Kidney Week

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

• Diabetic Kidney Disease: Basic - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Fujimoto, Daisuke, Department of Nephrology,Kumamoto University, Kumamoto, Japan

Daisuke Fujimoto,

• Kuwabara, Takashige, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

Takashige Kuwabara,

• Hata, Yusuke, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

Yusuke Hata,

• Umemoto, Shuro, Kumamoto University Graduate School of Medicine, Kumamoto, Japan

Shuro Umemoto,

• Kanki, Tomoko, Kumamoto University, Kumamoto, Japan

Tomoko Kanki,

• Nishiguchi, Yoshihiko, Kumamoto University Hospital, Kumamoto, Kumamoto, Japan

Yoshihiko Nishiguchi,

• Mizumoto, Teruhiko, Department of Nephrology Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

Teruhiko Mizumoto,

• Hayata, Manabu, Kumamoto University, Kumamoto, Japan

Manabu Hayata,

• Izumi, Yuichiro, Kumamoto University, Kumamoto, Japan

Yuichiro Izumi,

• Kakizoe, Yutaka, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

Yutaka Kakizoe,

• Mukoyama, Masashi, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan

Masashi Mukoyama,

Background

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.

Methods

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.

Results

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.

Conclusion

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.