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Abstract: TH-PO863

Intraglomerular Cross-Talk Between Mesangial Cells and Podocytes Inhibits Normal ER-Associated Degradation Processes and Induces Podocyte Injury in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Fujimoto, Daisuke, Department of Nephrology,Kumamoto University, Kumamoto, Japan
  • Kuwabara, Takashige, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Hata, Yusuke, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Umemoto, Shuro, Kumamoto University Graduate School of Medicine, Kumamoto, Japan
  • Kanki, Tomoko, Kumamoto University, Kumamoto, Japan
  • Nishiguchi, Yoshihiko, Kumamoto University Hospital, Kumamoto, Kumamoto, Japan
  • Mizumoto, Teruhiko, Department of Nephrology Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Hayata, Manabu, Kumamoto University, Kumamoto, Japan
  • Izumi, Yuichiro, Kumamoto University, Kumamoto, Japan
  • Kakizoe, Yutaka, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
  • Mukoyama, Masashi, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

We previously reported that endoplasmic reticulum (ER) stress induced by glucolipotoxicity and homeostatic inflammation through intraglomerular cellular crosstalk may play an important role in the progression of diabetic nephropathy. However, involvement with these consequences in podocyte injury still remains unclear.


Cluster analyses were performed using cDNA microarray data set of isolated glomeruli from two distinct diabetic mouse models. ER stress and apoptotic responses were evaluated in cultured mouse podocytes MPC5 stimulated with mesangial cell-cultured medium (MC-sup) under high- and low-glucose conditions (HG, LG). The effects of an ER-associated degradation (ERAD) inhibitor Eeyarestatin I (EerI) in MPC5 and db/db mice were also examined.


Commonly increased or decreased genes in both DM models were associated with apoptosis (enrichment score 3.03), inflammation (3.03), and energy metabolism (1.24), suggesting ER stress as a potential factor. Pathway-focused PCR array analysis revealed that ERAD pathway was suppressed, but apoptotic pathway was enhanced in podocytes stimulated with HG MC-sup. Besides, these responses were also observed in isolated diabetic glomeruli. In vitro, IRE1α and spliced XBP1 were suppressed in podocytes by HG MC-sup, although apoptosis evaluated by TUNEL-staining, Bax, ATF6 and CHOP was markedly increased. These results were augmented by HG MC-sup compared to LG MC-sup. Other types of cells, such as proximal tubular cells or macrophages, did not show any similar responses. Of note, treatment with EerI recapitulated these results in podocytes, and exacerbated albuminuria in db/db mice.


It is recently reported that ERAD pathway may play important roles in the maintenance of podocytes to avoid ER stress in several glomerular diseases including diabetic nephropathy. In the present study, we firstly reveal that intraglomerular crosstalk between mesangial cells and podocytes inhibits normal ERAD processes, potentially causing podocyte injury in diabetic conditions.