Lack of A1 adenosine receptors augments diabetic hyperfiltration and glomerular injury
Lack of A1 adenosine receptors augments diabetic hyperfiltration and glomerular injury
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DOI：
10.1681/asn.2007060721
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发表时间：
2008-04-01
影响因子：
13.6
通讯作者：
Schnermann, Jurgen
中科院分区：
文献类型：
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作者：
Faulhaber-Walter, Robert;Chen, Limeng;Schnermann, Jurgen
肾小球内高血压和肾小球高滤过可能参与糖尿病肾病的发病机制，而小管肾小球反馈（tubuloglomerular feedback， TGF）被认为在糖尿病高滤过中发挥作用。A1腺苷受体（A1AR）缺失的小鼠缺乏TGF反应，因此我们利用该模型研究TGF对糖尿病Ins2（+/-）秋田小鼠高滤过的贡献。TGF在Ins2(+/-) A1AR（-/-）双突变体中被消除，而在Ins2（+/-）小鼠中则被减弱。在14、24和33周时评估，Ins2（+/-）突变体的GFR比野生型（WT）小鼠高约30%，并且在Ins2(+/-) A1AR（-/-）突变体中进一步增加（与所有年龄的WT和Ins2（+/-）小鼠相比P < 0.01）。与单突变或WT小鼠相比，双突变小鼠肾小球损伤和尿白蛋白排泄的组织学证据更为明显。综上所述，在缺乏TGF反应的糖尿病小鼠中，GFR的显著升高表明，在秋田糖尿病模型中，TGF不需要引起高滤过。相反，a1ar依赖性机制（可能是TGF）限制了糖尿病高滤过和肾病的程度。
Intraglomerular hypertension and glomerular hyperfiltration likely contribute to the pathogenesis of diabetic nephropathy, and tubuloglomerular feedback (TGF) has been suggested to play a role in diabetic hyperfiltration. A1 adenosine receptor (A1AR) null mice lack a TGIF response, so this model was used to investigate the contribution of TGF to hyperfiltration in diabetic Ins2(+/-) Akita mice. TGF responses in Ins2(+/-) A1AR(-/-) double mutants were abolished, whereas they were attenuated in Ins2(+/-) mice. GFR, assessed at 14, 24, and 33 wk, was approximately 30% higher in Ins2(+/-) than in wild-type (WT) mice and increased further in Ins2(+/-) A1AR(-/-) mutants (P < 0.01 versus both WT and Ins2(+/-) mice at all ages). Histologic evidence of glomerular injury and urinary albumin excretion were more pronounced in double-mutant than single-mutant or WT mice. In summary, the marked elevation of GFR in diabetic mice that lack a TGF response indicates that TGF is not required to cause hyperfiltration in the Akita model of diabetes. Rather, an A1AR-dependent mechanism, possibly TGF, limits the degree of diabetic hyperfiltration and nephropathy.