Increased secretion of TGF‐β1 by peripheral blood mononuclear cells from patients with Type 1 diabetes mellitus with diabetic nephropathy

Korpinen, Eija; Groop, P.-H.; Fagerudd, J; Teppo, A M; Åkerblom, Hans K.; Vaarala, Outi

doi:10.1046/j.1464-5491.2001.00413.x

Cited by 24 publications

(14 citation statements)

References 27 publications

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“…WBCs in diabetic patients may be activated by advanced glycation end products or reactive oxygen species (12-14) and cytokines (16). Activated leukocytes secrete many kinds of cytokines and transcription factors that have a crucial role in inflammat i o n , i n c l u d i n g T N F -␣ , NF-B , interleukin-1␤, and transforming growth factor ␤, thereby contributing to glomerulosclerosis (17)(18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

“…Polymorpho-and mononuclear leukocytes can be activated by advanced glycation end products (12), oxidative stress (13, 14), angiotensin II (15), and cytokines (16) in a state of hyperglycemia. Leukocytes may be activated through the release of cytokines, such as tumor necrosis factor-␣ (TNF-␣) (17,18), transforming growth factor ␤1 (19), superoxide (20), nuclear factor B (NF-B) (21), monocyte chemoattractant protein 1, interleukin-1␤, and others (17) to participate in the pathogenesis of diabetic micro-and macrovascular complications. Elevated differential cell counts, including counts of eosinophils, neutrophils, and monocytes, also predict the future incidence of CAD (11,22,23).…”

Section: Diabetes Care 28:1710 -1717 2005mentioning

confidence: 99%

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Peripheral Total and Differential Leukocyte Count in Diabetic Nephropathy

et al. 2005

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OBJECTIVE -Because of increasing evidence that white blood cells (WBCs) play a role in the development and progression of diabetes complications, this study aimed to investigate the relation of circulating total and differential leukocyte counts to nephropathy in patients with type 2 diabetes. Plasma leptin levels were also measured to investigate their role in peripheral leukocytosis.RESEARCH DESIGN AND METHODS -For this study, 1,480 subjects with type 2 diabetes who were enrolled in a disease management program were stratified according to urinary microalbumin and serum creatinine measurements. The total and differential leukocyte profiles of peripheral blood were measured and plasma leptin was examined by enzyme-linked immunosorbent assay. Demographic and potential metabolic confounding factors were analyzed with linear and logistic regression to calculate the effects of leukocyte count on diabetic nephropathy.RESULTS -The peripheral total WBC, monocyte, and neutrophil counts increased in parallel with the advancement of diabetic nephropathy. In contrast, the lymphocyte count decreased. When WBC counts were analyzed per quartile and as continuous variables after adjusting for age, sex, and other known risk factors with multiple regression analysis, peripheral total WBC, monocyte, neutrophil, and lymphocyte counts were independently and significantly associated with diabetic nephropathy. Plasma leptin levels increased in patients with nephropathy and correlated significantly with total WBC count (r ϭ 0.194, P ϭ 0.014).CONCLUSIONS -Because leukocytes are activated and secrete cytokines in the diabetic state and leptin stimulates leukocyte proliferation and differentiation, our results suggest that circulating leukocytes contribute to the development and progression of nephropathy, partially through the effects of leptin, in patients with type 2 diabetes. Diabetes Care 28:1710 -1717, 2005P eripheral white blood cell (WBC) count has been shown to be associated with insulin resistance, type 2 diabetes (1-4), coronary artery disease (CAD) (5-8), stroke (5,8), and diabetes micro-and macrovascular complications (9,10). An association between leukocytes counts and CAD has been observed in prospective and retrospective cohort studies as well as in case-control studies; this association persists after adjusting for multiple coronary heart disease (CHD) risk factors, including smoking (11).Peripheral blood leukocytes are composed of polymorphonuclear cells, inc l u d i n g m o n o c y t e s a s w e l l a s lymphocytes. Polymorpho-and mononuclear leukocytes can be activated by advanced glycation end products (12), oxidative stress (13,14), angiotensin II (15), and cytokines (16) in a state of hyperglycemia. Leukocytes may be activated through the release of cytokines, such as tumor necrosis factor-␣ (TNF-␣) (17,18), transforming growth factor ␤1 (19), superoxide (20), nuclear factor B (NF-B) (21), monocyte chemoattractant protein 1, interleukin-1␤, and others (17) to participate in the pathogenesis of diabetic micro-and m...

