Growth Arrest-specific Gene 6 Is Involved in Glomerular Hypertrophy in the Early Stage of Diabetic Nephropathy

Nephropathy is one of the most common complications of diabetes mellitus. Glomerular hypertrophy is a hallmark in the early phase of the nephropathy. The mechanism of glomerular hypertrophy, however, remains incompletely understood. We have reported that Gas6 (growth arrest-specific gene 6) and its receptor, Axl, play a key role in the development of glomerulonephritis. Here we show the important role of Gas6/Axl in the pathogenesis of diabetic glomerular hypertrophy. In streptozotocin (STZ)-induced diabetic rats, mesangial and glomerular hypertrophy and an increase in the glomerular filtration rate (GFR) and albuminuria were observed after 12 weeks of STZ injection. The glomerular expression of Gas6 and Axl was increased in those rats. Administration of warfarin inhibited mesangial and glomerular hypertrophy and the increase in GFR and albuminuria in STZ rats. Moreover, we found less mesangial hypertrophy in STZ-treated Gas6 knockout mice than control mice. In vitro we found that stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Thus we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy. Nephropathy is one of the most common complications of diabetes mellitus. Glomerular hypertrophy is a hallmark in the early phase of the nephropathy. The mechanism of glomerular hypertrophy, however, remains incompletely understood. We have reported that Gas6 (growth arrest-specific gene 6) and its receptor, Axl, play a key role in the development of glomerulonephritis. Here we show the important role of Gas6/Axl in the pathogenesis of diabetic glomerular hypertrophy. In streptozotocin (STZ)-induced diabetic rats, mesangial and glomerular hypertrophy and an increase in the glomerular filtration rate (GFR) and albuminuria were observed after 12 weeks of STZ injection. The glomerular expression of Gas6 and Axl was increased in those rats. Administration of warfarin inhibited mesangial and glomerular hypertrophy and the increase in GFR and albuminuria in STZ rats. Moreover, we found less mesangial hypertrophy in STZ-treated Gas6 knockout mice than control mice. In vitro we found that stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Thus we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy. transforming growth factor-β1 streptozotocin glomerular filtration rate mitogen-activated protein Diabetes is the most common cause of end stage renal disease in many countries. Approximately 30% of type 1 diabetic patients suffer from diabetic nephropathy (1Bojestig M. Arnqvist H.J. Hermansson G. Karlberg B.E. Ludvigsson J. N. Engl. J. Med. 1994; 330: 15-18Crossref PubMed Scopus (422) Google Scholar, 2Krolewski M. Eggers P.W. Warram J.H. Kidney Int. 1996; 50: 2041-2046Abstract Full Text PDF PubMed Scopus (142) Google Scholar). Therefore, tremendous efforts have been made to elucidate the molecular mechanism of diabetic nephropathy to develop an effective treatment. The feature characteristic of diabetic nephropathy is persistent albuminuria and mesangial expansion followed by glomerulosclerosis and a decline in renal function. The development of glomerulosclerosis in diabetes mellitus is always preceded by the early hypertrophic processes in the glomerular compartment (3Ziyadeh F.N. Am. J. Kidney Dis. 1993; 22: 736-744Abstract Full Text PDF PubMed Scopus (231) Google Scholar). Because it is important to regulate the early stage of the disease process, extensive efforts have been made to elucidate growth factors and cytokines involved in mesangial expansion or hypertrophy (4Wolf G. Kidney Int. Suppl. 2000; 77: S59-S66Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Transforming growth factor-β1 (TGF-β1)1 and angiotensin II are found to be implicated in the development of diabetic nephropathy among them (5Lehmann R. Schleicher E.D. Clin. Chim. Acta. 2000; 297: 135-144Crossref PubMed Scopus (144) Google Scholar). Although angiotensin-converting enzyme inhibitors and/or type I angiotensin receptor blockers are effective to some extent, angiotensin-converting enzyme inhibitors can decrease the risk of developing diabetic nephropathy by only 12.5% in type 2 diabetic patients (6Ravid M. Brosh D. Levi Z. Bar-Dayan Y. Ravid D. Rachmani R. Ann. Intern. Med. 1998; 128: 982-988Crossref PubMed Google Scholar). Therefore, additional pathogenetic mechanisms are being urgently investigated to help design novel therapies for patients with diabetic nephropathy. Among other potential growth factors for glomerular cells, we have investigated the role of Gas6 (growth arrest-specific gene 