Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases

Müller-Deile, Janina; Dannenberg, Jan-Hermen; Schröder, Patricia; Lin, Meei-Hua; Miner, Jeffrey H.; Chen, Rongjun; Bräsen, Jan-Hinrich; Thum, Thomas; Nyström, Jenny; Staggs, Lynne; Haller, Hermann; Fiedler, Jan; Lorenzen, Johan M.; Schiffer, Mario

doi:10.1016/j.kint.2017.03.005

Cited by 65 publications

(96 citation statements)

References 53 publications

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“…MiR-378a-3p was found in urines samples from patients with MGN, FSGS and MCD and upregulated in cultured human podocytes in response to TGF-β treatment. In a previous study we could confirm the importance of miR-378a-3p for glomerular function as it is a regulator of the glomerular matrix protein nephronectin [17]. Thus, our data confirm that urinary miRs seem to be markers for renal injury.…”

Section: Discussionsupporting

confidence: 81%

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Identification of Cell-and Disease-Specific Micro RNAs in Glomerular Pathologies

Müller-Deile¹,

Dannenberg²,

P³

et al. 2017

J Mol Genet Med

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Background: MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression in physiological processes as well as in diseases. Currently miRs are already used to find novel mechanisms involved in diseases and in the future, they might serve as diagnostic markers. To identify miRs that play a role in glomerular diseases urinary miR-screenings are a frequently used tool. However, miRs that are detected in the urine might simply be filtered from the blood stream and could have been produced anywhere in the body, so they might be completely unrelated to the diseases. Methods:We performed a combined miR-screening in pooled urine samples from patients with different glomerular diseases as well as in cultured human podocytes, human mesangial cells, human glomerular endothelial cells, and human tubular cells. The miR-screening in renal cells was done in untreated conditions and after stimulation with TGF-β.Results: A merge of the detected regulated miRs led us to identify disease-specific, cell type-specific and cell stress-induced miRs. Further, urinary miRs from patients with different glomerular diseases could be assigned to the different renal cell types. Conclusion:Thus, a combined urinary and cell miR-screening can improve the interpretation of screening results. These data are useful to identify novel miRs potentially involved in glomerular diseases.

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Section: Discussionsupporting

confidence: 81%

“…For example, miR-378a-3p was specifically upregulated in cultured human podocytes. The importance of miR-378a-3p for glomerular filter function and ultrastructure was previously described by us [17].…”

Section: Mirs Regulated By Tgf-β In Cultured Renal Cellsmentioning

confidence: 82%

Identification of Cell-and Disease-Specific Micro RNAs in Glomerular Pathologies

Müller-Deile¹,

Dannenberg²,

P³

et al. 2017

J Mol Genet Med

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“…Cell adhesion assay analysis showed that the adhesion ability decreased significantly under the costimulation of high glucose combined with TGF‐β1, which suggested that podocyte dysfunction and injury occurred. At this moment, different concentrations of BBR (15, 30, 60 and 90 μmol/L) were added to the cultured cells, and the results showing that BBR could enhance the cell adhesion ability obviously seem to indicate that BBR could reverse podocyte dysfunction and injury after 48‐h stimulation.…”

Section: Discussionmentioning

confidence: 93%

Berberine ameliorates renal impairment and inhibits podocyte dysfunction by targeting the phosphatidylinositol 3‐kinase–protein kinase B pathway in diabetic rats

Zhou

Ding

et al. 2019

J of Diabetes Invest

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Aims/Introduction Amelioration of renal impairment is the key to diabetic nephropathy (DN) therapy. The progression of DN is closely related to podocyte dysfunction, but the detailed mechanism has not yet been clarified. The present study aimed to explore the renal impairment amelioration effect of berberine and related mechanisms targeting podocyte dysfunction under the diabetic state. Materials and Methods Streptozotocin (35 mg/kg) was used to develop a DN rat model together with a high‐glucose/high‐lipid diet. Renal functional parameters and glomerular ultrastructure changes were recorded. The alterations of phosphatidylinositol 3‐kinase (PI3K), protein kinase B (Akt) and phosphorylated Akt in the kidney cortex were determined by western blot. Meanwhile, podocyte dysfunction was induced and treated with berberine and LY294002. After that, podocyte adhesion functional parameters, protein biomarker and the alterations of the PI3K–Akt pathway were detected. Results Berberine reduces the increased levels of biochemical indicators, and significantly improves the abnormal expression of PI3K, Akt and phosphorylated Akt in a rat kidney model. In vitro, a costimulating factor could obviously reduce the podocyte adhesion activity, including decreased expression of nephrin, podocin and adhesion molecule α3β1 levels, to induce podocyte dysfunction, and the trends were markedly reversed by berberine and LY294002 therapy. Furthermore, reduction of PI3K and phosphorylated Akt levels were observed in the berberine (30 and 60 μmol/L) and LY294002 (40 μmol/L) treatment group, but the Akt protein expression showed little change. Conclusions Berberine could be a promising antidiabetic nephropathy drug through ameliorating renal impairment and inhibiting podocyte dysfunction in diabetic rats, and the underlying molecular mechanisms might be involved in the regulation of the PI3K–Akt signaling pathway.

