title: Mild electrical stimulation and heat shock ameliorates progressive proteinuria and renal inflammation in mouse model of Alport syndrome.
abstract: Alport syndrome is a hereditary glomerulopathy with proteinuria and nephritis caused by defects in genes encoding type IV collagen in the glomerular basement membrane. All male and most female patients develop end-stage renal disease. Effective treatment to stop or decelerate the progression of proteinuria and nephritis is still under investigation. Here we showed that combination treatment of mild electrical stress (MES) and heat stress (HS) ameliorated progressive proteinuria and renal injury in mouse model of Alport syndrome. The expressions of kidney injury marker neutrophil gelatinase-associated lipocalin and pro-inflammatory cytokines interleukin-6, tumor necrosis factor-α and interleukin-1β were suppressed by MES+HS treatment. The anti-proteinuric effect of MES+HS treatment is mediated by podocytic activation of phosphatidylinositol 3-OH kinase (PI3K)-Akt and heat shock protein 72 (Hsp72)-dependent pathways in vitro and in vivo. The anti-inflammatory effect of MES+HS was mediated by glomerular activation of c-jun NH(2)-terminal kinase 1/2 (JNK1/2) and p38-dependent pathways ex vivo. Collectively, our studies show that combination treatment of MES and HS confers anti-proteinuric and anti-inflammatory effects on Alport mice likely through the activation of multiple signaling pathways including PI3K-Akt, Hsp72, JNK1/2, and p38 pathways, providing a novel candidate therapeutic strategy to decelerate the progression of patho-phenotypes in Alport syndrome.
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences and Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.forename: Yukari
authors.initials: Y
authors.lastname: Kai
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Fukuda
authors.forename: Saori
authors.initials: S
authors.lastname: Morino-Koga
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.forename: Kosuke
authors.initials: K
authors.lastname: Koyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004599:Electric Stimulation Therapy; D005260:Female; D018869:Heat-Shock Response; D006358:Hot Temperature / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009393:Nephritis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009394:Nephritis, Hereditary / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010539:Permeability; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt