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Abstract: SA-PO407

MiR-200b Induces ZEB1-Mediated Upregulation of Matriptase and Affects Expression of Podocin: A Proposed Mechanism of Podocyte Effacement and Proteinuria in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Tati, Ramesh, AstraZeneca AB, Mölndal, Sweden
  • Müller-Deile, Janina, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
  • Walentinsson, Anna, AstraZeneca AB, Mölndal, Sweden
  • Sopel, Nina, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
  • Carracedo, Miguel, AstraZeneca AB, Mölndal, Sweden
  • Lassen, Emelie, AstraZeneca AB, Mölndal, Sweden
  • Ebefors, Kerstin, Gothenburg University, Gothenburg, Sweden
  • Soderberg, Magnus, AstraZeneca AB, Mölndal, Sweden
  • Daniel, Christoph, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
  • Laerkegaard Hansen, Pernille B., AstraZeneca AB, Mölndal, Sweden
  • Schiffer, Mario, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
  • Nystrom, Jenny C., Gothenburg University, Gothenburg, Sweden
  • Buvall, Lisa, AstraZeneca AB, Mölndal, Sweden
Background

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and a predominant reason for renal failure. Evidence from previous research indicates that abnormal expression of microRNAs (miRs) links closely to the occurrence and progression of DKD

Methods

Expression of miRs in urine samples from DKD patients and in cultured renal cells stressed with transforming growth factor beta 1 (TGF-β1) was evaluated by TaqMan assay. The emerging miR of interest and its downstream targets were analyzed in human renal sections, in cultured human podocytes and in zebrafish.

Results

Cell free urine screening showed increased abundance of miR-200b in samples from patients with DKD when compared to healthy controls. In situ hybridization confirmed expression of miR-200b in kidney specimens from DKD patients, but was not detected in healthy renal parenchyma. Transcriptome profiling of cultured human podocytes overexpressing miR-200b identified this miR as a regulator of the ZEB1 mediated matriptase (ST14)/ podocin pathway and found TGF- β1 and high glucose (HG) stress to be upstream activators of miR-200b expression in these cells. Immunofluorescence analysis of kidney sections from DKD patients showed increased expression of ST14 and decreased expression of podocin when compared to healthy controls. Furthermore, injection of a miR-200b mimic in zebrafish larvae caused an upregulation of ST14 and was accompanied by phenotypic changes such as edema, proteinuria and podocyte effacement.

Conclusion

Our results show that miR-200b is expressed in glomeruli and found at elevated levels in urine of DKD patients. Stressors such as high glucose or TGF-β1 can activate transcription of miR-200b in human podocytes, leading to increased levels of matriptase, a serine protease previously shown to cleave podocin. The observed decrease in podocin levels in glomeruli from DKD patients, together with the effect of a miR-200b mimic on proteinuria and ultrastructure of the pronephros in zebrafish positions miR-200b as a key regulator that modulates matriptase overactivation in DKD and warrants further studies.