scholarly journals Potential Targeting of Renal Fibrosis in Diabetic Kidney Disease Using MicroRNAs

2020 ◽  
Vol 11 ◽  
Author(s):  
Hiroko Sakuma ◽  
Shinji Hagiwara ◽  
Phillip Kantharidis ◽  
Tomohito Gohda ◽  
Yusuke Suzuki
Keyword(s):  
Kidney Disease ◽  
Transforming Growth Factor Beta ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Related Factor ◽  
Major Health Problem ◽  
Diabetic Kidney ◽  
End Stage

Diabetic kidney disease (DKD) is a major health problem and one of the leading causes of end-stage renal disease worldwide. Despite recent advances, there exists an urgent need for the development of new treatments for DKD. DKD is characterized by the excessive synthesis and deposition of extracellular matrix proteins in glomeruli and the tubulointerstitium, ultimately leading to glomerulosclerosis as well as interstitial fibrosis. Renal fibrosis is the final common pathway at the histological level leading to an end-stage renal failure. In fact, activation of the nuclear factor erythroid 2-related factor 2 pathway by bardoxolone methyl and inhibition of transforming growth factor beta signaling by pirfenidone have been assumed to be effective therapeutic targets for DKD, and various basic and clinical studies are currently ongoing. MicroRNAs (miRNAs) are endogenously produced small RNA molecules of 18–22 nucleotides in length, which act as posttranscriptional repressors of gene expression. Studies have demonstrated that several miRNAs contribute to renal fibrosis. In this review, we outline the potential of using miRNAs as an antifibrosis treatment strategy and discuss their clinical application in DKD.

scholarly journals Key profibrotic and pro-inflammatory pathways in the pathogenesis of diabetic kidney disease

2021 ◽  
Vol 1 (1) ◽  
pp. 15-26
Author(s):  
Devang M. Patel ◽  
Yuxin Yang ◽  
Kexin Shi ◽  
Tieqiao Wu ◽  
Mark E. Cooper ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Large Body ◽  
Noncommunicable Disease ◽  
Sirtuin 1 ◽  
Type I ◽  
Diabetic Kidney ◽  
Inflammatory Pathways

Abstract Diabetes is a noncommunicable disease and arguably represents the greatest pandemic in human history. Diabetic kidney disease (DKD) is seen in both type 1 and type 2 diabetes and can be detected in up to 30–50% of diabetic subjects. DKD is a progressive chronic kidney disease (CKD) and is a leading cause of mortality and morbidity in patients with diabetes. Renal fibrosis and inflammation are the major pathological features of DKD. There are a large number of independent and overlapping profibrotic and pro-inflammatory pathways involved in the pathogenesis and progression of DKD. Among these pathways, the transforming growth factor-β (TGF-β) pathway plays a key pathological role by promoting fibrosis. Sirtuin-1 (SIRT1) is a protein deacetylase that has been shown to be renoprotective with an anti-inflammatory effect. It is postulated that a reduction in renal SIRT1 levels could play a key role in the pathogenesis of DKD and that restoration of SIRT1 will attenuate DKD. Cell division autoantigen 1 (CDA1) synergistically enhances the profibrotic effect of TGF-β in DKD by regulating the expression of the TGF-β type I receptor (TβRI). CDA1 has also been found to be an inhibitor of SIRT1 in the DNA damage response. Indeed, targeting CDA1 in experimental DKD not only attenuates diabetes-associated renal fibrosis but also attenuates the expression of key pro-inflammatory genes such as tumor necrosis factor-α (TNF-α) and Monocyte Che moattractant Protein-1 (MCP-1). In conclusion, there is a large body of experimental data to support the view that targeting CDA1 is a superior approach to directly targeting TGF-β in DKD since it is not only safe but also efficacious in retarding both fibrosis and inflammation.

scholarly journals BKCa Mediates Dysfunction in High Glucose Induced Mesangial Cell Injury via TGF-β1/Smad2/3 Signaling Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Zhigui Wu ◽  
Wenxian Yin ◽  
Mengqi Sun ◽  
Yuankai Si ◽  
Xiaoxiao Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Diabetic Kidney