6) in the pathogenesis of kidney disease. Gas6, cloned from serum-starved fibroblasts (7Manfioletti G. Brancolini C. Avanzi G. Schneider C. Mol. Cell. Biol. 1993; 13: 4976-4985Crossref PubMed Scopus (532) Google Scholar), is posttranslationally activated by γ-carboxylation of glutamate residues at its N terminus in the presence of vitamin K and inhibited by the anticoagulant warfarin (8Nakano T. Higashino K. Kikuchi N. Kishino J. Nomura K. Fujita H. Ohara O. Arita H. J. Biol. Chem. 1995; 270: 5702-5705Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 9Nakano T. Kawamoto K. Kishino J. Nomura K. Higashino K. Arita H. Biochem. J. 1997; 323: 387-392Crossref PubMed Scopus (144) Google Scholar). Recently we showed that Gas6 is an autocrine growth factor for mesangial cells and that Gas6 and its receptor Axl play a critical role in the development of glomerulonephritis by showing that warfarin and the extracellular domain of Axl inhibit mesangial cell proliferation by specific blockade of the Gas6-mediated pathway in a mesangial proliferative model of glomerulonephritis (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 11Yanagita M. Ishimoto Y. Arai H. Nagai K. Ito T. Nakano T. Salant D.J. Fukatsu A. Doi T. Kita T. J. Clin. Invest. 2002; 110: 239-246Crossref PubMed Scopus (80) Google Scholar). However, the role of Gas6 and Axl in diabetic nephropathy is not determined. The present study is designed to examine whether Gas6 and Axl can contribute to the pathogenesis of diabetic glomerular hypertrophyin vivo and in vitro. In this study, we specifically asked whether Gas6 and Axl can play an important role in mesangial cell hypertrophy, which is a feature seen in the early phase of diabetic nephropathy and whether inhibition of the Gas6/Axl pathway can affect the progression of diabetic nephropathy in streptozotocin (STZ) rats and mice. STZ was obtained from Wako Pure Chemical Inc. Ltd. (Osaka, Japan). Recombinant human TGF-β1 was purchased from R&D Systems, Inc. (Minneapolis, MN). Male Sprague-Dawley rats weighing 170–200 g were purchased from Shimizu Laboratory Animal center (Hamamatsu, Japan). Gas6 knockout mice were generated with a targeted disruption of the Gas6 gene as previously described (11Yanagita M. Ishimoto Y. Arai H. Nagai K. Ito T. Nakano T. Salant D.J. Fukatsu A. Doi T. Kita T. J. Clin. Invest. 2002; 110: 239-246Crossref PubMed Scopus (80) Google Scholar). Control inbred C57BL/6 mice were obtained from Clea Japan, Inc. (Osaka, Japan). The animals were housed under specific pathogen-free conditions at the Animal Facilities of Kyoto University, Faculty of Medicine. All of the animal experiments were performed in accordance with institutional guidelines, and the Review Board of Kyoto University granted ethical permission to this study. The glomerular mesangial primary culture was established from glomeruli isolated from normal 4-week-old mice (C57BL/6JxSJL/J) and was identified according to the method previously described (12Doi T. Vlassara H. Kirstein M. Yamada Y. Striker G.E. Striker L.J. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 2873-2877Crossref PubMed Scopus (325) Google Scholar, 13MacKay K. Striker L.J. Elliot S. Pinkert C.A. Brinster R.L. Striker G.E. Kidney Int. 1988; 33: 677-684Abstract Full Text PDF PubMed Scopus (152) Google Scholar). Phenotypically stable mesangial cells, 12th to 16th passages, were plated on 100-mm plastic dishes (Nalge Nunc International, Roskilde, Denmark) and maintained in growth medium (3:1 mixture of Dulbecco's modified Eagle's medium/Ham's F-12 medium modified trace elements) (Nissui Pharmaceutical Co., Ltd., Tokyo, Japan) supplemented with 1 mm glutamine, penicillin at 100 units/ml, streptomycin at 100 μg/ml (Invitrogen) and 20% fetal bovine serum (Cansera International Inc., Rexdale, Canada). Male rats weighing 170–200 g were made diabetic by a single intravenous injection of STZ (55 mg/kg body weight) in 0.05 mol/liter citrate buffer (pH 4.5). Weight-matched 8-week-old mice (17–20 g) were made diabetic by two consecutive daily intraperitoneal injections of STZ (150 mg/kg) dissolved in 0.01 mol/liter citrate buffer. Rats and mice receiving an injection of citrate buffer were used as controls. The levels of blood glucose were determined 2 days after injection of STZ or vehicle, and rats and mice with blood glucose levels more than >16.7 mmol/liter were used as diabetic (14Koya D. Jirousek M.R. Lin Y.W. Ishii H. Kuboki K. King G.L. J. Clin. Invest. 1997; 100: 115-126Crossref PubMed Scopus (485) Google Scholar, 15Flyvbjerg A. Bennett W.F. Rasch R. Kopchick J.J. Scarlett J.A. Diabetes. 