Deletion of heterogeneous nuclear ribonucleoprotein F in renal tubules downregulates SGLT2 expression and attenuates hyperfiltration and kidney injury in a mouse model of diabetes.
Deletion of heterogeneous nuclear ribonucleoprotein F in renal tubules downregulates SGLT2 expression and attenuates hyperfiltration and kidney injury in a mouse model of diabetes.
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DOI：
10.1007/s00125-021-05538-9
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发表时间：
2021-11
期刊：
影响因子：
8.2
通讯作者：
Chan JSD
中科院分区：
文献类型：
--
作者：
Miyata KN;Lo CS;Zhao S;Zhao XP;Chenier I;Yamashita M;Filep JG;Ingelfinger JR;Zhang SL;Chan JSD
我们以前报道过，肾小管特异性缺失异质核核糖核蛋白F（Hnrnpf）导致HnrnpfRT敲除（KO）小鼠肾血管紧张素原（Agt）上调和钠-葡萄糖协同转运蛋白2（Sglt 2）下调。非糖尿病HnrnpfRT KO小鼠发生高血压、肾间质纤维化和糖尿，而Sglt 2表达下调没有肾保护作用。在此，我们研究了肾小管Hnrnpf缺失对1型糖尿病模型秋田小鼠超滤和肾损伤的影响。秋田HnrnpfRT KO小鼠是通过在C57 BL/6背景下使微管特异性（Pax 8）-Cre小鼠与秋田杂交的Hnrnpf小鼠杂交而产生的。研究雄性非糖尿病对照（Ctrl）、秋田和秋田HnrnpfRT KO小鼠，直至24周龄（n=8只/组）。与对照小鼠相比，秋田小鼠表现出升高的收缩压，其在秋田HnrnpfRT KO小鼠中显著高于秋田小鼠。与秋田小鼠相比，秋田HnrnpfRT KO小鼠的血糖水平较低，尿糖排泄增加。秋田小鼠出现肾脏肥大、肾小球超滤（肾小球滤过率增加）、肾小球肥大、系膜扩张、足细胞足突消失、肾小球基底膜增厚、肾间质纤维化和白蛋白尿增加。这些异常在秋田HnrnpfRT KO小鼠中减弱。用选择性A1腺苷受体抑制剂治疗秋田HnrnpfRT KO小鼠导致肾小球滤过率增加。肾Agt表达在秋田小鼠中升高，并在秋田HnrnpfRT KO小鼠中进一步增加。相反，Sglt 2表达在秋田中增加，在秋田HnrnpfRT KO小鼠中减少。当这些相反的因素在糖尿病条件下共存时，Sglt 2下调的肾保护作用克服了Agt的肾损伤作用，至少部分地通过激活肾小管-肾小球反馈。
We previously reported that renal tubule-specific deletion of Heterogeneous nuclear ribonucleoprotein F (Hnrnpf) results in upregulation of renal angiotensinogen (Agt) and downregulation of sodium-glucose co-transporter 2 (Sglt2) in HnrnpfRT knockout (KO) mice. Non-diabetic HnrnpfRT KO mice develop hypertension, renal interstitial fibrosis and glycosuria with no renoprotective effect from downregulated Sglt2 expression. Here, we investigated the effect of renal tubular Hnrnpf deletion on hyperfiltration and kidney injury in Akita mice, a model of type 1 diabetes. Akita HnrnpfRT KO mice were generated through crossbreeding tubule-specific (Pax8)-Cre mice with Akita floxed-Hnrnpf mice on a C57BL/6 background. Male non-diabetic control (Ctrl), Akita, and Akita HnrnpfRT KO mice were studied up to the age of 24 weeks (n=8/group). Akita mice exhibited elevated systolic blood pressure as compared with Ctrl mice, which was significantly higher in Akita HnrnpfRT KO mice than Akita mice. Compared with Akita mice, Akita HnrnpfRT KO mice had lower blood glucose levels with increased urinary glucose excretion. Akita mice developed kidney hypertrophy, glomerular hyperfiltration (increased glomerular filtration rate), glomerulomegaly, mesangial expansion, podocyte foot process effacement, thickened glomerular basement membranes, renal interstitial fibrosis and increased albuminuria. These abnormalities were attenuated in Akita HnrnpfRT KO mice. Treatment of Akita HnrnpfRT KO mice with a selective A1 adenosine receptor inhibitor resulted in an increase in glomerular filtration rate. Renal Agt expression was elevated in Akita mice and further increased in Akita HnrnpfRT KO mice. In contrast, Sglt2 expression was increased in Akita and decreased in Akita HnrnpfRT KO mice. The renoprotective effect of Sglt2 downregulation overcomes the renal injurious effect of Agt when these opposing factors coexist under diabetic conditions, at least partly via the activation of tubuloglomerular feedback.
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影响因子：
3.5
作者：
Li L;Konishi Y;Morikawa T;Zhang Y;Kitabayashi C;Kobara H;Masaki T;Nakano D;Hitomi H;Kobori H;Nishiyama A
通讯作者：
Nishiyama A
影响因子：
8.8
作者：
Haas, M.;Mirocha, J.
通讯作者：
Mirocha, J.
影响因子：
158.5
作者：
Perkovic, V.;Jardine, M. J.;Bentley-Lewis, Rhonda
通讯作者：
Bentley-Lewis, Rhonda
DOI：
10.1152/ajprenal.00497.2018
发表时间：
2019-08-01
影响因子：
4.2
作者：
Onishi, Akira;Fu, Yiling;Vallon, Volker
通讯作者：
Vallon, Volker
影响因子：
13.6
作者：
Borges-Junior, Avio A.;dos Santos, Danubia Silva;Girardi, Adriana C. C.
通讯作者：
Girardi, Adriana C. C.