Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

Diabetic nephropathy (DN) is characterized by metabolic disorder and inflammation. However, the regulatory effects that long noncoding RNAs (lncRNAs) have on the pathogenesis of DN and on the efficacy of rosiglitazone treatment have yet to be clearly defined. Herein, we performed unbiased RNA sequencing to characterize the transcriptomic profiles in db/db diabetic mouse model with or without rosiglitazone treatment that served to improve the phenotypes of DN. Moreover, RNA-seq profiling revealed that the development of DN caused an upregulation in the expression of 1176 mRNAs and a downregulation in the expression of 1010 mRNAs compared to controls, with the expression of 251 mRNAs being returned to normal following treatment with rosiglitazone. Further, 88 upregulated and 68 downregulated lncRNAs were identified in db/db mice compared to controls, 10 of which had their normal expression restored following treatment with rosiglitazone. Bioinformatic analysis revealed that the primary pathways involved in the pathogenesis of DN, and subsequently in the therapeutic effects of PPARγ, are related to inflammatory and metabolic processes. From bioinformatics analysis, lncRNA-AI838599 emerged as a novel molecular mechanism for rosiglitazone treatment in DN through TNFα-NFκb pathway. These findings may indicate a new molecular regulatory approach for the development of DN therapeutic agents.

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Current RNA-based Therapeutics in Clinical Trials

Current Gene Therapy ◽

10.2174/1566523219666190719100526 ◽

2019 ◽

Vol 19 (3) ◽

pp. 172-196 ◽

Cited By ~ 15

Author(s):

Ling-Yan Zhou ◽

Zhou Qin ◽

Yang-Hui Zhu ◽

Zhi-Yao He ◽

Ting Xu

Keyword(s):

Clinical Trials ◽

Rapid Development ◽

Genetic Diseases ◽

Three Dimensional ◽

Therapeutic Effects ◽

Messenger Rnas ◽

Small Interfering Rnas ◽

Rna Modifications ◽

Guide Rna ◽

Endogenous Genes

Long-term research on various types of RNAs has led to further understanding of diverse mechanisms, which eventually resulted in the rapid development of RNA-based therapeutics as powerful tools in clinical disease treatment. Some of the developing RNA drugs obey the antisense mechanisms including antisense oligonucleotides, small interfering RNAs, microRNAs, small activating RNAs, and ribozymes. These types of RNAs could be utilized to inhibit/activate gene expression or change splicing to provide functional proteins. In the meantime, some others based on different mechanisms like modified messenger RNAs could replace the dysfunctional endogenous genes to manage some genetic diseases, and aptamers with special three-dimensional structures could bind to specific targets in a high-affinity manner. In addition, the recent most popular CRISPR-Cas technology, consisting of a crucial single guide RNA, could edit DNA directly to generate therapeutic effects. The desired results from recent clinical trials indicated the great potential of RNA-based drugs in the treatment of various diseases, but further studies on improving delivery materials and RNA modifications are required for the novel RNA-based drugs to translate to the clinic. This review focused on the advances and clinical studies of current RNA-based therapeutics, analyzed their challenges and prospects.

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Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy

International Journal of Molecular Sciences ◽

10.3390/ijms22020956 ◽

2021 ◽

Vol 22 (2) ◽

pp. 956

Author(s):

Marlena Typiak ◽

Agnieszka Piwkowska

Keyword(s):

