Wolf G, Hamann A, Han D C, Helmchen U, Thaiss F, Ziyadeh F N, Stahl R A
Department of Medicine, Division of Nephrology and Osteology, University of Hamburg, Germany.
Kidney Int. 1999 Sep;56(3):860-72. doi: 10.1046/j.1523-1755.1999.00626.x.
Leptin inhibits food intake and increases energy expenditure. Although the kidney expresses abundant transcripts of the short form of the leptin receptor (Ob-Ra), a role for this hormone in renal function remains unclear. Because individuals with massive obesity who may exhibit increased leptin serum concentrations develop renal glomerulosclerosis, we studied whether leptin can influence renal growth and profibrogenic processes.
The effects of recombinant leptin on proliferation and synthesis of transforming growth factor-beta1 (TGF-beta1) was investigated in cultured glomerular endothelial cells of the rat (GERs) and syngeneic mesangial cells. Furthermore, leptin receptor expression and potential signal transduction pathways were evaluated in GERs. In addition, leptin was also infused for different time periods (72 hr and 3 weeks) into naive rats.
Recombinant mouse leptin induced proliferation of GERs, but not of syngeneic mesangial cells. Coincubation with angiotensin II and leptin exerts additive proliferative effects in GERs. An antileptin-receptor antibody totally abolished this proliferation but did not influence serum-induced proliferation. GER expressed high affinity receptors of the Ob-Ra type (Kd, 4 nM; Bmax, 9700 receptors/cell). Leptin also stimulated phosphorylation of STAT1alpha, and kinase inhibitors attenuated proliferation, suggesting a pivotal role of phosphorylation in this process. Incubation of GERs with leptin also induced mRNA expression of TGF-beta1 and enhanced secretion of this profibrogenic cytokine. Short-term leptin infusion (72 hr) into naive rats induced a significant proliferation, mainly restricted to glomerular endothelial cells, and enhanced glomerular TGF-beta1 mRNA levels. In rats continuously infused for three weeks with leptin, glomerular TGF-beta1 expression was still enhanced, and an additional increase in glomerular collagen type IV mRNA and protein expression was detected. These animals revealed an increase in proteinuria compared with control-infused rats.
Our findings are the first in vitro and in vivo demonstration that leptin is a renal growth and profibrogenic factor. These results may be an important contribution to our understanding of how leptin can contribute to renal damage, characterized by endocapillary proliferation and subsequent development of glomerulosclerosis, in pathophysiological situations with high circulating levels such as in diabetics or obese individuals. Although the effects of leptin itself are moderate, growth-promoting and profibrogenic effects may be enhanced in concert with other factors such as angiotensin II.
瘦素抑制食物摄入并增加能量消耗。尽管肾脏表达了丰富的短型瘦素受体（Ob-Ra）转录本，但该激素在肾功能中的作用仍不清楚。由于肥胖个体可能表现出血清瘦素浓度升高，且会发生肾小球硬化，因此我们研究了瘦素是否会影响肾脏生长和促纤维化过程。
在大鼠肾小球内皮细胞（GERs）和同基因系膜细胞中研究重组瘦素对转化生长因子-β1（TGF-β1）增殖和合成的影响。此外，还评估了GERs中瘦素受体的表达及潜在的信号转导途径。另外，还对未处理的大鼠进行了不同时间段（72小时和3周）的瘦素输注。
重组小鼠瘦素可诱导GERs增殖，但不能诱导同基因系膜细胞增殖。与血管紧张素II和瘦素共同孵育对GERs具有相加的增殖作用。抗瘦素受体抗体完全消除了这种增殖，但不影响血清诱导的增殖。GER表达Ob-Ra型高亲和力受体（解离常数Kd为4 nM；最大结合容量Bmax为9700个受体/细胞）。瘦素还刺激了信号转导及转录激活因子1α（STAT1α）的磷酸化，激酶抑制剂减弱了增殖，表明磷酸化在此过程中起关键作用。用瘦素孵育GERs还可诱导TGF-β1的mRNA表达，并增强这种促纤维化细胞因子的分泌。对未处理的大鼠进行短期瘦素输注（72小时）可诱导显著增殖，主要局限于肾小球内皮细胞，并提高肾小球TGF-β1的mRNA水平。在连续3周输注瘦素的大鼠中，肾小球TGF-β1表达仍增强，且检测到肾小球IV型胶原mRNA和蛋白表达进一步增加。与输注对照的大鼠相比，这些动物的蛋白尿增加。
我们的研究结果首次在体外和体内证明瘦素是一种肾脏生长和促纤维化因子。这些结果可能对我们理解在糖尿病患者或肥胖个体等高循环水平的病理生理情况下，瘦素如何导致以内皮细胞增殖和随后肾小球硬化为特征的肾脏损伤具有重要意义。尽管瘦素本身的作用中等，但与血管紧张素II等其他因素协同作用时，其促生长和促纤维化作用可能会增强。
