Departments of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; and.
Am J Physiol Regul Integr Comp Physiol. 2013 Oct 1;305(7):R727-34. doi: 10.1152/ajpregu.00382.2012. Epub 2013 Aug 7.
The present study compared the progression of renal injury in Sprague-Dawley (SD) and Dahl salt-sensitive (SS) treated with streptozotocin (STZ). The rats received an injection of STZ (50 mg/kg ip) and an insulin pellet (2 U/day sc) to maintain the blood glucose levels between 400 and 600 mg/dl. Twelve weeks later, arterial pressure (143 ± 6 vs. 107 ± 8 mmHg) and proteinuria (557 ± 85 vs. 81 ± 6 mg/day) were significantly elevated in STZ-SS rats compared with the values observed in STZ-SD rats, respectively. The kidneys from STZ-SS rats exhibited thickening of glomerular basement membrane, mesangial expansion, severe glomerulosclerosis, renal interstitial fibrosis, and occasional glomerular nodule formation. In additional studies, treatment with a therapeutic dose of insulin (4 U/day sc) attenuated the development of proteinuria (212 ± 32 mg/day) and renal injury independent of changes in arterial pressure in STZ-SS rats. Since STZ-SS rats developed severe renal injury, we characterized the time course of changes in renal hemodynamics during the progression of renal injury. Nine weeks after diabetes onset, there was a 42% increase in glomerular filtration rate in STZ-SS rats vs. time-control SS rats with reduced renal blood flow. These results indicate that SS rats treated with STZ develop hyperfiltration and progressive proteinuria and display renal histological lesions characteristic of those seen in patients with diabetic nephropathy. Overall, this model may be useful to study signaling pathways and mechanisms that play a role in the progression of diabetes-induced renal disease and the development of new therapies to slow the progression of diabetic nephropathy.
本研究比较了链脲佐菌素（STZ）处理的 Sprague-Dawley（SD）和 Dahl 盐敏感（SS）大鼠肾脏损伤的进展。大鼠接受 STZ（50mg/kg ip）注射和胰岛素微球（2U/天 sc）注射，以维持血糖水平在 400 至 600mg/dl 之间。12 周后，与 STZ-SD 大鼠相比，STZ-SS 大鼠的动脉压（143±6 与 107±8mmHg）和蛋白尿（557±85 与 81±6mg/天）显著升高。STZ-SS 大鼠的肾脏表现为肾小球基底膜增厚、系膜扩张、严重肾小球硬化、肾间质纤维化和偶尔的肾小球结节形成。在进一步的研究中，用治疗剂量的胰岛素（4U/天 sc）治疗可减轻蛋白尿（212±32mg/天）和肾脏损伤，而不改变 STZ-SS 大鼠的动脉压。由于 STZ-SS 大鼠发生严重的肾脏损伤，我们描述了在肾脏损伤进展过程中肾脏血液动力学变化的时间过程。糖尿病发病 9 周后，STZ-SS 大鼠的肾小球滤过率增加了 42%，而 SS 大鼠的肾血流量减少。这些结果表明，用 STZ 处理的 SS 大鼠发生高滤过和进行性蛋白尿，并表现出与糖尿病肾病患者相似的肾脏组织学损伤。总的来说，该模型可能有助于研究在糖尿病引起的肾脏疾病进展和开发减缓糖尿病肾病进展的新疗法中起作用的信号通路和机制。
