AT(2)R deficiency mediated podocyte loss via activation of ectopic hedgehog interacting protein (Hhip) gene expression

作者：Liao Min Chun; Zhao Xin Ping; Chang Shiao Ying; Lo Chao Sheng; Chenier Isabelle; Takano Tomoko; Ingelfinger Julie R; Zhang Shao Ling

来源：Journal of Pathology, 2017, 243(3): 279-293.

DOI：10.1002/path.4946

• Hhip expression
• podocytes and AT(2)R deficiency

Angiotensin II type 2 receptor (AT(2)R) deficiency in AT(2)R knockout (KO) mice has been linked to congenital abnormalities of the kidney and urinary tract; however, the mechanisms by which this occurs are poorly understood. In this study, we examined whether AT(2)R deficiency impaired glomerulogenesis and mediated podocyte loss/dysfunction in vivo and in vitro. Nephrin-cyan fluorescent protein (CFP)-transgenic (Tg) and Nephrin/AT(2)RKO mice were used to assess glomerulogenesis, while wild-type and AT(2)RKO mice were used to evaluate maturation of podocyte morphology/function. Immortalized mouse podocytes (mPODs) were employed for in vitro studies. AT(2)R deficiency resulted in diminished glomerulogenesis in E15 embryos, but had no impact on actual nephron number in neonates. Pups lacking AT(2)R displayed features of renal dysplasia with lower glomerular tuft volume and podocyte numbers. In vivo and in vitro studies demonstrated that loss of AT(2)R was associated with elevated NADPH oxidase 4 levels, which in turn stimulated ectopic hedgehog interacting protein (Hhip) gene expression in podocytes. Consequently, ectopic Hhip expression activation either triggers caspase-3 and p53-related apoptotic processes resulting in podocyte loss, or activates TGF1-Smad2/3 cascades and -SMA expression to transform differentiated podocytes to undifferentiated podocyte-derived fibrotic cells. We analyzed HHIP expression in the kidney disease database (Nephroseq) and then validated this using HHIP immunohistochemistry staining of human kidney biopsies (controls versus focal segmental glomerulosclerosis). In conclusion, loss of AT(2)R is associated with podocyte loss/dysfunction and is mediated, at least in part, via augmented ectopic Hhip expression in podocytes.

• 出版日期2017-11