1999; 48: 377-382Crossref PubMed Scopus (145) Google Scholar). Twelve weeks after STZ injection, the rats and mice were weighed and sacrificed. The rats were divided into four groups: control rats without treatment, control rats with warfarin treatment, diabetic rats without treatment, and diabetic rats with warfarin treatment. The rats with warfarin treatment were administered with 0.25 mg/liter warfarin potassium (provided by Eisai Co. Ltd., Tokyo, Japan) in drinking water from the day of STZ injection. The dosage of warfarin was determined based on the previous report (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Because diabetic rats drink much more water, the dosage of warfarin was reduced to 0.06 mg/liter from 2 days after injection of STZ. Twelve weeks after injection, the rats were weighed and sacrificed. Blood was collected at sacrifice. Prothrombin times, hematocrits, serum creatinine, and plasma concentrations of warfarin were measured as described (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). HbA1c was measured using DCA2000 analyzer (Bayer Medical, Tokyo, Japan). Before sacrifice, creatinine and albumin were measured from 24-h urine collection. Kidney tissues from each animal were snap frozen in cold acetone in optimal cutting temperature compound (Sakura Finetechnical Co. Ltd., Tokyo, Japan), and cryostat sections (4 μm) were stained by indirect immunofluorescence procedure with the following primary antibodies: rabbit polyclonal antibodies against rat Gas6 (16Yanagita M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar) and human Axl (generous gift from Dr. Brian Varnum, Amgen, Thousand Oaks, CA). Glomeruli were isolated from renal cortices of rats using the differential sieving method (17Ziswiler R. Steinmann-Niggli K. Kappeler A. Daniel C. Marti H.P. J. Am. Soc. Nephrol. 1998; 9: 2055-2066PubMed Google Scholar, 18Pippin J.W. Qu Q. Meijer L. Shankland S.J. J. Clin. Invest. 1997; 100: 2512-2520Crossref PubMed Scopus (131) Google Scholar). The purity of the glomeruli was >90%. Isolated glomeruli were suspended in RIPA buffer (50 mm mm 1 2 mm 1 μg/ml of and for 1 at the were used as cell of each was to the were to The were with rabbit Gas6, Axl, rabbit mitogen-activated protein polyclonal or rabbit polyclonal followed by with The were using and the The mesangial cell was measured in a by each mesangial cell were The glomerular and the were determined using an analyzer for Chemical Co., Tokyo, Japan) Y. Doi T. H. Ohashi S. M. T. S. S. S. H. H. J. Clin. Invest. 2001; PubMed Scopus Google Scholar, M. K. K. K. T. N. Doi T. Nephrol. 2002; PubMed Scopus Google Scholar). each glomeruli were was measured at 12 weeks by 24-h urine from rats housed in the urine the rats were to and and urine creatinine concentrations were and GFR was by the following GFR F.N. A. J.A. Am. J. 1998; Google Scholar). The albumin in the urine was measured by Inc., cells were plated at in the cells were serum-starved in Dulbecco's modified Eagle's medium bovine serum albumin for The medium was with the medium concentrations of or the cells were with for and the of into was determined. of cell the cells were in and with a Ltd., The were by by the cell and showed as cells were plated at in 100-mm The cells were as the treatment, mesangial cells were by with at for and in mesangial cells were by on a CA). The are as the among each was performed by of followed by to the two of was to be showed that glomerular hypertrophy and an increase in GFR and albuminuria were observed after 12 weeks of STZ injection in rats. Therefore, to examine the role of Gas6/Axl in the early phase of diabetic nephropathy in we used diabetic rat We the after 12 weeks of STZ injection and found that expression of Gas6 and Axl was increased in the STZ-treated and that were at and mesangial cells Because expression of Gas6 and Axl was in diabetic rats, the Gas6/Axl pathway to play a role in the development of diabetic nephropathy in the early phase of the disease Therefore, we whether this pathway can be effective in this diabetic nephropathy. We rats with warfarin in drinking water as in concentrations of warfarin in rats were 0.05 and 0.05 which were than the concentrations as an The body and kidney were not by warfarin treatment. of times, or was not observed in the rats the of warfarin treatment as we found in previous study not 12 weeks of STZ injection, we isolated glomeruli from the rats and found increased glomerular expression of Gas6 and Axl by as in we STZ rats with we found that the expression of Axl was inhibited in STZ rats than STZ rats. Although warfarin treatment not affect Gas6 it might be to the that the used for or Because we have that Gas6 can in vitro (16Yanagita M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar), we whether can be in diabetic glomerular and whether warfarin treatment can affect the in was in the glomerular in STZ rats, and warfarin treatment Because glomerular hypertrophy is one of the in diabetic we measured mesangial cell and glomerular in diabetic rat kidney and the of warfarin on glomerular hypertrophy. 