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Section: Discussionmentioning

confidence: 99%

Section: Diabetes Care 28:1710 -1717 2005mentioning

confidence: 99%

Peripheral Total and Differential Leukocyte Count in Diabetic Nephropathy

et al. 2005

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“…Moreover, activated macrophages secrete factors such as PDGF that promote fibroblast proliferation (129). Increased secretion of TGF-␤ by peripheral blood mononuclear cells was reported in patients with type 1 DN (130). With respect to the interaction between macrophages and mesangial cells, it has been shown that the culture supernatant of macrophages can stimulate mesangial cells to produce fibronectin in vitro (131).…”

Section: Role Of Immune Cells In Endothelial Dysfunctionmentioning

confidence: 99%

Leukocyte Recruitment and Vascular Injury in Diabetic Nephropathy

Galkina

Ley²

2006

Journal of the American Society of Nephrology

323

240

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Different types of activated leukocytes play a crucial role in the pathogenesis of most kidney diseases from acute to chronic stages; however, diabetic nephropathy was not considered an inflammatory disease in the past. This view is changing now because there is a growing body of evidence implicating inflammatory cells at every stage of diabetic nephropathy. Renal tissue macrophages, T cells, and neutrophils produce various reactive oxygen species, proinflammatory cytokines, metalloproteinases, and growth factors, which modulate the local response and increase inflammation within the diabetic kidney. Although the precise mechanisms that direct leukocyte homing into renal tissues are not fully identified, it has been reported that intercellular adhesion molecule-1 and the chemokines CCL2 and CX3CL1 probably are involved in leukocyte migration in diabetic nephropathy. This review focuses on the molecular mechanisms of leukocyte recruitment into the diabetic kidney and the involvement of immigrated immune cells in the damage to renal tissues.J Am Soc Nephrol 17: 368 -377, 2006368 -377, . doi: 10.1681 Diabetic NephropathyDiabetic nephropathy (DN) is the leading case of end-stage renal failure (review in reference [1]). The major features of DN include albuminuria, progressive reduction of GFR, and increased risk for cardiovascular diseases (1-3). DN is associated with the expansion of mesangial cells and development of characteristic features of renal injury, such as thickening of the glomerular basement membrane. In the end, glomerulosclerosis and tubulointerstitial fibrosis are observed in patients with diabetic pathology (4,5). Approximately 30% of patients with type 1 diabetes develop DN (6,7). Barkis et al. (8) reported that approximately 25 to 30% of patients with type 2 diabetes will develop overt DN. Recently, several murine models of DN were developed (review in reference [9]). The well-established streptozotocin (STZ)-induced (10 -14) and nonobese diabetic (NOD) (15-18) mouse models are most commonly used to study type 1 diabetes. A few models of type 2 diabetes include db/db mice (19,20), ob/ob mice (21), agouti mice on different backgrounds (22,23), and C57BL/6 on high-fat diet (24). Although some features such as the absence of renal failure complicate the interpretations of the studies in murine models, several distinct stages of DN can be detected in murine models (9). Genetically deficient mice that lack different inflammatory molecules are expected to help dissect the molecular mechanisms of initiation and development of DN.It is well known that hyperglycemia is a major factor risk for DN (25), but hyperglycemia does not account for all changes that are observed in renal tissues (26). It has been suggested that advanced glycation end products (AGE) (27-30), activation of protein kinase C (31), and overexpression of different growth factors (32) are associated with the pathogenesis of DN. Extracellular matrix accumulation is one of the hallmarks in the development of the disease that leads to the ...

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“…Levels of plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF), both key mediators of profibrotic TGF-β activity, are also significantly increased in tissue and plasma of experimental and human diabetic nephropathy [15][16][17][18][19][20]. Furthermore, Korpinen et al have demonstrated increased secretion of TGF-β by 2-day cultured peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes and showed an association of these TGF-β levels with the occurrence of diabetic nephropathy [21]. In contrast, renal expression of another member of the TGF-β superfamily, the antifibrotic bone morphogenetic protein 7 (BMP7), is decreased during the course of experimental diabetic nephropathy [22], and in vitro studies with human mesangial cells have revealed that a high glucose concentration induces the expression of BMP antagonists CTGF and gremlin [23,24].…”

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confidence: 99%