Diabetes Mellitus ◽

Diabetic Nephropathy ◽

Calcium Metabolism ◽

Renal Involvement ◽

Therapeutic Effects ◽

Beneficial Effects ◽

Early Biomarker ◽

Klotho Protein ◽

Urine Levels ◽

Proinflammatory Factors

Klotho was initially introduced as an antiaging molecule. Klotho deficiency significantly reduces lifespan, and its overexpression extends it and protects against various pathological phenotypes, especially renal disease. It was shown to regulate phosphate and calcium metabolism, protect against oxidative stress, downregulate apoptosis, and have antiinflammatory and antifibrotic properties. The course of diabetes mellitus and diabetic nephropathy resembles premature cellular senescence and causes the activation of various proinflammatory and profibrotic processes. Klotho was shown to exert many beneficial effects in these disorders. The expression of Klotho protein is downregulated in early stages of inflammation and diabetic nephropathy by proinflammatory factors. Therefore, its therapeutic effects are diminished in this disorder. Significantly lower urine levels of Klotho may serve as an early biomarker of renal involvement in diabetes mellitus. Recombinant Klotho administration and Klotho overexpression may have immunotherapeutic potential for the treatment of both diabetes and diabetic nephropathy. Therefore, the current manuscript aims to characterize immunopathologies occurring in diabetes and diabetic nephropathy, and tries to match them with antiinflammatory actions of Klotho. It also gives reasons for Klotho to be used in diagnostics and immunotherapy of these disorders.

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Induction of leukocyte adhesion molecules and renal physiologically active molecules in Porphyromonas gingivalis lipopolysaccharide-induced diabetic nephropathy

10.21203/rs.3.rs-43555/v1 ◽

2020 ◽

Author(s):

Koichiro Kajiwara ◽

Yoshihiko Sawa ◽

Takahiro Fujita ◽

Sachio Tamaoki

Keyword(s):

Diabetic Nephropathy ◽

Adhesion Molecules ◽

Leukocyte Adhesion ◽

Diabetic Mouse ◽

Renal Parenchyma ◽

Periodontal Pathogen ◽

Diabetic Patients ◽

Renal Tubules ◽

Diabetic Mice ◽

Leukocyte Adhesion Molecules

Abstract Background We recently reported that the glomerular endothelium expresses toll-like receptor (TLR)2 and TLR4 in diabetic environments and established that the TLR2 ligand Porphyromonas (P.) gingivalis lipopolysaccharides (LPS) induces nephropathy in diabetic mice. It is thought that P. gingivalis LPS promotes the chronic inflammation with the overexpression of leukocyte adhesion molecules and renal-specific metabolic enzymes by the recognition of P. gingivalis LPS via TLR in the diabetic kidneys. The present study aims to examine the expression of leukocyte adhesion molecules and renal metabolic factors in mouse kidneys with periodontal pathogen P. gingivalis LPS-induced diabetic nephropathy that was recently established. Methods The immunohistochemical investigation was performed on mouse kidney with P. gingivalis LPS-induced diabetic nephropathy model with glomerulosclerosis in glomeruli. Results There were no vessels which expressed vascular cell adhesion molecule-1 (VCAM-1), E-selectin, or fibroblast growth factor (FGF) 23 in diabetic mice, or in healthy mice administered P. gingivalis LPS. However, in diabetic mouse kidneys with P. gingivalis LPS-induced nephropathy the expression of VCAM-1 and the accumulation of FGF23 were established in renal tubules and glomeruli, and the expression of E-selectin was established in renal parenchyma and glomeruli. The angiotensin-converting enzyme 2 (ACE2) was detected in the proximal tubules but not in other regions including not in distal tubules of diabetic mice without LPS, and not in healthy mice administered P. gingivalis LPS. In diabetic mouse kidneys with P. gingivalis LPS-induced nephropathy ACE2 was detected both in renal tubules as well as in glomeruli. The macrophage-1 (Mac-1) and podoplanin-positive cells increased in the renal parenchyma with diabetic condition and there was accumulation in P. gingivalis LPS-induced diabetic nephropathy. As the expression of VCAM-1 and E-selectin is upregulated in glomeruli, tubules, and intertubular capillaries, it is thought that the inflammatory infiltration of the monocyte-macrophage lineage promoted in kidneys with P. gingivalis LPS-induced the diabetic nephropathy. Conclusions P. gingivalis LPS may progressively accelerate the development of the renal inflammatory environment in LPS-accumulated glomeruli with the macrophage infiltration via the renal expression of VCAM-1 and E-selectin, and with ACE2 overexpression and FGF23 accumulation. Periodontitis may be a critical factor in the progress of nephropathy in diabetic patients.

