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Abstract: SA-PO228

Placental Growth Factor Deficiency Aggravates Diabetic Nephropathy Through AMP-Activated Protein Kinase-Dependent Pathway

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Kim, Yaeni, The Catholic University of Korea, Seoul, Korea (the Republic of)
  • Lim, Ji Hee, The Catholic University of Korea, Seoul, Korea (the Republic of)
  • Kim, Eun Nim, The Catholic University of Korea, Seoul, Korea (the Republic of)
  • Park, Cheol Whee, The Catholic University of Korea, Seoul, Korea (the Republic of)
Background

Reduced angiogenesis is implicated in the progression of diabetic kidney disease (DKD). Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family, that promotes angiogenesis through VEGF receptor (VEGF-R) and AMP-activated protein kinase (AMPK) in hypoxic tissues under pathologic condition. We aimed to investigate the role of PlGF in the development of DKD.

Methods

Diabetes was induced by a low-dose streptozotocin injection in 9-week-old male C57BL/6J PlGF-KO and wild-type mice and biochemical and morphological parameters were examined at 12 weeks later.

Results

Streptozotocin-induced PlGF-KO diabetic mice showed aggravation of albuminuria and pathognomic phenotypes of DKD due to decreases in the expression of VEGF-receptor2 (VEGF-R2) and CaMKK/phosphorylation of LKB1 and AMPK and their downstream signaling pathways including PI3K/phospho-Akt/FoxO3a/phospho-eNOS and PPARα/PGC-1α/ERRα/ChREBP/SREBP-1c, which caused endothelial dysfunction and lipotoxicity-induced renal inflammation (M1 polarization), oxidative stress, and apoptosis in the kidney. PlGF expression in glomerular endothelial cells (GECs) and PDGFR-Β-positive-mesangial cells was significantly decreased in diabetic PlGF-KO compared to non-diabetic PlGF-KO mice in association with vascular rarefaction as demonstrated by reduced PECAM-1 expression. In cultured human GECs and mesangial cells in high-glucose condition, PlGF-deficiency induced by siPlGF decreased the expression of VEGF-R2 and AMPK-PI3K-Akt phosphorylation/eNOS and suppressed PGC-1α/PPARα, which ultimately led to increased level of oxidative stress and apoptosis.

Conclusion

This study provides a new insight into the role of PlGF in renal damage and that PlGF activation may be a promising therapeutic target for DKD.