Midkine, a heparin-binding protein, is increased in the diabetic mouse kidney postmenopause

Estrogen is thought to protect against the development of chronic kidney disease, and menopause increases the development and severity of diabetic kidney disease. In this study, we used streptozotocin (STZ) to induce diabetes in the 4-vinylcyclohexene diepoxide (VCD)-treated mouse model of menopause. DNA microarrays were used to identify gene expression changes in the diabetic kidney postmenopause. An ANOVA model, CARMA, was used to isolate the menopause effect between two groups of diabetic mice, diabetic menopausal (STZ/VCD) and diabetic cycling (STZ). In this diabetic study, 8,864 genes of the possible 15,600 genes on the array were included in the ANOVA; 99 genes were identified as demonstrating a >1.5-fold up- or downregulation between the STZ/VCD and STZ groups. We randomly selected genes for confirmation by real-time PCR; midkine (Mdk), immediate early response gene 3 (IEX-1), mitogen-inducible gene 6 (Mig6), and ubiquitin-specific protease 2 (USP2) were significantly increased in the kidneys of STZ/VCD compared with STZ mice. Western blot analysis confirmed that Mdk and IEX-1 protein abundance was significantly increased in the kidney cortex of STZ/VCD compared with STZ mice. In a separate study, DNA microarrays and CARMA analysis were used to identify the effect of menopause on the nondiabetic kidney; VCD-treated mice were compared with cycling mice. Of the possible 15,600 genes on the array, 9,142 genes were included in the ANOVA; 20 genes were identified as demonstrating a >1.5-fold up- or downregulation; histidine decarboxylase and vanin 1 were among the genes identified as differentially expressed in the postmenopausal nondiabetic kidney. These data expand our understanding of how hormone status correlates with the development of diabetic kidney disease and identify several target genes for further studies.

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MicroRNAs in Diabetic Kidney Disease

International Journal of Endocrinology ◽

10.1155/2014/593956 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 18

Author(s):

Rong Li ◽

Arthur C. K. Chung ◽

Xueqing Yu ◽

Hui Y. Lan

Keyword(s):

Kidney Disease ◽

Messenger Rna ◽

Diabetic Kidney Disease ◽

Target Genes ◽

Therapeutic Potential ◽

Expression Patterns ◽

Diagnostic Tools ◽

Diabetic Kidney ◽

Functional Studies ◽

Gene Expression Studies

Rapid growth of diabetes and diabetic kidney disease exerts a great burden on society. Owing to the lack of effective treatments for diabetic kidney disease, treatment relies on drugs that either reduces its progression or involve renal replacement therapies, such as dialysis and kidney transplantation. It is urgent to search for biomarkers for early diagnosis and effective therapy. The discovery of microRNAs had lead to a new era of post-transcriptional regulators of gene expression. Studies from cells, experimental animal models and patients under diabetic conditions demonstrate that expression patterns of microRNAs are altered during the progression of diabetic kidney disease. Functional studies indicate that the ability of microRNAs to bind 3′ untranslated region of messenger RNA not only shows their capability to regulate expression of target genes, but also their therapeutic potential to diabetic kidney disease. The presence of microRNAs in plasma, serum, and urine has been shown to be possible biomarkers in diabetic kidney disease. Therefore, identification of the pathogenic role of microRNAs possesses an important clinical impact in terms of prevention and treatment of progression in diabetic kidney disease because it allows us to design novel and specific therapies and diagnostic tools for diabetic kidney disease.

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FcER1: A Novel Molecule Implicated in the Progression of Human Diabetic Kidney Disease

Frontiers in Immunology ◽

10.3389/fimmu.2021.769972 ◽

2021 ◽

Vol 12 ◽

Author(s):

Swastika Sur ◽

Mark Nguyen ◽

Patrick Boada ◽

Tara K. Sigdel ◽

Hans Sollinger ◽

...