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The circRAB3IP Mediated by eIF4A3 and LEF1 Contributes to Enzalutamide Resistance in Prostate Cancer by Targeting miR-133a-3p/miR-133b/SGK1 Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.752573 ◽

2021 ◽

Vol 11 ◽

Author(s):

Dong Chen ◽

Yaqin Wang ◽

Feiya Yang ◽

Adili Keranmu ◽

Qingxin Zhao ◽

...

Keyword(s):

Prostate Cancer ◽

Real Time ◽

Expression Pattern ◽

Real Time Pcr ◽

Bioinformatic Analysis ◽

Biological Functions ◽

Quantitative Real Time Pcr ◽

Regulatory Effects

An increasing number of studies have shown that circRNAs are closely related to the carcinogenesis and development of prostate cancer (PCa). However, little is known about the effect of the biological functions of circRNAs on the enzalutamide resistance of PCa. Through bioinformatic analysis and experiments, we investigated the expression pattern of circRNAs in enzalutamide-resistant PCa cells. Quantitative real-time PCR was used to detect the expression of circRAB3IP, and plasmids that knock down or overexpress circRAB3IP were used to evaluate its effect on the enzalutamide sensitivity of PCa cells. Mechanistically, we explored the potential regulatory effects of eIF4A3 and LEF1 on the biogenesis of circRAB3IP. Our in vivo and in vitro data indicated that increased expression of circRAB3IP was found in enzalutamide-resistant PCa, and knockdown of circRAB3IP significantly enhanced enzalutamide sensitivity in PCa cells. However, upregulation of circRAB3IP resulted in the opposite effects. Further mechanistic research demonstrated that circRAB3IP could regulate the expression of serum and glucocorticoid-regulated kinase 1 (SGK1) by serving as a sponge that directly targets miR-133a-3p/miR-133b. Then, we showed that circRAB3IP partially exerted its biological functions via SGK1 signaling. Furthermore, we discovered that eIF4A3 and LEF1 might increase circRAB3IP expression in PCa.

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Liraglutide Regulates the Kidney and Liver in Diabetic Nephropathy Rats through the miR-34a/SIRT1 Pathway

Journal of Diabetes Research ◽

10.1155/2021/8873956 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Shan Xiao ◽

Ye Yang ◽

Yue-Tong Liu ◽

Jun Zhu

Keyword(s):

Electron Microscopy ◽

Diabetic Nephropathy ◽

Treated Group ◽

Protective Role ◽

Control Group ◽

Related Factors ◽

Qrt Pcr ◽

Regulatory Effects ◽

Tgf Β1 ◽

Liver Tissues

Purpose. To explore the regulatory effects of liraglutide on the kidney and liver through the miR-34a/SIRT1 pathway with related factors in diabetic nephropathy (DN) rats. Methods. DN rats were randomly divided into two groups ( n = 10 ) and were injected with liraglutide or normal saline twice a day. The 24-hour urine microalbumin content and biochemical index levels were measured. qRT-PCR was performed to detect the expression of miR-34a in the kidney and liver tissues. The levels of SIRT1, HIF-1a, Egr-1, and TGF-β1 in kidney and liver tissues were determined using qRT-PCR, western blot, and immunohistochemistry. Electron microscopy and HE staining were used to observe the ultrastructure and pathological changes. Results. Liraglutide treatment in DN rats decreased blood glucose, 24-hour urine microalbumin, TC, TG, LDL-C, UA, Cr, UREA, ALT, and AST levels and increased the level of HDL-C ( P < 0.05 ). Compared with the control group, the miR-34a levels were significantly decreased in kidney and liver tissues followed by liraglutide treatment ( P < 0.05 ). The levels of SIRT1 in the liraglutide group are significantly higher than those in the control group with the kidney and liver tissues ( P < 0.05 ). Conversely, the contents of HIF-1a, Egr-1, and TGF-β1 were significantly lower in the liraglutide group than in the control group ( P < 0.05 ). Electron microscopy showed that the kidney of the liraglutide-treated group exhibited minor broadening of the mesangial areas, fewer deposits, and a well-organized foot process. HE staining revealed that the kidney of the liraglutide-treated rats had a more regular morphology of the glomerulus and Bowman sac cavity and lighter tubular edema. Additionally, the liraglutide-treated DN rats had a clear hepatic structure, a lower degree of steatosis, and mild inflammatory cell infiltration. Conclusion. Liraglutide, through its effect on the miR-34a/SIRT1 pathway, may have a protective role in the kidney and liver of DN rats.

