Department of Medicine, University of California San Diego, La Jolla, California 92093, USA.
Annu Rev Physiol. 2012;74:351-75. doi: 10.1146/annurev-physiol-020911-153333.
Diabetes mellitus affects the kidney in stages. At the onset of diabetes mellitus, in a subset of diabetic patients the kidneys grow large, and glomerular filtration rate (GFR) becomes supranormal, which are risk factors for developing diabetic nephropathy later in life. This review outlines a pathophysiological concept that focuses on the tubular system to explain these changes. The concept includes the tubular hypothesis of glomerular filtration, which states that early tubular growth and sodium-glucose cotransport enhance proximal tubule reabsorption and make the GFR supranormal through the physiology of tubuloglomerular feedback. The diabetic milieu triggers early tubular cell proliferation, but the induction of TGF-β and cyclin-dependent kinase inhibitors causes a cell cycle arrest and a switch to tubular hypertrophy and a senescence-like phenotype. Although this growth phenotype explains unusual responses like the salt paradox of the early diabetic kidney, the activated molecular pathways may set the stage for tubulointerstitial injury and diabetic nephropathy.
糖尿病会分阶段影响肾脏。在糖尿病发病初期，一部分糖尿病患者的肾脏会增大，肾小球滤过率（GFR）变得高于正常水平，这是日后发生糖尿病肾病的危险因素。本文综述了一个以肾小管系统为重点的病理生理学概念，用以解释这些变化。该概念包括肾小球滤过的肾小管假说，该假说指出，早期肾小管生长和钠-葡萄糖共转运增强了近端肾小管重吸收，通过管球反馈的生理学机制使 GFR 高于正常水平。糖尿病微环境会引发早期肾小管细胞增殖，但 TGF-β和细胞周期蛋白依赖性激酶抑制剂的诱导会导致细胞周期停滞，并向肾小管肥大和衰老样表型转变。虽然这种生长表型解释了早期糖尿病肾脏的“盐悖论”等异常反应，但激活的分子通路可能为肾小管间质损伤和糖尿病肾病奠定了基础。