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Target Genes ◽

Kidney Tissue ◽

Kidney Injury ◽

Rational Drug Design ◽

Transcriptional Analysis ◽

Peripheral Blood Mononuclear ◽

Tissue Samples ◽

Diabetic Kidney

Diabetic kidney disease (DKD) is a key microvascular complication of diabetes, with few therapies for targeting renal disease pathogenesis and progression. We performed transcriptional and protein studies on 103 unique blood and kidney tissue samples from patients with and without diabetes to understand the pathophysiology of DKD injury and its progression. The study was based on the use of 3 unique patient cohorts: peripheral blood mononuclear cell (PBMC) transcriptional studies were conducted on 30 patients with DKD with advancing kidney injury; Gene Expression Omnibus (GEO) data was downloaded, containing transcriptional measures from 51 microdissected glomerulous from patients with DKD. Additionally, 12 independent kidney tissue sections from patients with or without DKD were used for validation of target genes in diabetic kidney injury by kidney tissue immunohistochemistry and immunofluorescence. PBMC DKD transcriptional analysis, identified 853 genes (p < 0.05) with increasing expression with progression of albuminuria and kidney injury in patients with diabetes. GEO data was downloaded, normalized, and analyzed for significantly changed genes. Of the 325 significantly up regulated genes in DKD glomerulous (p < 0.05), 28 overlapped in PBMC and diabetic kidney, with perturbed FcER1 signaling as a significantly enriched canonical pathway. FcER1 was validated to be significantly increased in advanced DKD, where it was also seen to be specifically co-expressed in the kidney biopsy with tissue mast cells. In conclusion, we demonstrate how leveraging public and private human transcriptional datasets can discover and validate innate immunity and inflammation as key mechanistic pathways in DKD progression, and uncover FcER1 as a putative new DKD target for rational drug design.

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A network pharmacology approach to explore the mechanism of HuangZhi YiShen Capsule for treatment of diabetic kidney disease

Journal of Translational Internal Medicine ◽

10.2478/jtim-2021-0020 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Xue-Feng Zhou ◽

Wei-E Zhou ◽

Wen-Jing Liu ◽

Min-Jing Luo ◽

Xia-Qing Wu ◽

...

Keyword(s):

Molecular Docking ◽

Kidney Disease ◽

Signaling Pathways ◽

Diabetic Kidney Disease ◽

Target Genes ◽

Chemical Constituents ◽

Mendelian Inheritance ◽

Network Pharmacology ◽

Active Compounds ◽

Diabetic Kidney

Abstract Background and Objective HuangZhi YiShen Capsule (HZYS) is a Chinese patent herbal drug that protects kidney function in diabetic kidney disease (DKD) patients. However, the pharmacologic mechanisms of HZYS remain unclear. This study would use network pharmacology to explore the pharmacologic mechanisms of HZYS. Methods Chemical constituents of HZYS were obtained through the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and literature search. Potential targets of HZYS were identified by using the TCMSP and the SwissTarget Prediction databases. DKD-related target genes were collected by using the Online Mendelian Inheritance in Man, Therapeutic Target Database, GeneCards, DisGeNET, and Drugbank databases. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out to further explore the mechanisms of HZYS in treating DKD. Molecular docking was conducted to verify the potential interactions between the prime compounds and the hub genes. Results 179 active compounds and 620 target genes were obtained, and 571 common targets were considered potential therapeutic targets. The top 10 main active compounds of HZYS were heparin, quercetin, kaempferol, luteolin, methyl14-methylpentadecanoate, methyl (Z)-11-hexadecenoate, 17-hydroxycorticosterone, 4-pregnene-17α, 20β, 21-triol-3, 11-dione, wogonin, and hydroxyecdysone. Hub signaling pathways by which HZYS treating DKD were PI3K-Akt, MAPK, AGE-RAGE in diabetic complications, TNF, and apoptosis. The top 10 target genes associated with these pathways were IL6, MAPK1, AKT1, RELA, BCL2, JUN, MAPK3, MAP2K1, CASP3, and TNF. Quercetin and Luteolin were verified to have good binding capability with the hub potential targets IL6, MAPK1, AKT1 through molecular docking. Conclusion HZYS appeared to treat DKD by regulating the inflammatory, oxidative stress, apoptotic, and fibrosis signaling pathways. This study provided a novel perspective for further research of HZYS.

