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 NH2-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.
Highlights
Alport syndrome is a hereditary glomerulopathy with progressive proteinuria and nephritis caused by defects in the genes encoding a-3, a-4, or a-5 chains of type IV collagen (COL4A3, COL4A4, COL4A5) in the glomerular basement membrane
Congruent with the previous characterization of the established mouse model of X-linked Alport syndrome [15], proteinuria was observed in 24-week-old Alport mice but not in wild type (WT) mice (Fig. S1a)
In Alport syndrome, mutations of type IV collagen cause glomerular basement membrane (GBM) injury and subsequent podocyte injuries that lead to a vicious cycle of massive proteinuria and renal inflammation, and cause end-stage renal disease (Fig. 6e)
Summary
Alport syndrome is a hereditary glomerulopathy with progressive proteinuria and nephritis caused by defects in the genes encoding a-3, a-4, or a-5 chains of type IV collagen (COL4A3, COL4A4, COL4A5) in the glomerular basement membrane. X-linked Alport syndrome comprises around 85% of all known cases. Almost all of the Alport syndrome patients develop end-stage renal disease by age 20 to 30 years [1]. Renal inflammation, including the up-regulation of proinflammatory cytokines and the infiltration of inflammatory cells, causes tissue injury and fibrosis and subsequently leads to irreversible kidney dysfunction [5,6]. A therapeutic approach of modulating both progressive proteinuria and inflammatory cytokine expression might benefit Alport disease
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