Leptin stimulates proliferation and TGF-beta expression in renal glomerular endothelial cells: Potential role in glomerulosclerosis

Background. Leptin inhibits food intake and increases energy expenditure. A lthough 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 w hether leptin can influence renal growth and profibrogenic processes. Methods. The effects of recombinant leptin on proliferation and synthesis o f transforming growth factor-beta 1 (TGF-beta 1) was investigated in cultur ed glomerular endothelial cells of the rat (GERs) and syngeneic mesangial c ells. Furthermore, leptin receptor expression and potential signal transduc tion pathways were evaluated in GERs. In addition, leptin was also infused for different time periods (72 hr and 3 weeks) into naive rats. Results. Recombinant mouse leptin induced proliferation of GERs, but not of syngeneic mesangial cells. Coincubation with angiotensin II and leptin exe rts additive proliferative effects in GERs. An antileptin-receptor antibody totally abolished this proliferation but did not influence serum-induced p roliferation. GER expressed high affinity receptors of the Ob-Ra type (K-d, 4 nM; B-max, 9700 receptors/cell). Leptin also stimulated phosphorylation of STAT1 alpha, 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-beta 1 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-beta 1 mRNA levels. In rats continuously infused for three weeks with leptin, glomerular TGF-beta 1 exp ression was still enhanced, and an additional increase in glomerular collag en type IV mRNA and protein expression was detected. These animals revealed an increase in proteinuria compared with control-infused rats. Conclusion. Our findings are the first in vitro and in vivo demonstration t hat leptin is a renal growth and profibrogenic factor. These results may be an important contribution to our understanding of how leptin can contribut e to renal damage, characterized by endocapillary proliferation and subsequ ent development of glomerulosclerosis, in pathophysiological situations wit h high circulating levels such as in diabetics or obese individuals. Althou gh the effects of leptin itself are moderate, growth-promoting and profibro genic effects may be enhanced in concert with other factors such as angiote nsin II.