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Kidney Week

Abstract: PO0658

Recombinant Slit2 Attenuates Renal Fibrosis in a Mouse Model of Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • He, Xiaolin, St. Michael's Hospital, Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada
  • Liu, Guang-Ying, Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Vukosa, Noah, St. Michael's Hospital, Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada
  • Robinson, Lisa, Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Yuen, Darren A., St. Michael's Hospital, Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada
Background

We recently described Akita+/- Ren+/− mice as a model that replicates many features of human diabetic nephropathy (DN) , including hyperglycemia, hypertension, albuminuria, reduced glomerular filtration rate, glomerulosclerosis and interstitial fibrosis. Previously, we showed that recombinant N terminal Slit2 (Slit2) inhibited renal fibrosis in mouse models of postischemic renal fibrosis and obstructive uropathy. To date, however, the anti-fibrotic effects of Slit2 have not been tested in a model of DN. Here we examine the effects of Slit2 therapy in the Akita+/− Ren+/− mouse.

Methods

At 6 weeks of age, Akita+/− Ren+/− and Akita-/− Ren-/− mice were randomized to receive thrice weekly intraperitoneal injections of Slit2 (2 ug) or saline, and followed for a further 20 weeks.

Results

When compared with saline-treated Akita+/− Ren+/−mice, Slit2-treated Akita+/− Ren+/− mice demonstrated improved survival (66.67% vs. 50%) and decreased systolic blood pressure (142±6.1mmHg vs.167±8.5 mmHg). Structurally, Slit2-treated Akita+/− Ren+/− mice displayed decreased glomerulosclerosis (glomerular picrosirius red score: 0.22±0.02 vs. 0.28±0.02 ) and interstitial fibrosis (picrosirius red staining: 0.08±0.01 vs. 0.10±0.01, a-smooth muscle actin (aSMA) staining: 0.02±0.00 vs. 0.05±0.01, and vimentin staining: 0.11±0.01 vs. 0.15±0.01). Slit2 treatment attenuated the nuclear translocation of the pro-fibrotic proteins YAP (26.44±7.87% vs 66.20±7.63%) and TAZ (28.55±2.99% vs. 71.42±7.90%, a marker of YAP/TAZ activation) in aSMA positive fibroblasts in mouse kidneys. In vitro, Slit2 decreased TGF-b-induced YAP and TAZ activation in cultured NRK49F fibroblasts, as evidenced by a reduction in YAP (55.55±4.67% vs 92.54±1.36%) and TAZ (30.85±7.877.319 % vs 80.2±3.44%) nuclear localization. All p values < 0.05.

Conclusion

Taken together, our results show that Slit2 attenuates diabetic kidney fibrosis, possibly through inhibition of fibroblast YAP and TAZ activity.