A role for leptin in glomerulosclerosis?
Authors: Barbara J. Ballermann
Journal: Kidney International (1999)

Focal and segmental glomerulosclerosis (FSGS) leading to the nephrotic syndrome is sometimes found in patients with morbid obesity. Whether and by what mechanisms obesity causes this glomerular lesion is unclear1.Weisinger J.R. Kempson R.L. Eldridge F.L. Swenson R.S. The nephrotic syndrome: a complication of massive obesity.Ann Intern Med. 1974; 81: 440-447Crossref PubMed Scopus (244) Google Scholar,2.Kasiske B.L. Napier J. Glomerular sclerosis in patients with massive obesity.Am J Nephrol. 1985; 5: 45-50Crossref PubMed Scopus (88) Google Scholar. In this issue of Kidney International, Wolf et al.3.Wolf G. Hamann A. Han D.C. Helmchen U. Thaiss F. Ziyadeh F.N. Stahl R.A.K. Leptin Stimulates proliferation and TGF-β expression in renal glomerular endothelial cells: potential role in glomerulosclerosis.Kidney Int. 1999; 56: 860-872Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar report that leptin stimulates glomerular endothelial cell proliferation in vitro and in vivo and that leptin administration in rats causes proteinuria and glomerular mesangial matrix expansion. The work suggests a potential link between the hormonal system controlling body fat stores and glomerular size and matrix content, and implicates leptin as a causal factor for FSGS. Discovery of the leptin gene was reported in the landmark paper by Zhang et al.4.Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Crossref PubMed Scopus (11379) Google Scholar in mice carrying the autosomal recessive ob mutation. This was the first step in unlocking the puzzle of hormonal control of body fat stores, and brought with it the hope that leptin replacement therapy might eventually prove useful in the treatment of obesity in humans. The ob gene product, leptin, is a circulating 16-kDa hormone produced by adipocytes that acts predominantly in the hypothalamus to signal negative energy balance5.Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4370) Google Scholar. Ob-/ob- mice, in which bioactive leptin is lacking, suffer from massive obesity and type II diabetes, as well as hypothermia, hyperphagia, and infertility. Leptin receptor abnormalities cause a similar phenotype. Five normal splice variants of leptin receptors (Ob-Ra through Ob-Re) are known; they differ in the length of the carboxyterminus. The longest of them, Ob-Rb, is expressed predominantly in the hypothalamus and is critical for the obesity-controlling function of leptin. The cytoplasmic signaling domains of the long Ob-Rb and the shorter Ob-Ra contain Jak/Stat signaling motifs, and both can activate insulin-like receptor substrate and Erk1 kinase. At least four different truncation mutations of Ob-Rb, are found in mice (db, dbPas, db3J, facp); they produce the same obese phenotype in homozygous animals as observed in leptin deficient mice. In Zucker obese rats a single mutation in the ligand binding domain of leptin receptors similarly produces the obese, type II diabetes phenotype. In humans, hereditary leptin deficiency as a cause of morbid obesity has also been described, but it is exceedingly rare. Indeed, in most obese patients leptin levels are higher than normal and correlate strongly with body mass index, indicating resistance to leptin6.Considine R.V. Sinha M.K. Heiman M.L. Kriauciunas A. Stephens T.W. Nyce M.R. Ohannesian J.P. Marco C.C. McKee L.J. Bauer T.L. Caro J.F. Serum immunoreactive-leptin concentrations in normal-weight and obese humans.N Engl J Med. 1996; 334: 292-295Crossref PubMed Scopus (5379) Google Scholar. Hence, some of the initial excitement about this hormone as a potential therapy has waned. Nevertheless, high-dose leptin therapy is under investigation for the treatment of human obesity5.Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4370) Google Scholar. The study by Wolf et al.3.Wolf G. Hamann A. Han D.C. Helmchen U. Thaiss F. Ziyadeh F.N. Stahl R.A.K. Leptin Stimulates proliferation and TGF-β expression in renal glomerular endothelial cells: potential role in glomerulosclerosis.Kidney Int. 1999; 56: 860-872Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar describes both in vitro and in vivo actions of leptin in renal glomeruli. Their provocative findings raise important questions about the leptin system and its potential impact on glomerular structure and function. First, could chronic stimulation of glomerular cells by leptin contribute to glomerular remodeling, and if so, by what mechanisms? In the study reported here, only Ob-Ra was present in glomerular endothelial cells and induced phosphorylation of Stat-1α. In addition, leptin treatment of endothelial cells induced TGF-β1 synthesis. Direct leptin-stimulated endothelial cell activation and angiogenesis were previously reported in nonglomerular endothelial cells, but induction of endothelial cell TGF-β1 synthesis is a novel and important finding. Furthermore, the observation that glomerular TGF-β1 mRNA abundance similarly increased and remained elevated during 3 weeks of chronic leptin infusion and was associated with enhanced type IV collagen deposition suggests importance in vivo. It is of note that the concentrations of leptin capable of stimulating endothelial cell proliferation in this study are about one order of magnitude higher than circulating levels in obese patients6.Considine R.V. Sinha M.K. Heiman M.L. Kriauciunas A. Stephens T.W. Nyce M.R. Ohannesian J.P. Marco C.C. McKee L.J. Bauer T.L. Caro J.F. Serum immunoreactive-leptin concentrations in normal-weight and obese humans.N Engl J Med. 1996; 334: 292-295Crossref PubMed Scopus (5379) Google Scholar, leaving open the question whether direct leptin effects in the glomerulus could occur if less drastic increases in leptin levels persisted over prolonged periods. It is also unclear whether the in vivo effects of leptin observed are explained by direct leptin actions, or whether there is also a role for activation of the renin angiotensin cascade through leptin induced activation of renal sympathetic nerve activity5.Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4370) Google Scholar and/or intraglomerular capillary hypertension. Whatever the mechanism, however, the findings by Wolf et al.3.Wolf G. Hamann A. Han D.C. Helmchen U. Thaiss F. Ziyadeh F.N. Stahl R.A.K. Leptin Stimulates proliferation and TGF-β expression in renal glomerular endothelial cells: potential role in glomerulosclerosis.Kidney Int. 1999; 56: 860-872Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar suggest that leptin could be the culprit that explains proteinuria and glomerular sclerosis in patients with morbid obesity. Furthermore, the study also suggests that great caution will need to be exercised, including close monitoring of renal protein excretion, if high dose leptin therapy is to be used in obese patients. An additional question raised by the findings of Wolf et al.3.Wolf G. Hamann A. Han D.C. Helmchen U. Thaiss F. Ziyadeh F.N. Stahl R.A.K. Leptin Stimulates proliferation and TGF-β expression in renal glomerular endothelial cells: potential role in glomerulosclerosis.Kidney Int. 1999; 56: 860-872Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar concerns the role of endothelial cells in the process of glomerular remodeling and matrix deposition. Wolf and colleagues observed leptin receptors and proliferative responses in endothelial but not in mesangial cells in vitro, and saw evidence for in vivo glomerular endothelial cell proliferation in rats given intraperitoneal leptin. Earlier reports had suggested that endothelial cell injury, apoptosis and proliferation may be the initiating event in the development of glomerular sclerosis in the remnant kidney model7.Lee L.K. Meyer T.W. Pollock A.S. Lovett D.H. Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney.J Clin Invest. 1995; 96: 953-964Crossref PubMed Scopus (180) Google Scholar. Furthermore, the finding that protein excretion rates increased in rats given leptin is of particular interest, given that some have suggested that the glomerular endothelium serves an important role in maintaining the permselectivity of the glomerular capillary wall8.Sorensson J. Matejka G.L. Ohlson M. Haraldsson B. Human endothelial cells produce orosomucoid, an important component of the capillary barrier.Am J Physiol. 1999; 276: H530-H534PubMed Google Scholar. Insofar as leptin may have endothelial cell specific effects in the glomerulus, the work by Wolf et al.3.Wolf G. Hamann A. Han D.C. Helmchen U. Thaiss F. Ziyadeh F.N. Stahl R.A.K. Leptin Stimulates proliferation and TGF-β expression in renal glomerular endothelial cells: potential role in glomerulosclerosis.Kidney Int. 1999; 56: 860-872Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar would tend to support the notion that activation of endothelial cells and elaboration of endothelial cell derived mediators such as TGF-β1 could be central to the glomerular remodeling response. Could leptin also play a role in the development of diabetic nephropathy? At first glance, the finding that the leptin deficient ob/ob mice are relatively resistant to the development of diabetic glomerulopathy would seem to support a role for leptin in this process. Leptin levels tend to be elevated in patients with type II diabetes, leptin contributes to insulin resistance in these patients, and activation of leptin receptors can stimulate phosphorylation of the insulin-like receptor substrate5.Friedman J.M. Halaas J.L. Leptin and the regulation of body weight in mammals.Nature. 1998; 395: 763-770Crossref PubMed Scopus (4370) Google Scholar. It therefore seems plausible that leptin could act via mechanisms similar to IGF-I in stimulating glomerular remodeling. However, Wolfe et al.3.Wolf G. Hamann A. Han D.C. Helmchen U. Thaiss F. Ziyadeh F.N. Stahl R.A.K. Leptin Stimulates proliferation and TGF-β expression in renal glomerular endothelial cells: potential role in glomerulosclerosis.Kidney Int. 1999; 56: 860-872Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar found no evidence for leptin-induced mesangial cell proliferation. Also, although leptin is essential for the regulation of Glut-2 expression in pancreatic cells9.Wang M.Y. Koyama K. Shimabukuro M. Mangelsdorf D. Newgard C.B. Unger R.H. Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion.Proc Natl Acad Sci USA. 1998; 95: 11921-11926Crossref PubMed Scopus (85) Google Scholar, a similar effect on Glut-1 in mesangial cells is unlikely because they do not bear receptors for leptin, nor does leptin alter glucose transporter expression in nonpancreatic cells. It is also of note that Zucker rats, in which all leptin receptors (including Ob-Ra and Ob-Rb) are defective, are prone to glomerulosclerosis. Furthermore, in patients with insulin-dependent diabetes mellitus, circulating leptin levels are generally reduced, resembling the pathophysiologic state of starvation. Based on such observations, it seems doubtful that leptin plays a primary role in the development of diabetic nephropathy.