Reduced Glomerular Endothelial Thrombomodulin Is Associated with Glomerular Macrophage Infiltration in Diabetic Nephropathy

Abstract

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ETAR) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ETAR with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ETAR antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin. The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ETAR) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ETAR with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ETAR antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin. Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the Western world,1LeCaire T.J. Klein B.E.K. Howard K.P. Lee K.E. Klein R. Risk for end-stage renal disease over 25 years in the population-based WESDR cohort.Diabetes Care. 2014; 37: 381-388Crossref PubMed Scopus (30) Google Scholar occurring in approximately 40% of patients with diabetes mellitus.2Gross J.L. de Azevedo M.J. Silveiro S.P. Canani L.H. Caramori M.L. Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment.Diabetes Care. 2005; 28: 164-176Crossref PubMed Scopus (1127) Google Scholar Impaired function of the glomerular endothelial cells occurs in the early stages of diabetic kidney damage, with a reduction in the glomerular endothelial glycocalyx and altered expression of endothelial adhesion proteins contributing to inflammation and fibrosis.3Bus P. Scharpfenecker M. Van Der Wilk P. Wolterbeek R. Bruijn J.A. Baelde H.J. The VEGF-A inhibitor sFLT-1 improves renal function by reducing endothelial activation and inflammation in a mouse model of type 1 diabetes.Diabetologia. 2017; 60: 1813-1821Crossref PubMed Scopus (22) Google Scholar,4van den Berg B.M. Wang G. Boels M.G.S. Avramut M.C. Jansen E. Sol W.M.P.J. Lebrin F. Jan van Zonneveld A. de Koning E.J.P. Vink H. Gröne H.-J. Carmeliet P. van der Vlag J. Rabelink T.J. Glomerular function and structural integrity depend on hyaluronan synthesis by glomerular endothelium.J Am Soc Nephrol. 2019; 30: 1886-1897Crossref PubMed Scopus (26) Google Scholar The thrombomodulin/protein C signaling pathway is critical for maintaining glomerular endothelial homeostasis and preventing inflammation.5Esmon C.T. Inflammation and the activated protein C anticoagulant pathway.Semin Thromb Hemost. 2006; 32 Suppl 1: 49-60Crossref PubMed Scopus (207) Google Scholar Indeed, animal studies indicate that impaired glomerular thrombomodulin signaling contributes to the pathogenesis of DN.6Isermann B. Vinnikov I.A. Madhusudhan T. Herzog S. Kashif M. Blautzik J. Corat M.A. Zeier M. Blessing E. Oh J. Gerlitz B. Berg D.T. Grinnell B.W. Chavakis T. Esmon C.T. Weiler H. Bierhaus A. Nawroth P.P. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.Nat Med. 2007; 13: 1349-1358Crossref PubMed Scopus (304) Google Scholar Encoded by the THBD gene, the transmembrane glycoprotein thrombomodulin is expressed primarily by endothelial cells and is a component of the endothelial surface glycocalyx.7Esmon C.T. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface.FASEB J. 1995; 9: 946-955Crossref PubMed Scopus (352) Google Scholar The thrombomodulin protein contains an N-terminal lectin-like domain, six epidermal growth factor (EGF)–like repeats, a serine/threonine-rich domain, a transmembrane domain, and a cytoplasmic C-terminal domain. Under physiological conditions, thrombomodulin binds circulating thrombin via the EGF-like domain, driving activation of the serine-protease‒activated protein C (APC), which exerts cytoprotective effects by regulating coagulation, inflammation, and apoptosis.8Mosnier L.O. Zlokovic B.V. Griffin J.H. The cytoprotective protein C pathway.Blood. 2007; 109: 3161-3172Crossref PubMed Scopus (605) Google Scholar Renal thrombomodulin is down-regulated in a mouse model of DN, leading to the reduced production of APC and resulting in increased glomerular apoptosis, glomerulosclerosis, and albuminuria.6Isermann B. Vinnikov I.A. Madhusudhan T. Herzog S. Kashif M. Blautzik J. Corat M.A. Zeier M. Blessing E. Oh J. Gerlitz B. Berg D.T. Grinnell B.W. Chavakis T. Esmon C.T. Weiler H. Bierhaus A. Nawroth P.P. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.Nat Med. 2007; 13: 1349-1358Crossref PubMed Scopus (304) Google Scholar In addition, thrombomodulin prevents inflammation via APC-independent pathways; thrombomodulin's lectin-like domain directly interferes with macrophage recruitment by regulating NF-κB activity and endothelial adhesion molecule expression9Geudens N. Van de Wouwer M. Vanaudenaerde B.M. Vos R. Van De Wauwer C. Verleden G.M. Verbeken E. Lerut T. Van Raemdonck D.E.M. Conway E.M. The lectin-like domain of thrombomodulin protects against ischaemia–reperfusion lung injury.Eur Respir J. 2008; 32: 862-870Crossref PubMed Scopus (25) Google Scholar,10Conway E.M. Van de Wouwer M. Pollefeyt S. Jurk K. Van Aken H. De Vriese A. Weitz J.I. Weiler H. Hellings P.W. Schaeffer P. Herbert J.-M. Collen D.S. Theilmeier G. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor κB and mitogen-activated protein kinase pathways.J Exp Med. 2002; 196: 565-577Crossref PubMed Scopus (293) Google Scholar and suppresses glomerular complement activation in DN.11Wang H. Vinnikov I. Shahzad K. Bock F. Ranjan S. Wolter J. Kashif M. Oh J. Bierhaus A. Nawroth P. Kirschfink M. Conway E.M. Madhusudhan T. Isermann B. The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition.Thromb Haemost. 2012; 108: 1141-1153Crossref PubMed Scopus (44) Google Scholar Moreover, treating diabetic mice with thrombomodulin reduces the development of DN and glomerulosclerosis by suppressing glomerular inflammation.12Yang S.M. Ka S.M. Wu H.L. Yeh Y.C. Kuo C.H. Hua K.F. Shi G.Y. Hung Y.J. Hsiao F.C. Yang S.S. Shieh Y.S. Lin S.H. Wei C.W. Lee J.S. Yang C.Y. Chen A. Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-kappaB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis.Diabetologia. 2014; 57: 424-434Crossref PubMed Scopus (74) Google Scholar Similar nephroprotective effects of thrombomodulin treatment are reported in animal models of nephrotoxic serum glomerulonephritis and progressive renal fibrosis.13Tachibana S. Iyoda M. Matsumoto K. Wada Y. Suzuki T. Iseri K. Kanazawa N. Shibata T. Recombinant human soluble thrombomodulin attenuates anti-glomerular basement membrane glomerulonephritis in Wistar–Kyoto rats through anti-inflammatory effects.Nephrol Dial Transplant. 2018; 34: 774-782Crossref Scopus (8) Google Scholar,14Takeshita A. Yasuma T. Nishihama K. D'Alessandro-Gabazza C.N. Toda M. Totoki T. Okano Y. Uchida A. Inoue R. Qin L. Wang S. D'Alessandro V.F. Kobayashi T. Takei Y. Mizoguchi A. Yano Y. Gabazza E.C. Thrombomodulin ameliorates transforming growth factor-β1–mediated chronic kidney disease via the G-protein coupled receptor 15/Akt signal pathway.Kidney Int. 2020; 98: 1179-1192Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Thus, impaired glomerular thrombomodulin function plays a central in the pathogenesis of DN in animal and treatment with thrombomodulin effects with to reducing inflammation in the studies to the expression of glomerular thrombomodulin in patients with DN, studies reported that the serum levels of soluble thrombomodulin the cleaved domain of are serum levels of APC are in diabetic Y. T. Y. of of serum and of soluble thrombomodulin in diabetic as a for endothelial Full Text PDF PubMed Scopus (30) Google K. Yano Y. Gabazza E.C. R. M. H. A. Y. Y. activated protein C and in type diabetic Med. 2007; PubMed Scopus Google Scholar may impaired thrombomodulin function at the level, with to thrombomodulin expression and signaling in the glomerular thrombomodulin serum levels associated with impaired function of the endothelial glycocalyx in patients with chronic kidney M. Lee van den Berg B.M. Boels M.G.S. van van der Vlag J. van Zonneveld Vink H. Rabelink T.J. of kidney function with in the endothelial surface Am Soc Nephrol. 