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Section: The Zebrafish Model To Study the Role Of Micrornas In Glomermentioning

confidence: 99%

“…The clinical relevance of miR-378a-3p was shown by the detection of upregulated miR-378a-3p in urine samples as well as glomeruli of kidney biopsies of patients with idiopathic membranous glomeruolonephritis and focal segmental glomerulosclerosis [24]. Due to the nature of miRs that often have multiple targets; we cannot rule out completely that the observed phenotypes in the zebrafish after miR-143-3p and miR-378a-3p over expression were due to knockdown of other targets than vcans and sdcs a.e.…”

mentioning

confidence: 99%

The Zebrafish Model to Study the Role of microRNAs in Glomerular Function and Disease

Müller-Deile¹,

Schiffer²

2017

Adv Tech Biol Med

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The zebrafish physiology of many organs including the kidney is very similar to that of human beings. Zebrafish develop from a fertilized egg to free-swimming larvae in only 48 h. The zebrafish larvae's correlate for the human kidney is the pronephros consisting of two nephrons with glomeruli fused at the embryo mid-line ventral to the dorsal aorta [1] ( Figure 1a).The glomerular filtration barrier of the pronephros is ultrastructurally almost indistinguishable from a mammalian glomerulus with interdigitating podocyte foot processes, a thin glomerular basement membrane and a fenestrated glomerular endothelium [2]. These structures can be found in 120 h old zebrafish larvae on ultrastructural level (Figures 1b and 1c). To generate these pictures zebrafish larvae were fixed in solution D and embedded in EPON. Ultrathin sectioning from head to tail was performed with a microtome until the glomerular region was found and sections transferred onto copper slit grids that were stained with uranyl acetate and lead citrate. Imaging was done with a transmission electron microscope.The pronephros tubular epithelium is composed of two proximal tubule segments, a proximal straight tubule as well as the early and late distal tubus [3]. The tubular system expresses a brush border of microvilli on the apical side for reabsorption processes (Figure 1d). The glomerular filtration of the zebrafish pronephros begins around 48 h post fertilization (hpf) [4]. Taking into consideration the structural and functional similarities and the fact that zebrafish gene expression can easily be influenced by specific knockdown and overexpression techniques using microinjections of morpholinos (MOs), mRNAs, microRNAs (miRs), small RNAs or CRISPR/Cas9 technology, the zebrafish serves as an ideal model to study glomerular diseases [5]. We and others successfully used the zebrafish model to screen for novel genes involved in kidney diseases [6][7][8]. On the other hand, gene mutations identified from human genetic studies can be verified as causative factors of proteinuric kidney disease in the zebrafish model. An upcoming field of research interest is the role of miRs in disease processes. MiRs regulate gene expression posttranscriptional by binding to the 3'-untranslated region (3' UTR) of a target mRNA and inhibiting translation [9,10]. Different miRs have been found to be enriched in human kidneys include miR-192, miR-194, miR-204, miR-215 and miR-216 [11]. MiRs are also essential for podocyte homeostasis [12][13][14][15] and can be secreted in body fluids [16,17].To antagonize the function of miRs, several antagomirs have been engineered and are commercially available. On the contrary, miR effects can be enhanced with miR mimics, which are chemically modified short double-stranded RNA sequences.Delivery of miRs in the zebrafish larvae system can be accomplished by microinjection of miR mimics in one-to-four cell stage or at 48 hpf by cardinal vein (c.v.) injection. After injections in egg stage the miR mimic is equally distributed in all zebra...

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Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases

Cited by 65 publications

References 53 publications

Identification of Cell-and Disease-Specific Micro RNAs in Glomerular Pathologies

Identification of Cell-and Disease-Specific Micro RNAs in Glomerular Pathologies

Berberine ameliorates renal impairment and inhibits podocyte dysfunction by targeting the phosphatidylinositol 3‐kinase–protein kinase B pathway in diabetic rats

The Zebrafish Model to Study the Role of microRNAs in Glomerular Function and Disease

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