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A model for diabetic nephropathy: Advantages of the inducible cAMP early repressor transgenic mouse over the streptozotocin-induced diabetic mouse

Journal of Cellular Physiology ◽

10.1002/jcp.21316 ◽

2008 ◽

Vol 215 (2) ◽

pp. 383-391 ◽

Cited By ~ 27

Author(s):

Akari Inada ◽

Hiroshi Kanamori ◽

Hidenori Arai ◽

Tomoyuki Akashi ◽

Makoto Araki ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Transgenic Mouse ◽

Diabetic Mouse ◽

Inducible Camp Early Repressor

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Softened food reduces weight loss in the streptozotocin-induced male mouse model of diabetic nephropathy

Laboratory Animals ◽

10.1177/0023677217747915 ◽

2018 ◽

Vol 52 (4) ◽

pp. 373-383 ◽

Cited By ~ 4

Author(s):

Sisse A Nørgaard ◽

Fredrik W Sand ◽

Dorte B Sørensen ◽

Klas SP Abelson ◽

Henrik Søndergaard

Keyword(s):

Weight Loss ◽

Diabetic Nephropathy ◽

Mouse Model ◽

Diabetic Mouse ◽

Diabetic Mice ◽

Reduce Weight Loss ◽

Normal Chow ◽

Corticosterone Metabolites ◽

Reducing Stress ◽

Humane Endpoint

The streptozotocin (STZ)-induced diabetic mouse is a widely used model of diabetes and diabetic nephropathy (DN). However, it is a well-known issue that this model is challenged by high weight loss, which despite supportive measures often results in high euthanization rates. To overcome these issues, we hypothesized that supplementing STZ-induced diabetic mice with water-softened chow in addition to normal chow would reduce weight loss, lower the need for supportive treatment, and reduce the number of mice reaching the humane endpoint of 20% weight loss. In a 15 week STZ-induced DN study we demonstrated that diabetic male mice receiving softened chow had reduced acute weight loss following STZ treatment ( p = 0.045) and additionally fewer mice were euthanized due to weight loss. By supplementing the diabetic mice with softened chow, no mice reached 20% weight loss whereas 37.5% of the mice without this supplement reached this humane endpoint ( p = 0.0027). Excretion of corticosterone metabolites in faeces was reduced in diabetic mice on softened chow ( p = 0.0007), suggesting lower levels of general stress. Finally, it was demonstrated that the water-softened chow supplement did not significantly affect the induction of key disease parameters, i.e. %HbA1C and albuminuria nor result in abnormal teeth wear. In conclusion, supplementation of softened food is refining the STZ-induced diabetic mouse model significantly by reducing stress, weight loss and the number of animals sacrificed due to humane endpoints, while maintaining the key phenotypes of diabetes and nephropathy.

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The therapeutic effect and mechanism of Qishen Yiqi dripping pills on cardiovascular and cerebrovascular diseases and diabetic complications

Current Molecular Pharmacology ◽

10.2174/1874467214666210811153610 ◽

2021 ◽

Vol 14 ◽

Author(s):

Chunlai Zhao ◽

Wenjia Wang ◽

Kaijing Yan ◽

He Sun ◽

Jihong Han ◽

...

