scholarly journals TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Rachel E. Carlisle ◽  
Zahraa Mohammed-Ali ◽  
Chao Lu ◽  
Tamana Yousof ◽  
Victor Tat ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Er Stress ◽  
Interstitial Fibrosis ◽  
Health Concern ◽  
Tubular Damage ◽  
Wild Type ◽  
Renal Interstitial Fibrosis ◽  
Β Receptor ◽  
Dependent Mechanism

AbstractChronic kidney disease (CKD) is characterized by the gradual loss of renal function and is a major public health concern. Risk factors for CKD include hypertension and proteinuria, both of which are associated with endoplasmic reticulum (ER) stress. ER stress-induced TDAG51 protein expression is increased at an early time point in mice with CKD. Based on these findings, wild-type and TDAG51 knock-out (TDKO) mice were used in an angiotensin II/deoxycorticosterone acetate/salt model of CKD. Both wild-type and TDKO mice developed hypertension, increased proteinuria and albuminuria, glomerular injury, and tubular damage. However, TDKO mice were protected from apoptosis and renal interstitial fibrosis. Human proximal tubular cells were used to demonstrate that TDAG51 expression induces apoptosis through a CHOP-dependent mechanism. Further, a mouse model of intrinsic acute kidney injury demonstrated that CHOP is required for ER stress-mediated apoptosis. Renal fibroblasts were used to demonstrate that TGF-β induces collagen production through an IRE1-dependent mechanism; cells treated with a TGF-β receptor 1 inhibitor prevented XBP1 splicing, a downstream consequence of IRE1 activation. Interestingly, TDKO mice express significantly less TGF-β receptor 1, thus, preventing TGF-β-mediated XBP1 splicing. In conclusion, TDAG51 induces apoptosis in the kidney through a CHOP-dependent mechanism, while contributing to renal interstitial fibrosis through a TGF-β-IRE1-XBP1 pathway.

scholarly journals Shen Shuai II Recipe Attenuates Renal Interstitial Fibrosis by Improving Hypoxia via the IL-1β/c-Myc Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Liuyi Yang ◽  
Meng Wang ◽  
Yuan Zhou ◽  
Jing Yang ◽  
Chaoyang Ye ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Renal Function ◽  
Chronic Renal Failure ◽  
Kidney Disease ◽  
Protein Expression ◽  
Interstitial Fibrosis ◽  
Renal Interstitial Fibrosis ◽  
Related Factors

Background. Renal interstitial fibrosis is a pathological manifestation of progression of chronic kidney disease induced by various factors. Shen Shuai II Recipe (SSR) has been used in clinical practice for more than 20 years, and clinical studies have confirmed that SSR significantly improves the renal function of patients with chronic kidney disease. However, the specific mechanisms underlying its efficacy require further research. This study aims to explore the influencing factors of renal interstitial fibrosis in the context of hypoxia via the IL-1β/c-Myc pathway and the potential molecular mechanisms of SSR intervention in vivo and in vitro. Methods. A rat model of chronic renal failure was developed by performing 5/6 (ablation/infarction, A/I) surgery on randomly selected, male Sprague Dawley rats. Thirty-six successfully modeled rats were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + SSR, and 5/6 (A/I) + losartan. Another 12 rats were used as the sham group. After 8 weeks of the corresponding intervention, renal function, liver function, and protein expression of renal-fibrosis-related factors, HIF-1α, IL-1β, and c-Myc, were detected. In vitro analysis was performed using hypoxia-induced rat renal tubular epithelial cells (NRK-52E) and IL-1β-stimulated rat renal interstitial fibroblasts (NRK-49F). IL-1β concentration in the culture medium and IL-1β protein expression in hypoxic NRK-52E treated with different concentrations of SSR were investigated. Furthermore, we also studied the changes in protein expression of c-Myc and fibrosis-related factors after c-Myc gene silencing in IL-1β-stimulated NRK-49F treated with SSR. Results. Shen Shuai II Recipe significantly reduced RIF and downregulated the expression of HIF-1α, c-Myc, and IL-1β proteins in 5/6 (A/I) rats with chronic renal failure. It also inhibited IL-1β secretion from NRK-52E induced by hypoxia, which in turn inhibited fibroblast activation mediated by the IL-1β/c-Myc pathway, and finally reduced the overproduction of the extracellular matrix. Conclusion. The renoprotective effects of SSR in rats with chronic renal failure may be related to its inhibition of hypoxia via the IL-1β/c-Myc pathway. Thus, SSR is a potentially effective drug for delaying the progression of renal interstitial fibrosis.

Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease

2015 ◽  
Vol 38 (7) ◽  
pp. 463-470 ◽  
Author(s):  
Yoshiro Naito ◽  
Aya Fujii ◽  
Hisashi Sawada ◽  
Makiko Oboshi ◽  
Toshihiro Iwasaku ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Rat Model ◽  
Interstitial Fibrosis ◽  
Iron Accumulation ◽  
Renal Interstitial Fibrosis

Inhibition of CTCF-regulated miRNA-185-5p mitigates renal interstitial fibrosis of chronic kidney disease

Epigenomics ◽  
2021 ◽  
Author(s):  
Jiajun Zhou ◽  
Han Zhou ◽  
Yong Liu ◽  
Caixin Liu
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mouse Model ◽  
Ureteral Obstruction ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Renal Interstitial Fibrosis ◽  
Underlying Mechanisms

Aim: The present study aimed to elucidate the effect of CTCF on renal interstitial fibrosis in chronic kidney disease (CKD) and underlying mechanisms. Materials & methods: We measured NPHS2 expression and investigated its function in a unilateral ureteral obstruction-induced mouse model of CKD. Results: NPHS2 was poorly expressed in CKD mice. miR-185-5p targeted NPHS2 and reduced its expression, leading to increased α-SMA and COL I/III expression, increased renal interstitial fibrosis area and elevated phosphorylated vasodilator-stimulated phosphoprotein/vasodilator-stimulated phosphoprotein ratio. Cotreatment with CTCF downregulated miR-185-5p expression and abolished its effects in the CKD model. Conclusion: CTCF suppressed miR-185-5p and upregulated its target NPHS2, with a net effect of alleviating renal interstitial fibrosis in CKD.

scholarly journals Pomolic Acid Ameliorates Fibroblast Activation and Renal Interstitial Fibrosis through Inhibition of SMAD-STAT Signaling Pathways

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2236 ◽  
Author(s):  
Ji-Hyun Park ◽  
Kyung Jang ◽  
Hyun An ◽  
Jung-Yeon Kim ◽  
Mi-Gyeong Gwon ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Interstitial Fibrosis ◽  
Fibroblast Cells ◽  
Potential Candidate ◽  
Renal Interstitial Fibrosis ◽  
Fibroblast Activation ◽  
Pomolic Acid ◽  
Kidney Fibroblast ◽  
Tgf Β1

Fibrosis is a common pathological feature in most kinds of chronic kidney disease. Transforming growth factor β1 (TGF-β1) signaling is the master pathway regulating kidney fibrosis pathogenesis, in which mothers against decapentaplegic homolog 3 (SMAD3) with signal transducer and activator of transcription 3 (STAT3) act as the integrator of various pro-fibrosis signals. We examine the effects of pomolic acid (PA) on mice with unilateral ureteral obstruction (UUO) and TGF-β1 stimulated kidney fibroblast cells. UUO mice were observed severe tubular atrophy, and tubulointerstitial fibrosis and extracellular matrix (ECM) deposition at seven days postoperatively. However, PA-treated UUO mice demonstrated only moderate injury, minimal fibrosis, and larger reductions in the expression of ECM protein and epithelial-mesenchymal transition (EMT) progress. PA inhibited the SMAD-STAT phosphorylation in UUO mice. PA effects were also confirmed in TGF-β1 stimulated kidney fibroblast cells. In this study, we first demonstrated that PA ameliorates fibroblast activation and renal interstitial fibrosis. Our results indicate that PA may be useful as a potential candidate in the prevention of chronic kidney disease.

scholarly journals Normoalbuminuric chronic kidney disease in diabetes

2018 ◽  
Vol 90 (10) ◽  
pp. 94-98
Author(s):  
V V Klimontov ◽  
A I Korbut
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Interstitial Fibrosis ◽  
Treatment Options ◽  
Practical Importance ◽  
Future Research ◽  
Diabetic Patients ◽  
Tubular Damage ◽  
Diabetic Kidney

Urinary albumin excretion (UAE) is widely used in clinical practice as indicator of diabetic kidney disease. According to the classical concept of the natural course of diabetic nephropathy, an increase in UAE usually precedes a decline in renal function. Meanwhile, a growing body of evidences indicates a high prevalence of normoalbuminuric chronic kidney disease (NA-CKD) in diabetic subjects, especially among patients with type 2 diabetes. An increase in NA-CKD prevalence can be results of improved glucose, blood pressure, and lipid control, widespread use of renin-angiotensin system blockers, and smoking cessation. It was shown that NA-CKD is more prevalent among women and is associated with arterial hypertension and coronary artery disease. The renal structure in subjects with NA-CKD is more heterogeneous when compared to patients with increased albuminuria, wherein interstitial changes and arteriolosclerosis could be the principal morphological findings, while signs of glomerulopathy may be absent. The prognostic value of NA-CKD needs to be clarified. It was shown that NA-CKD increases the risk of myocardial infarction, stroke and cardiovascular death in patients with diabetes. The search for alternative diagnostic markers for detecting of diabetic kidney disease in the absence of albuminuria, is of practical importance. The evaluations of the markers of tubular damage and interstitial fibrosis, as well as proteomic approaches, are considered as perspective diagnostic and prognostic options in NA-CKD. The study of pathogenesis, pathology, clinical course of NA-CKD in diabetic patients, as well as the development of more specific diagnostic and treatment options is a challenge for future research.