Objective. To explore the role and mechanism of BKCa in diabetic kidney disease. Methods. Rat mesangial cells (MCs) HBZY-1 were cultured with high glucose to simulate the high-glucose environment of diabetic kidney disease in vivo. The effects of large conductance calcium-activated potassium channel (BKCa) on proliferation, migration, and apoptosis of HBZY-1 cells were observed. The contents of transforming growth factor beta 1 (TGF-β1), Smad2/3, collagen IV (Col IV), and fibronectin (FN) in the extracellular matrix were also observed. Results. High glucose significantly damaged HBZY-1 cells, which enhanced the ability of cell proliferation, migration, and apoptosis, and increased the secretion of Col IV and FN. Inhibition of BKCa and TGF-β1/Smad2/3 signaling pathways can inhibit the proliferation, migration, and apoptosis of HBZY-1 cells and suppress the secretion of Col IV and FN. The effect of excitation is the opposite. Conclusions. BKCa regulates mesangial cell proliferation, migration, apoptosis, and secretion of Col IV and FN and is associated with TGF-β1/Smad2/3 signaling pathway.

How to inhibit transforming growth factor beta safely in diabetic kidney disease

2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Yuxin Yang ◽  
Kexin Shi ◽  
Devang M. Patel ◽  
Fang Liu ◽  
Tieqiao Wu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Transforming Growth Factor Beta ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Diabetic Kidney ◽  
Growth Factor Beta

scholarly journals Development of the Diabetic Kidney Disease Mouse Model Culturing Embryos in α-Minimum Essential Medium In Vitro, and Feeding Barley Diet Attenuated the Pathology

2021 ◽  
Vol 12 ◽  
Author(s):  
Shiori Ishiyama ◽  
Mayu Kimura ◽  
Takao Nakagawa ◽  
Yuka Fujimoto ◽  
Kohei Uchimura ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Transforming Growth Factor Beta ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Control Diet ◽  
Renal Tubules ◽  
Minimum Essential Medium ◽  
Diabetic Kidney

Diabetic kidney disease (DKD) is a critical complication associated with diabetes; however, there are only a few animal models that can be used to explore its pathogenesis. In the present study, we established a mouse model of DKD using a technique based on the Developmental Origins of Health and Disease theory, i.e., by manipulating the embryonic environment, and investigated whether a dietary intervention could ameliorate the model’s pathology. Two-cell embryos were cultured in vitro in α-minimum essential medium (MEM; MEM mice) or in standard potassium simplex-optimized medium (KSOM) as controls (KSOM mice) for 48 h, and the embryos were reintroduced into the mothers. The MEM and KSOM mice born were fed a high-fat, high-sugar diet for 58 days after they were 8 weeks old. Subsequently, half of the MEM mice and all KSOM mice were fed a diet containing rice powder (control diet), and the remaining MEM mice were fed a diet containing barley powder (barley diet) for 10 weeks. Glomerulosclerosis and pancreatic exhaustion were observed in MEM mice, but not in control KSOM mice. Renal arteriolar changes, including intimal thickening and increase in the rate of hyalinosis, were more pronounced in MEM mice fed a control diet than in KSOM mice. Immunostaining showed the higher expression of transforming growth factor beta (TGFB) in the proximal/distal renal tubules of MEM mice fed a control diet than in those of KSOM mice. Pathologies, such as glomerulosclerosis, renal arteriolar changes, and higher TGFB expression, were ameliorated by barley diet intake in MEM mice. These findings suggested that the MEM mouse is an effective DKD animal model that shows glomerulosclerosis and renal arteriolar changes, and barley intake can improve these pathologies in MEM mice.

scholarly journals Group 2 Innate Lymphoid Cells Participate in Renal Fibrosis in Diabetic Kidney Disease Partly via TGF-β1 Signal Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Cuiping Liu ◽  
Ludan Qin ◽  
Jingya Ding ◽  
Luping Zhou ◽  
Chenlin Gao ◽  
...  
Keyword(s):  
Kidney Disease ◽  
High Glucose ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Innate Lymphoid Cells ◽  
Signal Pathway ◽  
Lymphoid Cells ◽  
Diabetic Kidney ◽  
Group 2