2014; 9: PubMed Scopus Google Scholar a thrombomodulin expression and glycocalyx Moreover, treatment with the endothelin A receptor (ETAR) the glomerular glycocalyx in a mouse model of Avramut M.C. A. M.J. Lee van der Vlag J. van Zonneveld van E. H.J. van den Berg B.M. Rabelink T.J. reduces by the glomerular endothelial glycocalyx in diabetic PubMed Scopus (74) Google Scholar the of ETAR which by renal in patients with G. R. and renal in patients with type diabetes and chronic kidney disease a 2019; Full Text Full Text PDF PubMed Scopus Google Scholar may glomerular thrombomodulin signaling in DN. glomerular thrombomodulin protein levels measured in renal samples from a of patients with diabetes with and without DN, and the glomerular thrombomodulin levels and the of glomerular macrophages was In addition, glomerular THBD mRNA was measured in microdissected glomeruli from patients with DN. Finally, thrombomodulin expression was in diabetic mice following treatment with atrasentan. Renal tissue from a P. J.S. M. Wolterbeek R. van C. Bruijn J.A. Baelde H.J. activation in patients with diabetic 2018; Full Text Full Text PDF PubMed Scopus Google M. J.I. Wolterbeek R. Bruijn J.A. that diabetic nephropathy is Int. Full Text Full Text PDF PubMed Scopus Google Scholar from the of the the In samples from diabetic patients with DN diabetic patients with or of DN or renal and and nondiabetic The renal samples for a of DN by with to the and DN was in with the for K. F. M. de E. K. L.H. J. Bruijn J.A. of diabetic Am Soc Nephrol. PubMed Scopus Google Scholar tissue by renal biopsies from patients with DN of samples was as A by Baelde H.J. M. P.P. van der R. Rabelink T.J. de E. Bruijn J.A. of VEGF-A and expression in diabetic nephropathy is associated with podocyte Int. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar was to glomerular THBD mRNA In glomeruli from biopsies from diabetic patients with DN and from nondiabetic for for and the of samples and in with and in with the of the of The diabetic mouse model in Avramut M.C. A. M.J. Lee van der Vlag J. van Zonneveld van E. H.J. van den Berg B.M. Rabelink T.J. reduces by the glomerular endothelial glycocalyx in diabetic PubMed Scopus (74) Google Scholar In mice diabetic by of that a of the selective ETAR atrasentan was to the for which the mice and renal and in for thrombomodulin glomeruli from the renal animal in with for the and of and by the kidney the following mouse EGF-like domain of thrombomodulin mouse domain of thrombomodulin and mouse the following thrombomodulin and The an or with as the and a was was the thrombomodulin and factor by the and which the an was as a the glomerular thrombomodulin the number of glomerular kidney which of thrombomodulin and in the kidney in a for and a The The was measured in 25 glomeruli and is expressed to the glomerular The glomeruli for at and the and with to the and DN with glomeruli from with DN stages of DN. the thrombomodulin expression and the number of cells was in glomeruli measured in a of diabetic patients with or without DN and nondiabetic from the the thrombomodulin and was measured by and examined glomeruli at was from microdissected glomeruli mRNA was measured with the in a to the The following human THBD and human and mouse and and mouse and endothelial cells in at in cells at in in with serum endothelial cells in and to with against THBD or a for which cells to in with factor or for which cells to for at under human endothelial cells with to the in for by with The number of cells was measured with an a 25 of was in compared the or of compared the or the in glomerular thrombomodulin protein levels in the a model that of patients was The was to the glomerular thrombomodulin and the number of models with effects for the patients and effects of thrombomodulin and and an for a of on the thrombomodulin at in the are reported as the The 90 diabetic patients with DN and 55 diabetic patients with of DN as as 37 renal samples from nondiabetic without renal The and of cases are in The of diabetes was in the diabetic patients with DN compared with the diabetic cases without DN with to diabetes of serum level, glomerular or The glomerular thrombomodulin levels thrombomodulin was in the of Furthermore, the of thrombomodulin protein glomeruli measured renal tissue in a nondiabetic for thrombomodulin and factor for endothelial that thrombomodulin is expressed in glomerular endothelial cells glomerular thrombomodulin expression was in the diabetic patients with DN compared with nondiabetic compared to DN was associated with glomerular thrombomodulin