CLAUDIN-1 INHIBITOR AMELIORATES DIABETIC KIDNEY DISEASE BY SUPPRESSING SRC/AKT/MTOR SIGNALING PATHWAY

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Abstract Title *

CLAUDIN-1 INHIBITOR AMELIORATES DIABETIC KIDNEY DISEASE BY SUPPRESSING SRC/AKT/MTOR SIGNALING PATHWAY

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Co-author 1

Kazuhiko Fukushima kfukushima37@gmail.com Okayama University Department of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama Japan *

Co-author 2

Kenji Tsuji ktsuji@s.okayama-u.ac.jp Okayama University Department of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama Japan -

Co-author 3

Hiroyuki Nakanoh bambubu2756@gmail.com Okayama University Department of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama Japan -

Co-author 4

Naruhiko Uchida p2jz11wz@s.okayama-u.ac.jp Okayama University Department of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama Japan -

Co-author 5

Shinji Kitamura sikitamura@gmail.com Okayama University Department of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama Japan -

Co-author 6

Jun Wada junwada@okayama-u.ac.jp Okayama University Department of Nephrology, Rheumatology, Endocrinology and Metabolism Okayama Japan -

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Introduction

Recent studies have reported that claudin-1 (CLDN1), which is reactively expressed in malignant tumors and inflammatory diseases, plays an important role in disease progression. In diabetic kidney disease, upregulated expression of CLDN1 in podocytes has also been shown to contribute to disease progression. However, it remains unclear whether CLDN1 itself could be a therapeutic target in diabetic kidney disease. In this study, we investigated whether the CLDN1 inhibitor PDS-0330 could ameliorate diabetic kidney disease.

Methods

Five-week-old male C57BL/6NJcl mice were fed either a high-fat diet (60 % kcal from fat; HFD) or a normal diet (13 % kcal from fat; ND). At 15 weeks of age, PDS-0330 (10 mg/kg; Inh) or vehicle (Ctrl) was administered orally once per week for four weeks. At the end of the treatment period, blood, urine, and kidney samples were collected.

Immortalized podocytes were treated with Inh (25 µM) or Ctrl and cultured for two days in either normal glucose medium (5.5 mM; NG) or high glucose medium (25 mM; HG), after which proteins were extracted for analysis.

Results

Mice fed an HFD showed significant increases in body weight and blood glucose levels compared with ND mice, and these parameters were not significantly affected by Inh treatment. HFD mice treated with Ctrl (HFD-Ctrl) exhibited significantly higher urinary albumin excretion than ND mice treated with Ctrl (ND-Ctrl), whereas the Inh-treated HFD mice (HFD-Inh) showed a significant reduction. Transmission electron microscopy revealed foot process effacement in HFD-Ctrl podocytes, which was markedly improved in HFD-Inh mice. Immunofluorescence staining demonstrated CLDN1 expression in podocytes of HFD mice. Furthermore, phospho-mTOR staining in podocytes was significantly increased in HFD-Ctrl compared with ND-Ctrl and was significantly attenuated in HFD-Inh. Western blot analysis of kidney samples revealed activation of the Src/Akt/mTOR signaling pathway in HFD-Ctrl mice, which was significantly reduced in HFD-Inh mice.

Ctrl-treated podocytes cultured in HG (HG-Ctrl) showed significant activation of Src/Akt/mTOR signaling compared with those in NG (NG-Ctrl). This activation was significantly suppressed in Inh-treated podocytes (HG-Inh).

Conclusion

These findings suggest that podocyte CLDN1 could be a potential therapeutic target in diabetic kidney disease.

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