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Abstract: TH-PO407

Targeting MicroRNA-132 Decreases Kidney Fibrosis: A Role for Altered Plasticity of Cells of Renin Lineage?

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 600 Development, Stem Cells, and Regenerative Medicine

Authors

  • van der Pluijm, Loïs, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Koudijs, Angela, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Rotmans, Joris I., Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Gross, Kenneth W., Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States
  • Van Zonneveld, Anton Jan, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
  • Bijkerk, Roel, Leids Universitair Medisch Centrum, Leiden, Zuid-Holland, Netherlands
Background

Recent research has highlighted the potential of cells of renin lineage (CoRL) in promoting intrinsic kidney regeneration. The juxtaglomerular CoRL can repopulate crucial glomerular cells such as podocytes and mesangial cells following renal injury. Besides beneficial redifferentiation, CoRL can give rise to pericytes and subsequently myofibroblasts, contributing to fibrotic tissue formation. Our recent findings suggest that cellular responses to injury are largely regulated at the post-transcriptional level, with microRNA-132 (miR-132) playing a pivotal role. Induced by high-salt conditions, miR-132 directly stimulates renin release from CoRL, while miR-132 also regulates genes involved in cell proliferation and kidney fibrosis. The current study aims to investigate the role of MiR-132 in CoRL plasticity.

Methods

We employed various experimental kidney injury models in Ren1cre-tdTomato CoRL-lineage trace mice, including 5/6 nephrectomy (5/6NX), uni- and bilateral ischemic reperfusion injury (uIRI and bIRI), while administering locked nucleic acid (LNA) antisense oligonucleotide inhibitor of miR-132 (antimir-132).

Results

Blood urea levels indicated improved kidney function in the loss-of-function models 5/6NX and bIRI upon miR-132 interference. Histological analysis showed a strong trend towards decreased fibrosis with miR-132 inhibition in all models, as well as an association of miR-132 knockdown with altered renin activity (PRA). Upon miR-132 knockdown, we observed a reduction in interstitial tdTomato+ cells, suggesting a decrease in CoRL-derived myofibroblasts. Intraglomerular cell fates of CoRL upon miR-132 modulation in the various injury models are currently explored.

Conclusion

Our study sheds light on the intricate role of miR-132 in kidney fibrosis and modulating the plasticity of CoRL therein. These findings suggest a potential therapeutic opportunity for targeting miR-132 to mitigate renal fibrosis. However, further investigation will be essential to fully elucidate the mechanisms underlying CoRL plasticity and the specific effects of miR-132 inhibition in different injury contexts.