12 weeks of STZ injection, were with control rats, and of warfarin the increase of mesangial and glomerular Because of mesangial extracellular is an early in diabetic we measured the in However, was in the control and diabetic that is glomerular after 12 weeks of STZ injection not In the early phase of diabetic GFR is increased in most of diabetic Therefore, we whether GFR is increased in STZ rats and whether warfarin treatment can affect 12 weeks of STZ injection, GFR and albumin were and the increased GFR and albuminuria were by warfarin treatment the of warfarin on the Gas6/Axl we used STZ-treated Gas6 knockout mice. showed that glomerular hypertrophy was observed after 12 weeks of STZ injection in mice. Therefore, we mesangial and glomerular hypertrophy in Gas6 knockout and type mice after 12 weeks of STZ injection. in Gas6 knockout mice were than type and HbA1c was in Gas6 knockout mice than in type mice. However, the blood glucose levels were the the study not Although the kidney was in diabetic Gas6 knockout mice with diabetic type was in mesangial cell and glomerular in diabetic type mice were than those in type mice. However, in diabetic Gas6 knockout the increase of was that Gas6 is involved in the development of the phase of diabetic nephropathy and that warfarin diabetic nephropathy specifically through the Gas6-mediated the mechanism by which Gas6 is involved in glomerular hypertrophy in diabetic rats, we whether Gas6 can cause mesangial cell hypertrophy in vitro. We measured in mesangial cells as a of hypertrophy after with concentrations of Recombinant Gas6 increased of with a increase at The of Gas6, which is an of Gas6 without not affect in mesangial The Gas6-mediated increase in was the as that of TGF-β1 whether mesangial cell hypertrophy is specifically through the we used the extracellular domain of Axl which is a protein of the extracellular domain of Axl and human as an of the with in medium for 1 Gas6 was to the serum-starved mesangial cells, and was The of inhibited the increased by Gas6, that the of Gas6 on hypertrophy is specific for the we the of mesangial cells by under the as We found that treatment of the cells with Gas6 100 or TGF-β1 increased the by not of mesangial cell The cells were as described in treatment, the mesangial cells were by with at for and in mesangial cells were by on a The are of experiments with control 100 of 100 of 1 of of of mesangial cells after treatment. The are as The are the of In this study, we have a novel mechanism of mesangial hypertrophy in diabetic nephropathy by is the that Gas6 can mesangial cell hypertrophy characteristic of the early stage of diabetic nephropathy and that warfarin is effective to the progression of diabetic nephropathy. study that Gas6 can be a novel growth factor that a role in the development of the phase of diabetic nephropathy. Here we have found a novel of warfarin as an show that warfarin treatment and albumin in STZ rats. Thus hypertrophy and might be an mechanism and to be J. Clin. Invest. 2001; PubMed Scopus Google Scholar). is that the Gas6/Axl pathway can the in diabetic nephropathy. Therefore, diabetic patients with warfarin to the nephropathy be one of the for treatment. However, the of warfarin be we diabetic patients with been used as an anticoagulant to and Med. J. 2000; PubMed Scopus Google Scholar, J. 2000; PubMed Scopus Google Scholar), and patients with this are by of to its anticoagulant patients have to be for the risk of S. N. Engl. J. Med. 2000; PubMed Scopus Google Scholar). However, the of warfarin was at serum concentrations of which is than the concentrations as an anticoagulant μm) Clin. PubMed Scopus Google Scholar). The of rats with warfarin in experiments were not and or was observed not mesangial cell hypertrophy was Although we have the of warfarin on the development of diabetic the remains the of the of We have that in mesangial cells warfarin specifically the Gas6/Axl pathway in vitro (16Yanagita M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar). the we have mice (11Yanagita M. Ishimoto Y. Arai H. Nagai K. Ito T. Nakano T. Salant D.J. Fukatsu A. Doi T. Kita T. J. Clin. Invest. 