Mild electrical stimulation and heat shock suppress renal pathology in adriamycin-induced nephrotic syndrome model

[Speaker] Keisuke Teramoto:1,2
[Co-author] Kohei Omachi:1,2, Tsubasa Yokota:1, Misato Kamura:1,2, Yu Tsurekawa:1,2, Shota Kaseda:1,2, Haruka Kojima:1, Maryann Suico:1, Tsuyoshi Shuto:1, Hirofumi Kai:1
1:Molecular medicine, Kumamoto University, Japan, 2:HIGO program, Kumamoto University, Japan

 Nephrotic syndrome (NS) is characterized by large amounts of proteinuria, hypoalbuminemia and edema. In clinics, steroids are selected as first-choice drug for therapy of NS. However, some NS patients exhibit steroid-resistant NS. Because there is no cure for these patients, development of novel therapy is urgently needed. Previously, our laboratory has shown that MES+HS ameliorates the pathologies of hereditary kidney disease, Alport syndrome. Here, we investigated the effects of MES+HS on the pathologies of NS in an attempt to establish a novel, steroid-independent NS therapy.
 Male BALB/c mice were intravenously injected with adriamycin (ADR; 10 mg/kg). MES+HS treatment was performed for 10 min twice a week and started one-day prior to (pre-treatment) or thirteen-days after (post-treatment) the induction of NS. The condition of MES was adjusted to 6 V/cm of direct current with individual pulse duration of 0.1 msec (55 pulse per second). The temperature at the surface of electrodes was set to 42oC for HS. All mice were sacrificed at 28 days after ADR injection. Renal function parameters, histological changes and alteration of gene expression were investigated. Additionally, protein expression was analyzed in whole kidney samples and mouse podocyte cell line.
 MES+HS significantly decreased urinary protein and albumin excretion compared with non-treated group, indicating an improvement of renal function. Histological analysis revealed that MES+HS ameliorated glomerulosclerosis and urinary cast. Furthermore, cleaved caspase 3 protein expression was suppressed by MES+HS. Because NS-like glomerulonephritis is partly due to apoptosis of podocyte, these results suggested that MES+HS prevents NS pathogenesis via exerting anti-apoptotic effect on podocyte. Q-RT-PCR analysis demonstrated that both pre- and post-treatment with MES+HS suppressed the expression levels of pro-inflammatory cytokines and pro-fibrotic genes, implying that MES+HS also inhibited kidney inflammation and fibrosis, which are critical phenotypes of NS pathology.
 The present study shows that MES+HS modulates NS pathologies and has renoprotective effects against ADR-induced NS. Therefore, MES+HS may have beneficial effects that make it a likely candidate as a novel therapeutic approach for steroid-resistant NS.
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