levels diabetic patients without DN reduced thrombomodulin levels compared to Glomerular thrombomodulin levels with the of glomerular and with the glomerular In patients with DN, glomerular thrombomodulin protein was with serum serum and the of glomerular In glomerular thrombomodulin protein was associated with as DN glomerular basement membrane renal and and glomerular or as glomerular and indicate that thrombomodulin protein is decreased in glomeruli of diabetic patients and that in glomerular thrombomodulin the of DN. In of the with glomerular thrombomodulin protein was decreased in samples from patients with DN compared with samples from nondiabetic patients THBD mRNA was measured in glomeruli from kidney biopsies from diabetic patients with DN and nondiabetic The are in the are in expression that THBD mRNA was in the glomeruli of patients with DN compared with that in with increased of glomerular THBD in diabetic patients with DN. the of decreased thrombomodulin protein in the glomeruli of diabetic patients, the increased expression of thrombomodulin at the mRNA may a compensatory in an to the reduced endothelial thrombomodulin protein levels in patients with thrombomodulin is cleaved in the glomerular in patients with DN was examined by renal from a with DN to the and in the domain was compared with that in the domain, in the was in the and with studies increased serum levels of soluble thrombomodulin in patients with Y. T. Y. of of serum and of soluble thrombomodulin in diabetic as a for endothelial Full Text PDF PubMed Scopus (30) Google Scholar that thrombomodulin is cleaved in the glomerular in DN, the domain via the reduction in glomerular thrombomodulin protein levels is associated with an increase in the number of glomerular macrophages was Similar to the with to thrombomodulin with to the number of glomerular macrophages was thrombomodulin and in the was to thrombomodulin and the macrophage in kidney from Reduced glomerular thrombomodulin was associated with of cells The and of the the the patients are to The number of cells in glomeruli that thrombomodulin of the glomerular was in DN compared with that in diabetic and nondiabetic In addition, to the and for and thrombomodulin and in glomeruli and thrombomodulin and in diabetic glomeruli C and thrombomodulin and to for the of thrombomodulin and the of cells are to the that glomerular thrombomodulin levels are associated with glomerular of the possibility that thrombomodulin may a in the of macrophages the diabetic was reduced endothelial thrombomodulin expression results in an increase in the adhesion of to activated endothelial endothelial cells with a or a and activated with or for which the number of was In and endothelial increased the number of compared with In the of in a increase in The of thrombomodulin expression and on adhesion was that thrombomodulin expression the of on endothelial that thrombomodulin expression reduces the adhesion of to endothelial cells activated by was examined the reduction in glomerular thrombomodulin is associated with in the structural integrity of the glycocalyx the Diabetic mice, which decreased glycocalyx with a selective ETAR that to and the glycocalyx to Avramut M.C. A. M.J. Lee van der Vlag J. van Zonneveld van E. H.J. van den Berg B.M. Rabelink T.J. reduces by the glomerular endothelial glycocalyx in diabetic PubMed Scopus (74) Google Scholar with the human glomerular thrombomodulin was decreased in diabetic mice compared with nondiabetic mice treating diabetic mice with atrasentan increased the levels of glomerular thrombomodulin to the levels in nondiabetic mice the mRNA level, was in glomerular levels diabetic mice and and treating diabetic mice with atrasentan on glomerular mRNA levels In to the in human was in glomerular and diabetic mice of glomeruli for thrombomodulin and are in C and Finally, renal tissue of a nondiabetic and a DN with thrombomodulin and which binds to in Thrombomodulin and and in the glomerular of the nondiabetic In glomeruli of the DN thrombomodulin was the of of glycocalyx on the glomerular endothelial surface that in glomerular thrombomodulin is decreased at the protein but increased