Aim. To explore the role of group 2 innate lymphoid cells (ILC2s) in the pathogenesis of renal fibrosis in diabetic kidney disease (DKD). Methods. The proportion of ILC2s and the levels of Th2 cytokines (IL-4, IL-5, and IL-13) in the peripheral blood of normal control subjects (NC) or patients with type 2 diabetes mellitus (DM), early diabetic kidney disease (DKD1), or late diabetic kidney disease (DKD2) were analyzed by flow cytometry and ELISA. The expression of transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen1, IL-4Rα, and IL-13Rα1 in renal tubular epithelial cells (HK-2) induced by IL-4, IL-13, or high glucose was analyzed by ELISA or qPCR. Results. The proportion of ILC2s and the levels of IL-4, IL-5, and IL-13 were significantly increased in DKD patients and were positively correlated with the severity of DKD (P<0.05). The expression of TGF-β1, FN, and collagen1 was significantly upregulated in HK-2 cells induced by IL-4 or IL-13 (P<0.05). Moreover, the IL-4Rα and IL-13Rα1 mRNA in HK2 cells were increased followed by high glucose alone or combined with IL-4 or IL-13, but the differences were not statistically significant (P>0.05). However, compared with high-glucose stimulation alone, the expression of TGF-β1, FN, and collagen1 was significantly increased in HK-2 cells induced by high glucose combined with IL-4 or IL-13 (P<0.05). Conclusions. ILC2s may participate in renal fibrosis in DKD partly via TGF-β1 signal pathway.

scholarly journals TGF-β1 and VCAM-1 Serum Concentrations as Diagnostic Biomarkers of Diabetic Kidney Disease Progression

2019 ◽  
Vol 26 (2) ◽  
pp. 169-175 ◽  
Author(s):  
Natalia Pertseva ◽  
Inna Borysova ◽  
Daria Chub
Keyword(s):  
Kidney Disease ◽  
Transforming Growth Factor Beta ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Quantitative Detection ◽  
Enzyme Linked Immunosorbent Assay ◽  
Diabetic Patients ◽  
Healthy Controls ◽  
Diabetic Kidney ◽  
Tgf Β1

Abstract Background and aims: Transforming growth factor-beta 1 (TGF-β1) and vascular adhesion molecule 1 (VCAM-1) have been proposed as promising biomarkers for multiple diseases. TGF-β1 and VCAM-1 are reported to be associated with diabetic kidney disease (DKD) and end stage renal disease in patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM). Material and methods: The aim of this study was to investigate the expression of circulating TGF-β1 and VCAM-1 and to assess their potential as a blood-based biomarker for DKD in T1DM and T2DM patients. Results:. The study included 124 participants: 66 patients with T1DM, 58 with T2DM and 20 healthy controls. The diabetic patients were classified according to the estimated glomerular filtration rate (eGFR). First group - eGFR ≥90ml/min/1.73 m2 (n=39), second group eGFR 89-60 ml/min/1.73m2 (n=45), and third group eGFR 59-45 ml/min/1.73m2 (n=40). Enzyme-linked immunosorbent assay for the quantitative detection of was used to evaluate blood TGF-β1 and VCAM-1 expression. It was found that there were higher TGF-β1 and VCAM-1 in all diabetic patients compared with healthy controls (P<0.05). TGF- β1 and VCAM-1 were higher in group with eGFR ≥90ml/min/1.73 m2 and gradually increased in the groups with eGFR89-60 ml/min/1.73m2 and eGFR 59-45 ml/min/1.73m2. TGF- β1 and VCAM-1 were less in T1DM, than T2DM in all study groups. Regression analysis revealed reverse associations between TGF- β1, VCAM-1 and eGFR (P<0.05). TGF- β1 and VCAM-1 correlated positively with albuminuria and negatively with renal function. Conclusion: In discriminating overall patients from healthy subjects, ROC analysis revealed areas under the curve (AUCs) of 1,0 for TGF- β1 for T1DM and T2DM, VCAM-1 0,866 for T1DM, 0,923 for T2DM (P<0.001). The results suggested that blood-based TGF- β1 and VCAM-1 may serve as potential biomarkers for early detection of DKD.

scholarly journals Modified arteriosclerosis score predicts the outcomes of diabetic kidney disease

