The inducible deletion of Drosha and microRNAs in mature podocytes results in a collapsing glomerulopathy

Zhdanova, Olga; Srivastava, S. K.; Di, Lie; Zhai, Li; Tchelebi, Leila; Dworkin, Sara; Johnstone, Duncan B.; Zavadil, Jiří; Chong, Mark M.W.; Littman, Dan R.; Holzman, Lawrence B.; Barisoni, Laura; Skolnik, Edward Y.

doi:10.1038/ki.2011.122

Cited by 107 publications

(81 citation statements)

References 57 publications

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“…[52][53][54][55][56][57][58][59][60] In the kidney, miRs have been linked to diabetic nephropathy, polycystic kidney disease, renal cancer, AKI, transplant rejection, and kidney development. 59,[61][62][63][64][65][66] Recently, several studies have focused on the role of miR-192, an miR known to be expressed in the kidney cortex, in the profibrotic progression of nephropathy. 66,67 MiRs also appear to play a significant role in normal kidney physiology as conditional deletion of Dicer or Drosha in podocytes results in glomerular damage.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport

Edinger

Coronnello²,

Bodnar³

et al. 2014

Journal of the American Society of Nephrology

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A role for microRNAs (miRs) in the physiologic regulation of sodium transport in the kidney has not been established. In this study, we investigated the potential of aldosterone to alter miR expression in mouse cortical collecting duct (mCCD) epithelial cells. Microarray studies demonstrated the regulation of miR expression by aldosterone in both cultured mCCD and isolated primary distal nephron principal cells. Aldosterone regulation of the most significantly downregulated miRs, mmu-miR-335-3p, mmu-miR-290-5p, and mmu-miR-1983 was confirmed by quantitative RT-PCR. Reducing the expression of these miRs separately or in combination increased epithelial sodium channel (ENaC)-mediated sodium transport in mCCD cells, without mineralocorticoid supplementation. Artificially increasing the expression of these miRs by transfection with plasmid precursors or miR mimic constructs blunted aldosterone stimulation of ENaC transport. Using a newly developed computational approach, termed ComiR, we predicted potential gene targets for the aldosterone-regulated miRs and confirmed ankyrin 3 (Ank3) as a novel aldosterone and miR-regulated protein.A dual-luciferase assay demonstrated direct binding of the miRs with the Ank3-39 untranslated region. Overexpression of Ank3 increased and depletion of Ank3 decreased ENaC-mediated sodium transport in mCCD cells. These findings implicate miRs as intermediaries in aldosterone signaling in principal cells of the distal kidney nephron.

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Section: Discussionmentioning

confidence: 99%

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport

Edinger

Coronnello²,

Bodnar³

et al. 2014

Journal of the American Society of Nephrology

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“…28,29 Podocyte-specific deletion of Drosha (i.e., another RNAase III required for production of pre-miRNA within nucleus) resulted in a similar phenotype, confirming the role for miRNAs in the maintenance of normal function of mature podocytes that is disrupted in podocytopathies. 30 Despite the recognized role of the miR-30 family in podocyte homeostasis, 28,29 the finding here that glomerular levels of miR-30 family were unchanged rules out its likely involvement in an intranephron pathway underlying propagation of glomerular injury in MWF rats. Similarly, upregulation of miR-192 was previously reported in both diabetic glomeruli and whole kidney of animals with nondiabetic proteinuric nephropathies 31,32 possibly explaining TGF-b-mediated injury.…”