scholarly journals Altered Emotional Phenotypes in Chronic Kidney Disease Following 5/6 Nephrectomy

2021 ◽  
Vol 11 (7) ◽  
pp. 882
Author(s):  
Yeon Hee Yu ◽  
Seong-Wook Kim ◽  
Dae-Kyoon Park ◽  
Ho-Yeon Song ◽  
Duk-Soo Kim ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Local Field ◽  
Smooth Muscle Actin ◽  
Local Field Potentials ◽  
Renal Tissue ◽  
Field Potentials ◽  
Wild Type ◽  
Sprague Dawley ◽  
Rat Models

Increased prevalence of chronic kidney disease (CKD) and neurological disorders including cerebrovascular disease, cognitive impairment, peripheral neuropathy, and dysfunction of central nervous system have been reported during the natural history of CKD. Psychological distress and depression are serious concerns in patients with CKD. However, the relevance of CKD due to decline in renal function and the pathophysiology of emotional deterioration is not clear. Male Sprague Dawley rats were divided into three groups: sham control, 5/6 nephrectomy at 4 weeks, and 5/6 nephrectomy at 10 weeks. Behavior tests, local field potentials, and histology and laboratory tests were conducted and investigated. We provided direct evidence showing that CKD rat models exhibited anxiogenic behaviors and depression-like phenotypes, along with altered hippocampal neural oscillations at 1–12 Hz. We generated CKD rat models by performing 5/6 nephrectomy, and identified higher level of serum creatinine and blood urea nitrogen (BUN) in CKD rats than in wild-type, depending on time. In addition, the level of α-smooth muscle actin (α-SMA) and collagen I for renal tissue was markedly elevated, with worsening fibrosis due to renal failures. The level of anxiety and depression-like behaviors increased in the 10-week CKD rat models compared with the 4-week rat models. In the recording of local field potentials, the power of delta (1–4 Hz), theta (4–7 Hz), and alpha rhythm (7–12 Hz) was significantly increased in the hippocampus of CKD rats compared with wild-type rats. Together, our findings indicated that anxiogenic behaviors and depression can be induced by CKD, and these abnormal symptoms can be worsened as the onset of CKD was prolonged. In conclusion, our results show that the hippocampus is vulnerable to uremia.

scholarly journals The Nephroprotective Properties of Extracellular Vesicles in Experimental Models of Chronic Kidney Disease: a Systematic Review

2021 ◽  
Author(s):  
Natalia Nowak ◽  
Masayuki Yamanouchi ◽  
Eiichiro Satake
Keyword(s):  
Systematic Review ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Interstitial Fibrosis ◽  
Cell Damage ◽  
Meta Analysis ◽  
Experimental Studies ◽  
Extracellular Vesicle ◽  
Experimental Models ◽  
Preclinical Research

AbstractExtracellular vesicle (EV)-based therapy was hypothesized as a promising regenerative approach which has led to intensive research of EVs in various pathologies. In this study, we performed a comprehensive systematic review of the current experimental evidence regarding the protective properties of EVs in chronic kidney disease (CKD). We evaluated the EV-based experiments, EV characteristics, and effector molecules with their involvement in CKD pathways. Including all animal records with available creatinine or urea data, we performed a stratified univariable meta-analysis to assess the determinants of EV-based therapy effectiveness. We identified 35 interventional studies that assessed nephroprotective role of EVs and catalogued them according to their involvement in CKD mechanism. Systematic assessment of these studies suggested that EVs had consistently improved glomerulosclerosis, interstitial fibrosis, and cell damage, among different CKD models. Moreover, EV-based therapy reduced the progression of renal decline in CKD. The stratified analyses showed that the disease model, administered dose, and time of therapeutic intervention were potential predictors of therapeutic efficacy. Together, EV therapy is a promising approach for CKD progression in experimental studies. Further standardisation of EV-methods, continuous improvement of the study quality, and better understanding of the determinants of EV effectiveness will facilitate preclinical research, and may help development of clinical trials in people with CKD. Graphical Abstract

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