Keyword(s):

Coronary Heart Disease ◽

Diabetic Nephropathy ◽

Heart Disease ◽

Ischemic Stroke ◽

Diabetic Complications ◽

Blood Stasis ◽

Blood Stasis Syndrome ◽

Syndrome Differentiation ◽

Therapeutic Effects ◽

The Common

: The alterations in vascular homeostasis is deeply involved in the development of numerous diseases, such as coronary heart disease, stroke, and diabetic complications. Changes in blood flow and endothelial permeability caused by vascular dysfunction are the common mechanisms for these three types of diseases. The disorders of glucose and lipid metabolism can result in changes of the energy production patterns in endothelium and surrounding cells which may consequently cause local energy metabolic disorders, oxidative stress and inflammatory responses. Traditional Chinese medicine (TCM) follows the principle of the “treatment by the syndrome differentiation”. TCM considers of that coronary heart disease, stroke and diabetes complications all as the type of “Qi deficiency and Blood stasis” syndrome, which mainly happens to the vascular system. Therefore, the common pathogenesis of these three types of diseases suggests the treatment strategy by TCM should be in a close manner and named as “treating different diseases by the same treatment”. Qishen Yiqi dripping pills is a modern Chinese herbal medicine which has been widely used for treatment of patients with coronary heart disease characterized as “Qi deficiency and blood stasis” in China. Recently, many clinical reports have demonstrated the potent therapeutic effects of Qishen Yiqi dripping pills on ischemic stroke and diabetic nephropathy. Based on these reports, we will summarize the clinical applications of Qishen Yiqi dripping pills on coronary heart disease, ischemic stroke and diabetic nephropathy, including the involved mechanisms with basic researches.

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Anti-Metastatic Effects of Plant Sap-Derived Extracellular Vesicles in a 3D Microfluidic Cancer Metastasis Model

Journal of Functional Biomaterials ◽

10.3390/jfb11030049 ◽

2020 ◽

Vol 11 (3) ◽

pp. 49

Author(s):

Kimin Kim ◽

Jik-Han Jung ◽

Hye Ju Yoo ◽

Jae-Kyung Hyun ◽

Ji-Ho Park ◽

...

Keyword(s):

Extracellular Vesicles ◽

Cancer Metastasis ◽

Folk Medicine ◽

Therapeutic Effects ◽

Animal Testing ◽

Research Attention ◽

Altered Expression ◽

Dendropanax Morbifera ◽

Metastasis Model

Natural medicinal plants have attracted considerable research attention for their potential as effective drugs. The roots, leaves and stems of the plant, Dendropanax morbifera, which is endemic to southern regions of Asia, have long been used as a folk medicine to treat variety of diseases. However, the sap of this plant has not been widely studied and its bioactive properties have yet to be clearly elucidated. Here, we isolated extracellular vesicles from D. morbifera sap with the goal of improving the intracellular delivery efficiency and clinical effectiveness of bioactive compounds in D. morbifera sap. We further investigated the anti-metastatic effects of D. morbifera sap-derived extracellular vesicles (DMS-EVs) using a cancer metastasis model based on 3D microfluidic system that closely mimics the in vivo tumor environment. We found that DMS-EVs exerted a concentration-dependent suppressive effect on cancer-associated fibroblasts (CAFs), which are important mediators of cancer metastasis. DMS-EVs also altered expression level of genes, especially growth factor and extracellular matrix (ECM)-related genes, including integrin and collagen. Our findings suggest that DMS-EVs can act as anti-CAF agents to reduce CAFs in the tumor microenvironment. They further indicate the utility of our 3D microfluidic model for various drug-screening assays as a potential alternative to animal testing for use in validating therapeutic effects on cancer metastasis.

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Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1715554115 ◽

2018 ◽

Vol 115 (8) ◽

pp. 1697-1706 ◽

Cited By ~ 24

Author(s):

Xiaopu Zhou ◽

Yu Chen ◽

Kin Y. Mok ◽

Qianhua Zhao ◽

Keliang Chen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune System ◽

Chinese Population ◽

Disease Onset ◽

The Elderly ◽

Common Variants ◽

Altered Expression ◽

Risk Variants ◽

Regulatory Effects

Alzheimer’s disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10−14), two common variants, GCH1 (rs72713460, P = 4.36 × 10−5) and KCNJ15 (rs928771, P = 3.60 × 10−6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype–phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.

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