at the mRNA level, and the reduction in glomerular thrombomodulin protein is associated with an increased of macrophages in the In addition, the endothelin A receptor glomerular thrombomodulin protein levels in a diabetic mouse that the reduction in glomerular endothelial thrombomodulin occurs at an early of diabetic damage and contributes to glomerular inflammation in DN. in human tissue samples are with a of reduced thrombomodulin expression at the protein and mRNA levels in the renal of diabetic B. Vinnikov I.A. Madhusudhan T. Herzog S. Kashif M. Blautzik J. Corat M.A. Zeier M. Blessing E. Oh J. Gerlitz B. Berg D.T. Grinnell B.W. Chavakis T. Esmon C.T. Weiler H. Bierhaus A. Nawroth P.P. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.Nat Med. 2007; 13: 1349-1358Crossref PubMed Scopus (304) Google Scholar In was a increase in THBD mRNA in the glomeruli of diabetic patients with DN, a to for the reduced glomerular thrombomodulin protein levels in is by a that diabetic increased serum levels of soluble thrombomodulin the cleaved S. Iyoda M. Matsumoto K. Wada Y. Suzuki T. Iseri K. Kanazawa N. Shibata T. Recombinant human soluble thrombomodulin attenuates anti-glomerular basement membrane glomerulonephritis in Wistar–Kyoto rats through anti-inflammatory effects.Nephrol Dial Transplant. 2018; 34: 774-782Crossref Scopus (8) Google Scholar which that thrombomodulin is cleaved in diabetes via Y. Bierhaus A. R. Nawroth P.P. of thrombomodulin from endothelial cells by of and in and in Google Scholar S. M. mechanisms for thrombomodulin is cleaved by Full Text Full Text PDF PubMed Google Scholar that to be treating diabetic mice with an ETAR restored glomerular thrombomodulin levels. mice an glomerular endothelial Avramut M.C. A. M.J. Lee van der Vlag J. van Zonneveld van E. H.J. van den Berg B.M. Rabelink T.J. reduces by the glomerular endothelial glycocalyx in diabetic PubMed Scopus (74) Google Scholar that thrombomodulin may glycocalyx Blocking glomerular ETAR signaling may endothelial thrombomodulin by P. M. A. P. F. J. thrombomodulin levels are decreased and restored by and 1995; Full Text PDF PubMed Scopus Google the resulting increase in thrombomodulin reduces the glomerular of which the E. R. J. E. A. E. H.L. the activity of Exp Med. 2002; 196: PubMed Scopus Google Scholar The resulting in glomerular may of the In of a of glomerular thrombomodulin was to the of glycocalyx in DN. The that thrombomodulin levels are restored following treatment with an ETAR is that ETAR renal function and in patients with G. R. and renal in patients with type diabetes and chronic kidney disease a 2019; Full Text Full Text PDF PubMed Scopus Google Scholar by the podocyte F. on podocyte number in diabetic nephropathy resulting from atrasentan and inhibition Renal 2020; PubMed Scopus Google Scholar Thus, the results that thrombomodulin may a in the nephroprotective effects of selective ETAR are as a critical in the pathogenesis and of DN. macrophages in the glomeruli of patients with F. P. in human progressive diabetic 2006; PubMed Scopus Google M. Wolterbeek R. Bruijn J.A. Rabelink T.J. in diabetic nephropathy in patients with type Dial Transplant. 2017; 32: Google Scholar as and transforming growth contributing to glomerulosclerosis by cells to J. adhesion to and Int. Full Text Full Text PDF PubMed Scopus Google Scholar Furthermore, reducing the glomerular of macrophages diabetic mice from P. Scharpfenecker M. Van Der Wilk P. Wolterbeek R. Bruijn J.A. Baelde H.J. The VEGF-A inhibitor sFLT-1 improves renal function by reducing endothelial activation and inflammation in a mouse model of type 1 diabetes.Diabetologia. 2017; 60: 1813-1821Crossref PubMed Scopus (22) Google E. adhesion is against nephropathy in type diabetic Am Soc Nephrol. 2005; PubMed Scopus Google E. the development of diabetic renal in Int. