ESPN 50th Annual Meeting

ESPN 2017

STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model
Tsubasa Yokota 1 Kohei Omachi 1 Misato Kamura 1 Haruka Kojima 1 Keisuke Teramoto 1 Shota Kaseda 1 Jun Kuwazuru 1 Ryosuke Fukuda 1 Mary Ann Suico 1 Tsuyoshi Shuto 1 Hirofumi Kai 1

1- Kumamoto University

Alport syndrome (AS) is a hereditary kidney disease caused by mutation of type collagen, which eventually leads to end stage renal disease (ESRD). It is important to understand the molecular mechanisms of progressive kidney failure, especially of early glomerular abnormality. In the present study, we sought to determine the critical regulator and the early cell-signaling pathway in AS progression. We took advantage of previous microarray-based studies and identified STAT3 signaling pathway as an activated pathway in AS mice. Here, we aimed to investigate the role of STAT3 in the progression of AS.

Material and methods:

Phosphorylated STAT3 expression was assessed by immunoblotting analysis of AS model mice (Col4a5 G5X mutant). To determine the effect of blocking STAT3 signaling, we treated AS mice with STAT3 inhibitor stattic (10 mg/kg i.p., 3 times/week, 10 weeks, n=10). We assessed the renal function (proteinuria, BUN, serum creatinine) and analyzed the glomerular injury score and fibrosis by histological staining. We further analyzed the gene expression of nephritis-associated molecules. 


Phosphorylated STAT3 was up-regulated in AS glomeruli and kidney. Treatment with stattic ameliorated the progressive renal dysfunction such as increased levels of proteinuria, BUN and serum creatinine. Histological analysis revealed that stattic treatment ameliorates the glomerular injury, renal fibrosis and inflammatory cell infiltration. Moreover, stattic also significantly suppressed the gene expression levels of renal injury markers (Lcn2, Kim-1), pro-inflammatory cytokines (Il-6, KC), pro-fibrotic genes (Tgf-β, Col1a1, α-Sma, Mmp9). 


STAT3 inhibition significantly ameliorated the renal dysfunction in AS mice. Our finding identifies STAT3 as an important regulator in AS progression, and provides a promising therapeutic target for AS.