Aims/hypothesis

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 Hnrnpf^RT knockout (KO) mice. Non-diabetic Hnrnpf^RT 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.

Methods

Akita Hnrnpf^RT 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 Hnrnpf^RT KO mice were studied up to the age of 24 weeks (n = 8/group).

Results

Akita mice exhibited elevated systolic blood pressure as compared with Ctrl mice, which was significantly higher in Akita Hnrnpf^RT KO mice than Akita mice. Compared with Akita mice, Akita Hnrnpf^RT 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 Hnrnpf^RT KO mice. Treatment of Akita Hnrnpf^RT 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 Hnrnpf^RT KO mice. In contrast, Sglt2 expression was increased in Akita and decreased in Akita Hnrnpf^RT KO mice.

Conclusions/interpretation

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.

Graphical abstract

中文翻译：

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在糖尿病小鼠模型中，肾小管中异质核核糖核蛋白 F 的缺失下调 SGLT2 表达并减轻超滤和肾损伤

目标/假设

我们之前报道了异质核核糖核蛋白 F ( Hnrnpf )的肾小管特异性缺失导致Hnrnpf ^RT敲除 (KO) 小鼠中肾血管紧张素原 ( Agt ) 的上调和钠-葡萄糖协同转运蛋白 2 ( Sglt2 ) 的下调。非糖尿病Hnrnpf ^RT KO 小鼠出现高血压、肾间质纤维化和糖尿，而下调的 Sglt2表达没有肾脏保护作用。在这里，我们研究了肾小管Hnrnpf缺失对秋田小鼠（一种 1 型糖尿病模型）的超滤和肾损伤的影响。

方法

Akita Hnrnpf ^RT KO 小鼠是通过在 C57BL/6 背景上将小管特异性 (Pax8) -Cre小鼠与 Akita floxed - Hnrnpf小鼠杂交产生的。研究了雄性非糖尿病对照 (Ctrl)、Akita 和 Akita Hnrnpf ^RT KO 小鼠直至 24 周龄 ( n  = 8/组)。

结果

与 Ctrl 小鼠相比，Akita 小鼠的收缩压升高，Akita Hnrnpf ^RT KO 小鼠的收缩压明显高于 Akita 小鼠。与 Akita 小鼠相比，Akita Hnrnpf ^RT 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、肾小球高滤过（肾小球滤过率增加）、肾小球肿大、系膜扩张、足细胞足突消失、肾小球基底膜增厚、肾间质纤维化和蛋白尿增加。这些异常在秋田Hnrnpf ^RT KO 小鼠中减弱。秋田Hnrnpf ^RT的治疗具有选择性 A1 腺苷受体抑制剂的 KO 小鼠导致肾小球滤过率增加。在 Akita 小鼠中肾Agt表达升高，在 Akita Hnrnpf ^RT KO 小鼠中进一步增加。相比之下，Sglt2表达在 Akita Hnrnpf RT KO 小鼠中增加，而在 Akita Hnrnpf ^RT KO 小鼠中减少。

结论/解释

当这些相反因素在糖尿病条件下共存时，至少部分通过激活肾小球反馈， Sglt2下调的肾脏保护作用克服了 Agt 的肾脏损伤作用。

图形概要