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Kidney Week

Abstract: SA-OR60

SARA in the Kidney: Regulation of Cell Phenotype as a Potential Therapeutic Target in Renal Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Dalal, Vidhi, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
  • Liang, Xiaoyan, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
  • Corano Scheri, Katia, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
  • Hayashida, Tomoko, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
Background

Epithelial cells play an important role in renal fibrosis. After injury, podocytes and renal tubular epithelial cells (TECs) dedifferentiate. When dedifferentiated, podocytes detach from the glomerular basement membrane, while TECs stimulate surrounding cells to transdifferentiate into myofibroblasts, thus resulting in glomerulosclerosis and tubulointerstitial fibrosis respectively. Our laboratory has identified a protein called Smad Anchor for Receptor Activation (SARA) as a key factor for maintaining cellular phenotype in the face of fibrogenesis. Here, we aim to determine if SARA overexpression in podocytes and TECs can prevent their dedifferentiation and reduce fibrosis in mouse models of glomerular and tubulointerstitial disease.

Methods

SARA overexpression was driven either by Podocin-Cre in podocytes (SARA podo) and Pax8-rtTA, tet-O-Cre in TECs (SARATEC) in mice. SARA negative littermates (Ctrlpodo and CtrlTEC mice) were used as controls. SARA/Ctrlpodo mice were treated with Adriamycin to induce podocyte injury and SARA/CtrlTEC mice with aristolochic acid (AA) to induce tubulointerstitial fibrosis. Urine, blood, and kidneys were harvested for histological and molecular analysis. Markers for fibrosis and injury were measured by qPCR. Podocytes were isolated by flow cytometry from SARA/Ctrpodo mouse kidneys

Results

SARApodo mice showed less glomerulosclerosis histologically and less proteinuria than Ctrlpodo mice after Adriamycin treatment. Tubular cell injury markers (KIM1, Sox9, NGAL) tended to be lower in SARATEC mice compared to CtrlTEC after AA treatment, but did not reach statistical significance. No significant difference in expression of markers of fibrosis was observed.
Gene expression profiles of podocytes isolated from SARA/Ctrlpodo mice are being analyzed by RNA sequencing. This will provide insight into the mechanisms by which SARA maintains cellular phenotype and protects against renal fibrosis.

Conclusion

SARA overexpression protects podocytes and TECs against injury. Elucidating the mechanisms by which SARA functions will help unearth new molecular targets for therapies directed at glomerulopathies.

Funding

  • NIDDK Support