Serum microRNAs levels in primary focal segmental glomerulosclerosis

Background: TGF-β is known as an important stress factor of podocytes in glomerular diseases. Apart from activation of direct pro-apoptotic pathways we wanted to analyze micro-RNA (miRs) driven regulation of components involved in the integrity of the glomerular filtration barrier induced by TGF-β. Since miR-143-3p (miR-143) is described as a TGF-β inducible miR in other cell types, we examined this specific miR and its ability to induce glomerular pathology. Methods: We analyzed miR-143 expression in cultured human podocytes after stimulation with TGF-β. We also microinjected zebrafish eggs with a miR-143 mimic or with morpholinos specific for its targets syndecan and versican and compared phenotype and proteinuria development. Results: We detected a time dependent, TGF-β inducible expression of miR-143 in human podocytes. Targets of miR-143 relevant in glomerular biology are syndecans and versican, which are known components of the glycocalyx. We found that syndecan 1 and 4 were predominantly expressed in podocytes while syndecan 3 was largely expressed in glomerular endothelial cells. Versican could be detected in both cell types. After injection of a miR-143 mimic in zebrafish larvae, syndecan 3, 4 and versican were significantly downregulated. Moreover, miR-143 overexpression or versican knockdown by morpholino caused loss of plasma proteins, edema, podocyte effacement and endothelial damage. In contrast, knockdown of syndecan 3 and syndecan 4 had no effects on glomerular filtration barrier. Conclusion: Expression of versican and syndecan isoforms is indispensable for proper barrier function. Podocyte-derived miR-143 is a mediator for paracrine and autocrine cross talk between podocytes and glomerular endothelial cells and can alter expression of glomerular glycocalyx proteins.

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“…This is well in line with other reports where miRs were upregulated under mechanical stress in podocytes or nephrotic diseases [14,32,33].…”

Section: Discussionsupporting

confidence: 82%

Overexpression of TGF-β Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans

Müller-Deile

Gellrich

Schenk

et al. 2016

Cell Physiol Biochem

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“…MiR-192 is one of the specific miRNAs highly expressed in the liver, pancreas, and kidneys [15,37]. It was reported that miR-192 increased in the renal tissues in diabetic nephropathy and hypertensive nephrosclerosis, as well as in focal segmental glomerulosclerosis circulation [16,18,24]. In the present study, the IgA nephropathy patients had a lower intrarenal and serum miR-192 expression than the normal controls.…”

Section: Discussionmentioning

confidence: 48%

Serum miR-192 Is Related to Tubulointerstitial Lesion and Short-Term Disease Progression in IgA Nephropathy

Fan

Zhu

et al. 2019

Nephron

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Background/Aims: Clinical manifestation and renal histology serve as the current “gold standard” for evaluation of renal lesions in IgA nephropathy. MiR-192 is regarded as a potential noninvasive biomarker for kidney disease. We sought to elucidate a relationship between intrarenal, serum, and urinary exosomal miR-192 with renal lesions and disease progression in IgA nephropathy. Methods: Serum and urinary exosomal miR-192 were detected and correlated with clinical and pathological parameters from consecutive IgA nephropathy patients (n = 50) and healthy control patients (n = 25). Patients then received a follow-up of 24 months after biopsy. Disease progression was defined as a 40% reduction in estimated glomerular filtration rate. Expression of miR-192 was quantified by Taqman RT-PCR. Intrarenal miR-192 was detected in 8 IgA nephropathy patients and 4 matched patients receiving kidney nephrectomy as controls via in situ hybridization. TGF-β1 and E-cadherin expression in renal tissue was evaluated using immunohistochemistry. Results: Intrarenal miR-192 was correlated with serum miR-192 (r = 0.690, p = 0.013). Both intrarenal and serum miR-192 decreased in IgA nephropathy patients and were correlated with estimated glomerular filtration ratio. Patients with lower intrarenal and serum miR-192 levels had a higher interstitial fibrosis and tubular atrophy score, more severe lesions in tubular atrophy, and interstitial inflammation. Renal E-cadherin expression was correlated (r = 0.484, p = 0.004) and TGF-β1 was inversely correlated (r = –0.527, p < 0.001) with serum miR-192 in IgA. Patients with higher serum miR-192 had a lower disease progression rate over the course of 2 years (0 vs. 16%, p = 0.028). No correlation was found in urinary exosomal miR-192 with the clinical and pathological parameters mentioned earlier. Conclusions: Lower serum miR-192 in IgA nephropathy patients indicates lower intrarenal miR-192 expression, more severe tubular atrophy, interstitial inflammation, and fibrotic tendency (with higher TGF-β and E-cadherin in renal miR-192). IgA nephropathy patients with higher serum miR-192 are less likely to have renal function decline over the course of 2 years.

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“…Mechanistically, miR-193a exerts its deleterious effect by downregulating WT1, a master regulator of podocyte homeostasis (24). Separately, in a cohort of patients with idiopathic nephrotic syndrome, miR-192 and miR-205 levels were higher in the serum of patients with FSGS than in those with minimalchange disease (25). miR-192 levels also correlated significantly with the degree of interstitial fibrosis in patients with FSGS (25).…”

mentioning

confidence: 87%

Can Biomarkers of Disease Activity Guide Treatment in FSGS?

2014

Clinical Journal of the American Society of Nephrology

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Serum microRNAs levels in primary focal segmental glomerulosclerosis

Cited by 43 publications

References 27 publications

Overexpression of TGF-β Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans

Overexpression of TGF-β Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans

Serum miR-192 Is Related to Tubulointerstitial Lesion and Short-Term Disease Progression in IgA Nephropathy

Can Biomarkers of Disease Activity Guide Treatment in FSGS?

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