Reduced Autophagy by a microRNA-mediated Signaling Cascade in Diabetes-induced Renal Glomerular Hypertrophy

Deshpande, Supriya; Abdollahi, Maryam; Wang, Mei; Lanting, Linda; Kato, Mitsuo; Natarajan, Rama

doi:10.1038/s41598-018-25295-x

Cited by 37 publications

(25 citation statements)

References 58 publications

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“…miR-NA-181a downregulates DEPTOR (mTOR inhibitor) and activates mTORC2, which activates Akt in TGFβ-induced glomerular MC hypertrophy and ECM protein expression [ 91 ]. Autophagy inhibition by the miR-192 cascade induces hypertrophy through Akt activation and FoxO3a phosphorylation [ 92 ]. About 40 miRNAs are included in the miR-379 cluster, which is regulated by endoplasmic reticulum (ER) stress in DKD [ 19 ].…”

Section: Ncrnas In the Early Stage Of Dkdmentioning

confidence: 99%

Noncoding RNAs as therapeutic targets in early stage diabetic kidney disease

Kato

2018

Kidney Res Clin Pract.

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Diabetic kidney disease (DKD) is a major renal complication of diabetes that leads to renal dysfunction and end-stage renal disease (ESRD). Major features of DKD include accumulation of extracellular matrix proteins and glomerular hypertrophy, especially in early stage. Transforming growth factor-β plays key roles in regulation of profibrotic genes and signal transducers such as Akt kinase and MAPK as well as endoplasmic reticulum stress, oxidant stress, and autophagy related to hypertrophy in diabetes. Many drugs targeting the pathogenic signaling in DKD (mostly through protein-coding genes) are under development. However, because of the limited number of protein-coding genes, noncoding RNAs (ncRNAs) including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are attracting more attention as potential new drug targets for human diseases. Some miRNAs and lncRNAs regulate each other (by hosting, enhancing transcription from the neighbor, hybridizing each other, and changing chromatin modifications) and create circuits and cascades enhancing the pathogenic signaling in DKD. In this short and focused review, the functional significance of ncRNAs (miRNAs and lncRNAs) in the early stages of DKD and their therapeutic potential are discussed.

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Section: Ncrnas In the Early Stage Of Dkdmentioning

confidence: 99%

Noncoding RNAs as therapeutic targets in early stage diabetic kidney disease

Kato

2018

Kidney Res Clin Pract.

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“…One severe complication of T2DM is type 2 diabetic nephropathy (T2DN), which is characterized by hypertension, albuminuria, and a progressive decline in glomerular filtration rate, developing into end-stage renal disease [ 17 , 18 ]. There is increasing evidence showing that TGF-β1 takes part in the pathogenesis of T2DN [ 19 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

Relationship between transforming growth factor-β1 and type 2 diabetic nephropathy risk in Chinese population

Zhou

Zhong

et al. 2018

BMC Med Genet

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BackgroundDiabetes mellitus (DM) is divided into four different etiological categories: type 1 DM (T1DM), type 2 DM (T2DM), other specific types, and gestational DM. One severe complication of T2DM is type 2 diabetic nephropathy (T2DN). The possible association of serum transforming growth factor-β1 (TGF-β1) levels and the TGF-β1 T869C gene polymorphism with patient susceptibility to T2DN in Chinese population is unclear at present. This study was conducted to assess these relationships in Chinese population by a meta-analysis.MethodsAssociation reports were searched and pulled from the Cochrane Library, the China Biological Medicine Database (CBM), and PubMed on March 1, 2018, and eligible studies were selected and used for calculations. The results were expressed as weighted mean differences (MD) for continuous data. Odds ratios (OR) were used to express the results for dichotomous data. Additionally, 95% confidence intervals (CI) were calculated.ResultsForty-eight reports for the relationship between serum TGF-β1 levels and the risk of T2DN and 13 studies on the association of the TGF-β1 T869C gene polymorphism with susceptibility to T2DN in Chinese population were retrieved from this study. Serum TGF-β1 levels in the T2DM group were higher than those in the normal control group (MD = 17.30, 95% CI: 12.69–21.92, P < 0.00001). The serum TGF-β1 level in the T2DN group was significantly higher than that in the normal control group (MD = 70.03, 95% CI: 60.81–79.26, P < 0.00001;). The serum TGF-β1 level in the T2DN group was significantly higher than that in the T2DM group (MD = 56.18, 95% CI: 46.96–65.39, P < 0.00001). Serum TGF-β1 levels in T2DM patients with microalbuminuria were increased when compared with those in T2DM patients with normoalbuminuria. Furthermore, serum TGF-β1 levels in T2DM patients with macroalbuminuria were increased when compared with those in T2DM patients with microalbuminuria. The TGF-β1 T allele, TT allele and CC genotype were associated with T2DN susceptibility in Chinese population (T: OR = 0.74, 95% CI: 0.59–0.92, P = 0.007; TT: OR = 0.55, 95% CI: 0.31–0.96, P = 0.04; CC: OR = 1.38, 95% CI: 1.14–1.67, P = 0.001).ConclusionsHigh levels of TGF-β1 are associated with susceptibility to T2DM, T2DN and the progression of proteinuria in T2DN patients in Chinese population. Further, the TGF-β1 T allele, and TT genotype were protective factors against the onset of T2DN and CC genotype was a risk factor for the susceptibility of T2DN in Chinese populations.

