Knockout of Macula Densa Neuronal Nitric Oxide Synthase Increases Blood Pressure in db/db Mice.
Knockout of Macula Densa Neuronal Nitric Oxide Synthase Increases Blood Pressure in db/db Mice.
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DOI：
10.1161/hypertensionaha.121.17643
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发表时间：
2021-12
期刊：
影响因子：
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通讯作者：
Liu R
中科院分区：
文献类型：
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作者：
Zhang J;Wang X;Cui Y;Jiang S;Wei J;Chan J;Thalakola A;Le T;Xu L;Zhao L;Wang L;Jiang K;Cheng F;Patel T;Buggs J;Vallon V;Liu R
高血压是糖尿病患者常见的合并症。糖尿病高血压的发病机制尚未完全阐明。原发性肾小管高重吸收可能是原因之一，但早期糖尿病肾脏的肾小球高滤过可能会抵消这一作用。在本研究中，我们假设在早期糖尿病中，黄斑致密神经元一氧化氮合酶（NOS1）衍生的一氧化氮（NO）生成增强，使小管肾小球反馈（TGF）反应钝化，促进肾小球高滤过，维持正常血压；相反，黄斑致密产生的NO不足通过降低肾小球滤过率（GFR）从而抑制尿钠而诱发高血压。为了验证这一假设，我们检测了瘦素受体缺陷（db/db）糖尿病小鼠模型中伴有或不伴有黄斑特异性NOS1缺失的黄斑NOS1表达和磷酸化的变化，以及NO产生、TGF反应、GFR、钠排泄和血压的变化。我们发现db/db小鼠表现为肾部分钠排泄（FENa）减少，血压仅小幅升高，这与黄斑致密NOS1的表达和活性上调、TGF反应抑制和肾小球高滤过有关。在db/db小鼠中，基因敲除致密斑NOS1恢复了TGF反应，减轻了肾小球高滤过，但也进一步降低了fea，显著升高了血压。综上所述，本研究表明，在瘦素受体缺失型糖尿病早期，黄斑致密NOS1上调可抑制TGF，增加GFR，从而抵消肾钠潴留，限制血压升高。
Hypertension is a common comorbid condition in patients with diabetes. The pathogenesis of hypertension in diabetes has not been fully clarified. Primary tubular hyperreabsorption may contribute, which may be counteracted by glomerular hyperfiltration in the early diabetic kidney. In this study, we hypothesize that in early diabetes, the macula densa neuronal nitric oxide synthase (NOS1)-derived nitric oxide (NO) production is enhanced, which blunts tubuloglomerular feedback (TGF) response, promotes glomerular hyperfiltration and maintains normal blood pressure; conversely, insufficient NO generation by the macula densa induces hypertension by lowering glomerular filtration rate (GFR) and thus inhibiting natriuresis. To test this hypothesis, we examined the changes of macula densa NOS1 expression and phosphorylation as well as NO production, TGF response, GFR, sodium excretion and blood pressure in a murine model of leptin receptor-deficient (db/db) diabetes with or without macula densa-specific NOS1 deletion. We found that db/db mice presented reduced fractional renal sodium excretion (FENa) and only a small increase in blood pressure, associated with upregulated expression and activity of macula densa NOS1, inhibited TGF response, and glomerular hyperfiltration. Genetic knockout of macula densa NOS1 restored the TGF response and attenuated glomerular hyperfiltration in db/db mice, but also further reduced FENa and substantially increased blood pressure. In conclusion, the present study demonstrates that in the early stage of leptin receptor-deficient diabetes, the upregulation of macula densa NOS1 inhibits TGF and increases GFR, which counteracts renal sodium retention and limits the rise in blood pressure.