Effect of Sodium-Glucose Cotransport Inhibition on Polycystic Kidney Disease Progression in PCK Rats.
Effect of Sodium-Glucose Cotransport Inhibition on Polycystic Kidney Disease Progression in PCK Rats.
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DOI：
10.1371/journal.pone.0125603
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Wüthrich RP
中科院分区：
文献类型：
--
作者：
Kapoor S;Rodriguez D;Riwanto M;Edenhofer I;Segerer S;Mitchell K;Wüthrich RP
钠-葡萄糖协同转运蛋白-2（SGLT 2）抑制剂达格列净（达帕）通过抑制肾脏葡萄糖重吸收诱导糖尿和渗透性利尿。由于增加的利尿延缓了多囊肾病（PKD）的进展，我们研究了达帕在PKD的PCK大鼠模型中的作用。通过管饲法向6周龄雄性PCK大鼠（每组n=9）给予达帕（10 mg/kg/d）或溶媒。治疗6周后评估肾功能、蛋白尿、肾脏重量和囊肿体积。达帕治疗组葡萄糖排泄量（23.6 ± 4.3 vs 0.3 ± 0.1 mmol/d）和尿量（57.3 ± 6.8 vs 19.3 ± 0.8 ml/d）明显增加。3周后，经DAPA处理的PCK大鼠的肌酐清除率（3.1 ± 0.1 vs 2.6 ± 0.2 ml/min）和BUN清除率（1.7 ± 0.1 vs 1.2 ± 0.1 ml/min）更高，白蛋白尿增加4倍。超声成像和组织学分析显示，达帕治疗6周后，囊肿体积更大，肾脏总重量增加23%。在第6周，达帕和载体之间的肾cAMP含量相似，并且Ki 67染色未显示细胞增殖增加。总之，SGLT 2特异性抑制剂达帕抑制葡萄糖重吸收导致PCK大鼠渗透性利尿、超滤、蛋白尿和囊肿体积增加。在PCK大鼠中，将糖尿与超滤、蛋白尿和囊肿体积增加联系起来的机制仍有待阐明。
The sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA) induces glucosuria and osmotic diuresis via inhibition of renal glucose reabsorption. Since increased diuresis retards the progression of polycystic kidney disease (PKD), we investigated the effect of DAPA in the PCK rat model of PKD. DAPA (10 mg/kg/d) or vehicle was administered by gavage to 6 week old male PCK rats (n=9 per group). Renal function, albuminuria, kidney weight and cyst volume were assessed after 6 weeks of treatment. Treatment with DAPA markedly increased glucose excretion (23.6 ± 4.3 vs 0.3 ± 0.1 mmol/d) and urine output (57.3 ± 6.8 vs 19.3 ± 0.8 ml/d). DAPA-treated PCK rats had higher clearances for creatinine (3.1 ± 0.1 vs 2.6 ± 0.2 ml/min) and BUN (1.7 ± 0.1 vs 1.2 ± 0.1 ml/min) after 3 weeks, and developed a 4-fold increase in albuminuria. Ultrasound imaging and histological analysis revealed a higher cyst volume and a 23% higher total kidney weight after 6 weeks of DAPA treatment. At week 6 the renal cAMP content was similar between DAPA and vehicle, and staining for Ki67 did not reveal an increase in cell proliferation. In conclusion, the inhibition of glucose reabsorption with the SGLT2-specific inhibitor DAPA caused osmotic diuresis, hyperfiltration, albuminuria and an increase in cyst volume in PCK rats. The mechanisms which link glucosuria to hyperfiltration, albuminuria and enhanced cyst volume in PCK rats remain to be elucidated.
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影响因子：
10.5
作者：
Harris PC;Torres VE
通讯作者：
Torres VE
DOI：
10.1056/nejmoa1205511
发表时间：
2012-12-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
Torres VE;Chapman AB;Devuyst O;Gansevoort RT;Grantham JJ;Higashihara E;Perrone RD;Krasa HB;Ouyang J;Czerwiec FS;TEMPO 3:4 Trial Investigators
通讯作者：
TEMPO 3:4 Trial Investigators
影响因子：
3.9
作者：
Obermeier, M.;Yao, M.;Humphreys, W. G.
通讯作者：
Humphreys, W. G.
影响因子：
7.7
作者：
Han, Songping;Hagan, Deborah L.;Whaley, Jean M.
通讯作者：
Whaley, Jean M.
影响因子：
13.6
作者：
Torres, Vicente E.;Harris, Peter C.
通讯作者：
Harris, Peter C.