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yifan Zhang ◽  
Qifeng Jiang ◽  
Jianteng Xie ◽  
Chunfang Qi ◽  
Sheng Li ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Prognostic Indicators ◽  
Urine Protein ◽  
Tubular Atrophy ◽  
Diabetic Kidney ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background The significance of renal arteriosclerosis in the prediction of the renal outcomes of diabetic kidney disease (DKD) remains undetermined. Methods We enrolled 174 patients with DKD from three centres from January 2010 to July 2017. The severity and extent of arteriosclerosis were analysed on sections based on dual immunohistochemical staining of CD31 and α-smooth muscle actin. An X-tile plot was used to determine the optimal cut-off value. The primary endpoint was renal survival (RS), defined as the duration from renal biopsy to end-stage renal disease or death. Results The baseline estimated glomerular filtration rate (eGFR) of 135 qualified patients was 45 (29 ~ 70) ml/min per 1.73 m2, and the average 24-h urine protein was 4.52 (2.45 ~ 7.66) g/24 h. The number of glomeruli in the biopsy specimens was 21.07 ± 9.7. The proportion of severe arteriosclerosis in the kidney positively correlated with the Renal Pathology Society glomerular classification (r = 0.28, P < 0.012), interstitial fibrosis and tubular atrophy (IFTA) (r = 0.39, P < 0.001), urine protein (r = 0.213, P = 0.013), systolic BP (r = 0.305, P = 0.000), and age (r = 0.220, P = 0.010) and significantly negatively correlated with baseline eGFR (r = − 0.285, P = 0.001). In the multivariable model, the primary outcomes were significantly correlated with glomerular class (HR: 1.72, CI: 1.15 ~ 2.57), IFTA (HR: 1.96, CI: 1.26 ~ 3.06) and the modified arteriosclerosis score (HR: 2.21, CI: 1.18 ~ 4.13). After risk adjustment, RS was independently associated with the baseline eGFR (HR: 0.97, CI: 0.96 ~ 0.98), urine proteinuria (HR: 1.10, CI: 1.04 ~ 1.17) and the modified arteriosclerosis score (HR: 2.01, CI: 1.10 ~ 3.67), and the nomogram exhibited good calibration and acceptable discrimination (C-index = 0.82, CI: 0.75 ~ 0.87). Conclusions The severity and proportion of arteriosclerosis may be helpful prognostic indicators for DKD.

scholarly journals Initial Combination Empagliflozin and Linagliptin Improves Kidney Fibrotic Marker in Patients With Type 2 Diabetes: A Randomized Controlled Trial

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A416-A416
Author(s):  
Nattapol Sathavarodom ◽  
Thanaporn Putthanuparp ◽  
Verapon Pinphanichakarn
Keyword(s):  
Type 2 Diabetes ◽  
Growth Factor ◽  
Kidney Disease ◽  
Transforming Growth Factor Beta ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Response To Therapy ◽  
Diabetic Kidney ◽  
Initial Combination

Abstract Background: Transforming growth factor-beta 1 (TGF- ß1) is a novel cytokine marker and also one of the therapeutic targets in the treatment of diabetic kidney disease. Both sodium glucose co-transporter 2 inhibitor and dipeptidyl-peptides 4 inhibitor reduce TGF- ß 1 level in animal studies, but whether it is effective in human is unknown. Objective: To evaluate the effects of combinations of empagliflozin/linagliptin, comparing with empagliflozin alone, in patients with type 2 diabetes. Material and Methods: Subjects are randomized to a combination of empagliflozin 10 mg and linagliptin 5 mg (n = 23), or empagliflozin 10 mg (n = 22) as add-on to standard treatment for 12 weeks. The primary end point is changed from baseline in serum TGF- ß1 at 12 weeks. Results: Among the 45 subjects who completed the study, mean change in TGF-ß1 was -928.2 + 1,204.2 pg/mL, and +206.6 + 592.5 pg/mL in the empagliflozin/linagliptin group and empagliflozin group, respectively (p &lt;0.001). Mean change in estimated glomerular filtration rate (eGFR) increased in the empagliflozin /linagliptin group 4.4 + 7.59 mL/min/1.73m2, whereas mean eGFR decreased in empagliflozin group -0.06 + 11.16 mL/min/1.73m2 (p =0.133). Mean change in HbA1c was -1.3 + 0.6% and -0.4 + 0.6% in empagliflozin/linagliptin and empagliflozin group, respectively (p&lt;0.001). Baseline level of eGFR significantly correlated with baseline TGF- ß1 but did not predict response to therapy. Conclusion: Initial combination empagliflozin and linagliptin may delay progression of kidney fibrosis as early as 12 weeks of treatment. Our study supports that this combination had synergistic action not only glycemic control but also beneficial in kidney protection. Keyword: transforming growth factor - ß1, diabetic kidney disease, combination empagliflozin and linagliptin

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