Takashima Yasutoshi, Keino-Masu Kazuko, Yashiro Hiroshi, Hara Satoshi, Suzuki Tomo, van Kuppevelt Toin H, Masu Masayuki, Nagata Michio
Kidney and Vascular Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan;
Molecular Neurobiology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan; and.
Am J Physiol Renal Physiol. 2016 Mar 1;310(5):F395-408. doi: 10.1152/ajprenal.00445.2015. Epub 2016 Jan 13.
Glomerular integrity and functions are maintained by growth factor signaling. Heparan sulfate, the major component of glomerular extracellular matrixes, modulates growth factor signaling, but its roles in glomerular homeostasis are unknown. We investigated the roles of heparan sulfate 6-O-endosulfatases, sulfatase (Sulf)1 and Sulf2, in glomerular homeostasis. Both Sulf1 and Sulf2 were expressed in the glomeruli of wild-type (WT) mice. Sulf1 and Sulf2 double-knockout (DKO) mice showed glomerular hypercellularity, matrix accumulation, mesangiolysis, and glomerular basement membrane irregularity. Platelet-derived growth factor (PDGF)-B and PDGF receptor-β were upregulated in Sulf1 and Sulf2 DKO mice compared with WT mice. Glomeruli from Sulf1 and Sulf2 DKO mice in vitro stimulated by either PDGF-B, VEGF, or transforming growth factor-β similarly showed reduction of phospho-Akt, phospho-Erk1/2, and phospho-Smad2/3, respectively. Since glomerular lesions in Sulf1 and Sulf2 DKO mice were reminiscent of diabetic nephropathy, we examined the effects of Sulf1 and Sulf2 gene disruption in streptozotocin-induced diabetes. Diabetic WT mice showed an upregulation of glomerular Sulf1 and Sulf2 mRNA by in situ hybridization. Diabetic DKO mice showed significant increases in albuminuria and serum creatinine and an acceleration of glomerular pathology without glomerular hypertrophy; those were associated with a reduction of glomerular phospho-Akt. In conclusion, Sulf1 and Sulf2 play indispensable roles to maintain glomerular integrity and protective roles in diabetic nephropathy, probably by growth factor modulation.
肾小球的完整性和功能由生长因子信号传导维持。硫酸乙酰肝素是肾小球细胞外基质的主要成分，可调节生长因子信号传导，但其在肾小球稳态中的作用尚不清楚。我们研究了硫酸乙酰肝素6-O-内硫酸酯酶、硫酸酯酶（Sulf）1和Sulf2在肾小球稳态中的作用。Sulf1和Sulf2均在野生型（WT）小鼠的肾小球中表达。Sulf1和Sulf2双敲除（DKO）小鼠表现出肾小球细胞增多、基质积聚、血管系膜溶解和肾小球基底膜不规则。与WT小鼠相比，Sulf1和Sulf2 DKO小鼠中的血小板衍生生长因子（PDGF）-B和PDGF受体-β上调。来自Sulf1和Sulf2 DKO小鼠的肾小球在体外分别受到PDGF-B、血管内皮生长因子（VEGF）或转化生长因子-β刺激后，磷酸化Akt、磷酸化细胞外信号调节激酶1/2（Erk1/2）和磷酸化Smad2/3分别减少。由于Sulf1和Sulf2 DKO小鼠的肾小球病变让人联想到糖尿病肾病，我们研究了Sulf1和Sulf2基因敲除在链脲佐菌素诱导的糖尿病中的作用。通过原位杂交发现，糖尿病WT小鼠肾小球Sulf1和Sulf2 mRNA上调。糖尿病DKO小鼠蛋白尿和血清肌酐显著增加，肾小球病理加速但无肾小球肥大；这些与肾小球磷酸化Akt减少有关。总之，Sulf1和Sulf2在维持肾小球完整性方面发挥不可或缺的作用，并且在糖尿病肾病中可能通过调节生长因子发挥保护作用。