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“…miRNA‐22 is found to suppress autophagy and inhibition of the endogenous miRNA‐22 increased autophagy and alleviated high glucose‐induced Col 4 and α‐SMA expression in NRK‐52E cells . Deshpande et al reported that the expression of autophagy genes was decreased in kidneys of STZ‐induced and db/db diabetic mice. miRNA‐192 inhibitors can reverse the reduction of autophagy genes in these mice.…”

Section: The Role Of Mirnas In the Pathogenesis Of Dkdmentioning

confidence: 99%

“…In kidneys of diabetic miRNA‐192‐KO mice, downregulation of autophagy genes was also attenuated. In mouse glomerular MCs with TGF‐β1 stimulation, miRNA‐192 mimic oligonucleotides decreased the expression of autophagy genes, indicating miRNA‐192 as a potential therapeutic target for DKD …”

Section: The Role Of Mirnas In the Pathogenesis Of Dkdmentioning

confidence: 99%

MicroRNA as novel biomarkers and therapeutic targets in diabetic kidney disease: An update

et al. 2019

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Diabetic kidney disease (DKD) is a life‐limiting condition characterized by progressive and irreversible loss of renal function. Currently, the estimated glomerular filtration rate (eGFR) and albuminuria are used as key markers to define DKD. However, they may not accurately indicate the degree of renal dysfunction and injury. Current therapeutic approaches for DKD, including attainment of blood pressure goals, optimal control of blood glucose and lipid levels, and the use of agents to block the renin‐angiotensin‐aldosterone system (RAAS) can only slow the progression of DKD. Hence, early diagnosis and innovative strategies are needed to both prevent and treat DKD. In recent years, a novel class of noncoding RNA, microRNAs (miRNAs) are reported to be involved in all biological processes, including cellular proliferation, apoptosis, and differentiation. miRNAs are small noncoding RNAs that regulate gene expression by posttranscriptional and epigenetic mechanisms. They are found to be in virtually all body fluids and used successfully as biomarkers for various diseases. Urinary miRNAs correlate with clinical and histologic parameters in DKD and differential urinary miRNA expression patterns have been reported. Kidney fibrosis is the common end stage of various CKD including DKD. Transforming growth factor‐β(TGF‐β) is regarded as the master regulator of kidney fibrosis, which is likely at least in part through regulating miRNA expression. miRNA are widely involved in the progression of DKD via many molecular mechanisms. In this review, the involvement of miRNA in fibrosis, inflammation, hypertrophy, autophagy, endoplasmic reticulum (ER) stress, oxidative stress, insulin resistance, and podocyte injury will be discussed, as these mechanisms are believed to offer new therapeutic targets that can be exploited to develop important treatments for DKD over the next decade.

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Reduced Autophagy by a microRNA-mediated Signaling Cascade in Diabetes-induced Renal Glomerular Hypertrophy

Cited by 37 publications

References 58 publications

Noncoding RNAs as therapeutic targets in early stage diabetic kidney disease

Noncoding RNAs as therapeutic targets in early stage diabetic kidney disease

Relationship between transforming growth factor-β1 and type 2 diabetic nephropathy risk in Chinese population

MicroRNA as novel biomarkers and therapeutic targets in diabetic kidney disease: An update

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