Kidney Week

Abstract: FR-OR105

Transcription Factor Meis1 Is Upregulated in Kidney Stroma after Injury and in Aging and Regulates Tubulointerstitial Cross-Talk

Session Information

• Stress Signaling and Fibrosis
  November 03, 2017 | Location: Room 277, Morial Convention Center
  Abstract Time: 04:30 PM - 04:42 PM

Category: Cell Biology

• 202 Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation

Authors

• Chang Panesso, Monica, Washington University in St. Louis, St Louis, Missouri, United States

Monica Chang Panesso, MD

• Kadyrov, Farid F, Washington University in St Louis, St Louis, Missouri, United States

Farid F Kadyrov,

• Machado, Flavia G., Washington University in St Louis, School of Medicine, St Louis, Missouri, United States

Flavia G. Machado,

• Humphreys, Benjamin D., Washington University School of Medicine, Clayton, Missouri, United States

Benjamin D. Humphreys,

Background

P16^INK4a, a cell cycle regulator and mediator of cellular senescence, accumulates during aging including in kidney. Meis1 is a transcription factor known to regulate p16^INK4a and other cyclin-dependent kinases. We hypothesized that Meis1 may mediate cell senescence in kidney and investigated the expression and function of Meis1 in kidney injury and aging.

Methods

We used Meis1ECFP reporter mice and antibody-based detection of endogenous Meis1. We also deleted Meis1 from kidney stroma by crossing a FoxD1-GFPCre with the Meis1-floxed allele.

Results

Meis1 was strongly expressed in PDGFRβ+ pericytes and fibroblasts based on both immunofluorescence and Meis1ECFP reporter mice. Meis1 mRNA and protein was upregulated after bilateral ischemia-reperfusion injury (IRI). It was also strongly upregulated in myofibroblasts of aged (23 mo) mice. To examine the functional role of Meis1 in kidney stroma, we generated bigenic Meis1^f/f;FoxD1GC^+/-. Examination by qPCR and IF staining showed efficient Meis1 deletion of approximately ~90% compared to controls. There was no gross histological abnormality at either P0 or P30 in the Meis1^f/f;FoxD1GC^+/- compared to littermate controls. However by P30, kidneys of Meis1^f/f;FoxD1GC^+/- mice weighed less compared to controls and had a higher BUN. Further histological evaluation at P30, revealed unexpected expression of Kidney Injury Molecule-1 (Kim1) protein expression in the outer medulla, indicating tubular injury. Kim1 upregulation was confirmed by qPCR. There was no NGAL expression indicating that the injury pattern was restricted to the S3 proximal tubular segment. Meis1 knockout mice had normal peritubular capillary density, normal numbers of glomeruli and no albuminuria.

Conclusion

Meis1 is upregulated in myofibroblasts during kidney fibrosis and in aging. Surprisingly, conditional deletion of Meis1 in the stromal lineage led to focal injury of the S3 segment of the proximal tubule in the absence of structural kidney abnormalities. These findings suggest that Meis1 expression in kidney stroma regulates proximal tubule health by a non cell-autonomous mechanism.

Funding

• NIDDK Support