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Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease

10.1101/2021.08.27.21262264 ◽

2021 ◽

Author(s):

Niina Sandholm ◽

Joanne B Cole ◽

Viji Nair ◽

Xin Sheng ◽

Hongbo Liu ◽

...

Keyword(s):

Kidney Disease ◽

Association Study ◽

Diabetic Kidney Disease ◽

Target Genes ◽

Genome Wide Association Study ◽

Transmembrane Protein ◽

Meta Analysis ◽

Novel Genes ◽

Diabetic Kidney ◽

Genome Wide

Background: Diabetes is the leading cause of kidney disease, and heritability studies demonstrate a substantial, yet poorly understood, contribution of genetics to kidney complications in people with diabetes. Methods: We performed genome-wide association study (GWAS) meta-analyses using ten different phenotypic definitions of diabetic kidney disease (DKD), including nearly 27,000 individuals with diabetes, and integrated the results with various kidney omics datasets. Results: The meta-analysis identified a novel low frequency intronic variant (rs72831309) in the TENM2 gene encoding teneurin transmembrane protein 2 associated with a lower risk of the combined chronic kidney disease (CKD; eGFR<60 ml/min/1.73 m2) and DKD (microalbuminuria or worse) phenotype ("CKD-DKD", odds ratio 2.08, p=9.8×10-9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN - RESP18, GPR158, INIP - SNX30, LSM14A, and MFF, p<2.7×10-6). Integration of GWAS data with human glomerular and tubular expression data in a transcriptome-wide association study demonstrated higher tubular AKIRIN2 gene expression in DKD versus non-DKD controls (p=1.1×10-6). The lead SNPs within the DCLK1, AKIRIN2, SNX30 and three other gene regions significantly alterated the methylation at this region in kidneys (p<2.2×10-11). Expression of target genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes. For example, tubular TENM2 expression positively correlated with eGFR (p=2.3×10-9) and negatively with tubulointerstitial fibrosis (p=4.7×10-9), tubular DCLK1 expression positively correlated with fibrosis (p=1.6×10-12), and SNX30 level positively correlated with eGFR (p=7.6×10-13) and negatively with fibrosis (p<2×10-16). Conclusions: GWAS meta-analysis and integration with renal omics data points to novel genes contributing to pathogenesis of DKD.

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Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease

Metabolites ◽

10.3390/metabo11080469 ◽

2021 ◽

Vol 11 (8) ◽

pp. 469

Author(s):

Judy Baek ◽

Subramaniam Pennathur

Keyword(s):

Kidney Disease ◽

Murine Model ◽

Diabetic Kidney Disease ◽

Fractional Excretion ◽

Tca Cycle ◽

Tubular Secretion ◽

Metabolic Reprogramming ◽

Kidney Cortex ◽

Diabetic Kidney

Metabolic reprogramming is a hallmark of diabetic kidney disease (DKD); nutrient overload leads to increased production of metabolic byproducts that may become toxic at high levels. One metabolic byproduct may be 2-hydroxyglutarate (2-HG), a metabolite with many regulatory functions that exists in both enantiomeric forms physiologically. We quantitatively determined the levels of L and D-2HG enantiomers in the urine, plasma, and kidney cortex of db/db mice, a pathophysiologically relevant murine model of type 2 diabetes and DKD. We found increased fractional excretion of both L and D-2HG enantiomers, suggesting increased tubular secretion and/or production of the two metabolites in DKD. Quantitation of TCA cycle metabolites in db/db cortex suggests that TCA cycle overload and an increase in 2-HG precursor substrate, α-ketoglutarate, drive the increased L and D-2HG production in DKD. In conclusion, we demonstrated increased 2-HG enantiomer production and urinary excretion in murine type 2 DKD, which may contribute to metabolic reprogramming and progression of diabetic kidney disease.

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