Section: Discussionmentioning

confidence: 83%

MicroRNA-324-3p Promotes Renal Fibrosis and Is a Target of ACE Inhibition

Macconi

Tomasoni

Romagnani

et al. 2012

Journal of the American Society of Nephrology

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The contribution of microRNA (miRNA) to the pathogenesis of renal fibrosis is not well understood. Here, we investigated whether miRNA modulates the fibrotic process in Munich Wistar Fromter (MWF) rats, which develop spontaneous progressive nephropathy. We analyzed the expression profile of miRNA in microdissected glomeruli and found that miR-324-3p was the most upregulated. In situ hybridization localized miR-324-3p to glomerular podocytes, parietal cells of Bowman's capsule, and most abundantly, cortical tubules. A predicted target of miR-324-3p is prolyl endopeptidase (Prep), a serine peptidase involved in the metabolism of angiotensins and the synthesis of the antifibrotic peptide N-acetyl-serylaspartyl-lysyl-proline (Ac-SDKP). In cultured tubular cells, transient transfection with a miR-324-3p mimic reduced Prep protein and activity, validating Prep as a target of this miRNA. In MWF rats, upregulation of miR-324-3p associated with markedly reduced expression of Prep in both glomeruli and tubules, low urine Ac-SDKP, and increased deposition of collagen. ACE inhibition downregulated glomerular and tubular miR-324-3p, promoted renal Prep expression, increased plasma and urine Ac-SDKP, and attenuated renal fibrosis. In summary, these results suggest that dysregulation of the miR-324-3p/Prep pathway contributes to the development of fibrosis in progressive nephropathy. The renoprotective effects of ACE inhibitors may result, in part, from modulation of this pathway, suggesting that it may hold other potential therapeutic targets. 23: 149623: -150523: , 201223: . doi: 10.1681 Munich Wistar Fromter (MWF) is an inbred rat strain characterized by inborn nephron deficit, glomerular hypertrophy, and high urinary protein excretion. 1,2 Males develop hypertension and overt proteinuria with age. 3,4 Angiotensin II (Ang II) has a direct role in the pathogenesis of proteinuria and glomerular injury by decreasing the size selectivity of the glomerular capillary barrier against the filtration of plasma proteins 5,6 that is followed by development of glomerulosclerosis. 4 Treatment with an angiotensin-converting enzyme inhibitor (ACEi) protects MWF rats from kidney damage by both preserving and remodeling the glomerular barrier, thus inducing regression of proteinuria and glomerulosclerosis. 7,8 A large body of evidence in this model and other animal models and clinical trials confirms that Ang II is a potential therapeutic target for remission/regression of progressive glomerulopathies. 9,10 In advanced nephropathy, J Am Soc Nephrol

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“…18 It was previously shown that global podocytespecific ablation of miRNAs by knockout of the miRNA processing enzymes Dicer or Drosha leads to proteinuria and glomerulosclerosis. 19,20 Here, we provide a mechanistic insight into the molecular pathogenesis of podocyte injury induced by dysregulation of a single miRNA.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-206 and its down-regulation of Wilms’Tumor-1 dictate podocyte health in adriamycin-induced nephropathy

Guo

2016

Renal Failure

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Background: Focal segmental glomerulosclerosis (FSGS) is a frequent and severe glomerular disease characterized by destabilization of podocyte foot processes. Emerging evidence suggests that microRNAs play crucial roles in podocyte homeostasis. The aim of the present study was to determine the role of miR-206 in podocyte injury and to elucidate the mechanisms responsible for the damage to podocyte. Methods: FSGS nephropathy model was induced by a single intravenous injection of Adriamycin (ADR) in BALB/c mice and the levels of proteinuria were measured on week of 1,3,5. The conditionally immortalized mouse podocyte cell line 5 was either transfected with microRNA mimics or negative control. Real-time PCR analysis was conducted to demonstrate the microRNA level in the glomeruli. Expression of Wilms' tumor-1 (WT1) and synaptopodin were detected by immunofluorescence and western blotting. Results: The results revealed that miR-206 was up-regulated in ADR nephropathy mice, which led to severe podocyte injury and inhibited the expression of WT1 and synaptopodin. Using luciferase reporter assays, WT1 was identified as a target gene of miR-206. In vitro, over expression of miR-206 induced WT1 and synaptopodin degradation and actin rearrangement, initiating a catastrophic collapse of the entire podocyte-stabilizing system. Conclusions: Over expression of miR-206 promotes podocyte injury via downregulation of WT1, which provides a new pathogenic mechanism for FSGS and miR-206 may be a potential therapeutic target.

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The inducible deletion of Drosha and microRNAs in mature podocytes results in a collapsing glomerulopathy

Cited by 107 publications

References 57 publications

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport

MicroRNA-324-3p Promotes Renal Fibrosis and Is a Target of ACE Inhibition

MicroRNA-206 and its down-regulation of Wilms’Tumor-1 dictate podocyte health in adriamycin-induced nephropathy

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