2002; 110: 239-246Crossref PubMed Scopus (80) Google Scholar) with STZ A. Bennett W.F. Rasch R. Kopchick J.J. Scarlett J.A. Diabetes. 1999; 48: 377-382Crossref PubMed Scopus (145) Google Scholar) and found that mesangial and glomerular were in mice with type mice. Therefore, we can that this of warfarin be specifically through the inhibition of in glomeruli been reported in diabetic nephropathy K. K. O. S. J. Full Text PDF PubMed Scopus Google Scholar), which might the renal function. A. C. J. M. M. J. D. B. Med. 2001; PubMed Scopus Google Scholar) reported that a of Gas6 mice from In this study, we used a of and at concentrations we found of not However, we reported that under warfarin can inhibit the of Gas6 in vitro and in vivo (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar, M. Arai H. Nakano T. Ohashi K. Mizuno K. Fukatsu A. Doi T. Kita T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). is that warfarin affect the and at Therefore, Gas6 might affect the development of diabetic renal disease by the The increase of extracellular followed by mesangial cell hypertrophy is one of the in diabetic nephropathy G. F.N. Kidney Int. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). J. Clin. Invest. PubMed Scopus Google Scholar) investigated the in a of patients with type 1 found a mesangial expansion and of diabetic nephropathy. (3Ziyadeh F.N. Am. J. Kidney Dis. 1993; 22: 736-744Abstract Full Text PDF PubMed Scopus (231) Google Scholar) showed that the development of renal in diabetes as is always preceded by the early hypertrophic processes in the glomerular In however, we not an of extracellular in STZ rats at 12 other have reported increased of extracellular in a phase of nephropathy in STZ rats H. Y. K. Z. Pathol. Mol. Pathol. 1992; PubMed Scopus Google Scholar). Because in this study is to the role of Gas6 in the phase of diabetic we to 12 weeks after STZ injection. The Gas6 and diabetic glomerulosclerosis be by the rats with warfarin for a or using animal STZ rats with a protein be to the glomerulosclerosis R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) and be in the We have that Gas6 is a growth factor for mesangial vitro and that Gas6 a key role in and of glomerulonephritis in vivo (10Yanagita M. Arai H. Ishii K. Nakano T. Ohashi K. Mizuno K. Varnum B. Fukatsu A. Doi T. Kita T. Am. J. Pathol. 2001; 158: 1423-1432Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar, M. Arai H. Nakano T. Ohashi K. Mizuno K. Fukatsu A. Doi T. Kita T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In those we have that Gas6 can mesangial proliferation through a Axl (11Yanagita M. Ishimoto Y. Arai H. Nagai K. Ito T. Nakano T. Salant D.J. Fukatsu A. Doi T. Kita T. J. Clin. Invest. 2002; 110: 239-246Crossref PubMed Scopus (80) Google Scholar, M. Ishii K. Ozaki H. Arai H. Nakano T. Ohashi K. Mizuno K. Kita T. Doi T. J. Am. Soc. Nephrol. 1999; 10: 2503-2509PubMed Google Scholar) and a factor and of M. Arai H. Nakano T. Ohashi K. Mizuno K. Fukatsu A. Doi T. Kita T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). However, in this study we have that Gas6 can mesangial hypertrophy in vivo and in vitro. Therefore, the is Gas6 only mesangial hypertrophy without the mesangial proliferation in this diabetic rat Although we determined the mesangial cell in the kidney of diabetic rats, we not that the glomerular cell was increased in diabetic rats not Although K. J. K. Kidney Int. 1995; Full Text PDF PubMed Scopus Google Scholar) reported that diabetic nephropathy be with some glomerular cell hypertrophy is the of diabetic nephropathy. remains Gas6 can be in glomerulonephritis and diabetic nephropathy and Gas6 not cell proliferation in diabetic nephropathy. is that some other growth factor or is an additional role in the of mesangial cell in the disease We have that was in the glomeruli after 12 weeks of STZ injection and that warfarin treatment the In the of growth factor to be for its hypertrophic in C. R. L. D.J. Biol. 2001; PubMed Scopus Google Scholar), and hypertrophy of protein and S. J. 2002; PubMed Scopus Google Scholar). Although we have to the role of in mesangial cell hypertrophy of might be used as a for the hypertrophy in diabetic nephropathy. The molecular mechanism of mesangial cell hypertrophy in diabetic nephropathy be in In this is the that Gas6 and Axl are involved in the development of the phase of diabetic nephropathy by mesangial cell hypertrophy. is a novel mechanism the development of diabetic nephropathy. this pathway be beneficial to the progression of nephropathy in diabetic We and University of for We and for

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