hong-luan Wu ◽  
Xue-qin Zhang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Degradation Process ◽  
Beclin 1 ◽  
Dependent Manner ◽  
Lysosomal Function ◽  
Diabetic Kidney ◽  
Glycation End Products

Abstract Autophagy, the intracellular lysosomal degradation process plays a pivotal role in podocyte homeostasis in diabetic kidney disease (DKD). Lysosomal function, autophagic activity, and their actions were investigated in vitro and in vivo. We found that LC3-II- and p62-positive vacuoles accumulated in podocytes of patients with DKD. Moreover, we found that advanced glycation end products (AGEs) could increase the protein expression of LC3-II and p62 in a dose- and time-dependent manner in cultured podocytes. However, the mRNA expression of LC3B, Beclin-1 or ATG7, as well as the protein level of Beclin-1 or ATG7 did not change significantly in the AGE-treated cells compared with that in control groups, suggesting that AGEs did not induce autophagy. In addition, AGEs led to an increase in the number of autophagosomes but not autolysosomes, accompanied with a failure in lysosomal turnover of LC3-II or p62, indicating that the degradation of autophagic vacuoles was blocked. Furthermore, we observed a dramatic decrease in the enzymatic activities, and the degradation of DQ-ovalbumin was significantly suppressed after podocytes were treated with AGEs. Plasma-irregular lysosomal-associated membrane protein 1 granules accompanied with the diffusion of cathepsin D expression and acridine orange redistribution were observed in AGE-treated podocytes, indicating that the lysosomal membrane permeability was triggered. Interestingly, we also found that AGEs-induced autophagic inhibition and podocyte injury were mimicked by the specific lysosomotropic agent, l-leucyl-l-leucine methyl ester. The exacerbated apoptosis and Rac-1-dependent actin-cytoskeletal disorganization were alleviated by an improvement in the lysosomal-dependent autophagic pathway by resveratrol plus vitamin E treatment in AGE-treated podocytes. However, the rescued effects were reversed by the addition of leupeptin, a lysosomal inhibitor. It suggests that restoring lysosomal function to activate autophagy may contribute to the development of new therapeutic strategies for DKD.

Long noncoding RNA: an emerging player in diabetes and diabetic kidney disease

2019 ◽  
Vol 133 (12) ◽  
pp. 1321-1339 ◽  
Author(s):  
Jia Guo ◽  
Zhangsuo Liu ◽  
Rujun Gong
Keyword(s):  
Kidney Disease ◽  
Noncoding Rna ◽  
Diabetic Kidney Disease ◽  
Therapeutic Targets ◽  
Developed Countries ◽  
Mechanisms Of Action ◽  
Renal Diseases ◽  
Diabetic Kidney ◽  
Definitive Therapy ◽  
Novel Therapeutic

AbstractDiabetic kidney disease (DKD) is among the most common complications of diabetes mellitus (DM), and remains the leading cause of end-stage renal diseases (ESRDs) in developed countries, with no definitive therapy yet available. It is imperative to decipher the exact mechanisms underlying DKD and identify novel therapeutic targets. Burgeoning evidence indicates that long non-coding RNAs (lncRNAs) are essential for diverse biological processes. However, their roles and the mechanisms of action remain to be defined in disease conditions like diabetes and DKD. The pathogenesis of DKD is twofold, so is the principle of treatments. As the underlying disease, diabetes per se is the root cause of DKD and thus a primary focus of therapy. Meanwhile, aberrant molecular signaling in kidney parenchymal cells and inflammatory cells may directly contribute to DKD. Evidence suggests that a number of lncRNAs are centrally involved in development and progression of DKD either via direct pathogenic roles or as indirect mediators of some nephropathic pathways, like TGF-β1, NF-κB, STAT3 and GSK-3β signaling. Some lncRNAs are thus likely to serve as biomarkers for early diagnosis or prognosis of DKD or as therapeutic targets for slowing progression or even inducing regression of established DKD. Here, we elaborated the latest evidence in support of lncRNAs as a key player in DKD. In an attempt to strengthen our understanding of the pathogenesis of DKD, and to envisage novel therapeutic strategies based on targeting lncRNAs, we also delineated the potential mechanisms of action as well as the efficacy of targeting lncRNA in preclinical models of DKD.

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