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar In the results that reduced endothelial thrombomodulin in diabetic patients contributes to glomerular inflammation, in patients DN. Thrombomodulin macrophage recruitment via the lectin-like regulates NF-κB and kinase activation and interferes with 1 signaling in endothelial adhesion molecule expression and macrophage N. Van de Wouwer M. Vanaudenaerde B.M. Vos R. Van De Wauwer C. Verleden G.M. Verbeken E. Lerut T. Van Raemdonck D.E.M. Conway E.M. The lectin-like domain of thrombomodulin protects against ischaemia–reperfusion lung injury.Eur Respir J. 2008; 32: 862-870Crossref PubMed Scopus (25) Google Scholar,10Conway E.M. Van de Wouwer M. Pollefeyt S. Jurk K. Van Aken H. De Vriese A. Weitz J.I. Weiler H. Hellings P.W. Schaeffer P. Herbert J.-M. Collen D.S. Theilmeier G. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor κB and mitogen-activated protein kinase pathways.J Exp Med. 2002; 196: 565-577Crossref PubMed Scopus (293) Google S. Iyoda M. Matsumoto K. Wada Y. Suzuki T. Iseri K. Kanazawa N. Shibata T. Recombinant human soluble thrombomodulin attenuates anti-glomerular basement membrane glomerulonephritis in Wistar–Kyoto rats through anti-inflammatory effects.Nephrol Dial Transplant. 2018; 34: 774-782Crossref Scopus (8) Google Scholar thrombomodulin's EGF-like domain with reducing R. L. and of PubMed Scopus Google Scholar and suppressing NF-κB activity via APC L.O. Zlokovic B.V. Griffin J.H. The cytoprotective protein C pathway.Blood. 2007; 109: 3161-3172Crossref PubMed Scopus (605) Google Scholar thrombomodulin suppresses the of in S.M. Ka S.M. Wu H.L. Yeh Y.C. Kuo C.H. Hua K.F. Shi G.Y. Hung Y.J. Hsiao F.C. Yang S.S. Shieh Y.S. Lin S.H. Wei C.W. Lee J.S. Yang C.Y. Chen A. Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-kappaB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis.Diabetologia. 2014; 57: 424-434Crossref PubMed Scopus (74) Google Scholar Thus, in of the soluble of thrombomodulin in the to a reduction in anti-inflammatory thrombomodulin proinflammatory in that the domain of which is to the increase the of macrophages to endothelial cells by the 1 and E. T. Y. G. Suzuki K. H. M. and to the serine/threonine-rich domain of PubMed Scopus Google Scholar of thrombomodulin's lectin-like and EGF-like the domain may in the the glomerular of macrophages. Thus, the of of thrombomodulin's anti-inflammatory in the diabetic together with increased of thrombomodulin's proinflammatory domain may the of macrophages the The that are by the of which may the of with to with serum samples of cases to the cleaved thrombomodulin levels. Furthermore, the of glomerular thrombomodulin in human renal was compared with the thrombomodulin in mouse The may by as in thrombomodulin levels. is as the by results renal Furthermore, thrombomodulin was in the of The of samples over an of patients with diabetes as renal analyzed of the or of diabetes the of the of and glomerular In addition, the of to glomeruli which is Finally, the restoration of thrombomodulin levels by atrasentan treatment of a are of an thrombomodulin and glycocalyx in DN. In results that the glycoprotein thrombomodulin is reduced in the glomeruli of diabetic patients, of the of DN, that reduced thrombomodulin levels to increased glomerular inflammation in Furthermore, the reduction in glomerular thrombomodulin protein with a reduction in the glomerular glycocalyx in diabetic mice and is restored by treating diabetic mice with the selective ETAR atrasentan. that impaired thrombomodulin signaling plays a in the development of DN in diabetic Thus, glomerular thrombomodulin levels ETAR may a for diabetic patients at for diabetic thrombomodulin protein levels are reduced in biopsies from diabetic patients with diabetic nephropathy (DN). samples from patients with renal tissue from nondiabetic patients was as a A and of an against the domain of thrombomodulin in from a nondiabetic and a with DN. Glomerular thrombomodulin measured in patients with DN and nondiabetic controls. patients with nondiabetic patients and regulates the adhesion of to activated endothelial cells with a or a and with factor or for which for The increase in the number of from to was in the increase in of of glomerular thrombomodulin may of glycocalyx in diabetic nephropathy (DN). of glomerular thrombomodulin and in a kidney from a nondiabetic of thrombomodulin and in a kidney from a with DN with with with

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