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Abstract: FR-PO389

Grem2 Mediates Podocyte Apoptosis in High Glucose Milieu

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Wen, Hongxiu, Southwest Medical University, Luzhou, Sichuan, China
  • Lan, Xiqian, Southwest Medical University, Luzhou, Sichuan, China
  • Kumar, Vinod, The Feinstein Institute for Medical Research, Northwell Health, MANHASSET, New York, United States
  • Mishra, Abheepsa, The Feinstein Institute for Medical Research, Northwell Health, MANHASSET, New York, United States
  • Aslam, Rukhsana, The Feinstein Institute for Medical Research, Northwell Health, MANHASSET, New York, United States
  • Marashi Shoshtari, Seyedeh Shadafarin, The Feinstein Institute for Medical Research, Northwell Health, MANHASSET, New York, United States
  • Hussain, Ali, The Feinstein Institute for Medical Research, Northwell Health, MANHASSET, New York, United States
  • Malhotra, Ashwani, The Feinstein Institute for Medical Research, Northwell Health, MANHASSET, New York, United States
  • Singhal, Pravin C., The Feinstein Institute for Medical Research, Northwell Health, MANHASSET, New York, United States
Background

The DAN family members (Grem1, Grem2, Grem3, Cerberus, NBL1, SOST, and USAG1) are highly expressed during development where they have an important role in kidney formation and morphogenesis; in adults, however, increased DAN protein levels are often associated with severe disease-states, including renal fibrosis. Grem1, SOST, and USAG1 have been demonstrated to be upregulated and play a critical role in the progression of diabetic nephropathy (DN); other DAN family members have not been reported to be related to renal disease, and their expression in DN kidneys has not be yet investigated. In this study, we investigated the expression and the role of Grem2 in type 2 DN mice.

Methods

In vivo studies, 14-weeks-old BTBR ob/ob (a type 2 diabetic mouse model) and control (BTBR, wild-type) mice were evaluated for renal function biomarkers (proteinuria and blood urea nitrogen [BUN]). Kidneys were harvested and renal tissues were analyzed by real-time PCR, Western blotting, and immunohistochemistry studies. In vitro studies, human podocytes transfected with Grem2 plasmid were evaluate for apoptosis (morphologic assay and Western blotting). To evaluate the Grem1-mediated downstream signaling, the phosphorylation status of Smad2/3 and Smad1/5/8 was assessed; additionally, SIS3, an inhibitor for Samd3, and BMP-7, an agonist for Smad1/5/8 were used to treat the cells.

Results

In vivo studies, the diabetic mice showed elevated levels of and proteinuria BUN. Real-time PCR and Western blotting analysis showed an increased expression of Grem2 in diabetic kidneys. Immuno-histochemical studies showed enhanced Grem2 expression both by tubular and glomerular cells. In vitro studies, high glucose increased Grem2 expression in cultured human podocytes, and silencing of Grem2 partially suppressed high glucose-induced apoptosis. Overexpression of Grem2 promoted podocyte apoptosis morphologically as well as by an increased Bax/Bcl2 ratio. Overexpression of Grem2 increased the phosphorylation of Smad2/3 and decreased the phosphorylation of Smad1/5/8, while addition of SIS3 or BMP-7 attenuated Grem2-induced podocyte apoptosis.

Conclusion

High glucose increases Grem2 expression in kidney cells. Grem2 mediates podocyte apoptosis through Smads. Grem2 plays an important role for the progression of DN.