Chapter 2 - Cytokines in diabetic nephropathy
Section snippets
Abstract
Diabetic nephropathy (DN), the most common cause of end-stage renal disease (ESRD), is increasingly considered an inflammatory process characterized by leukocyte infiltration at every stage of renal involvement. Cytokines act as pleiotropic polypeptides that regulate inflammatory and immune responses, providing important signals in the pathologic and physiologic processes. Inflammation and activation of the immune system are closely involved in the pathogenesis of diabetes and its microvascular
Cytokines and Diabetes Nephropathy: Cause or Consequence?
Cytokines are a group of small molecules (approximately 8–80 kDa) with pleiotropic actions and complex networks that regulate immune responses and related signaling pathways [13]. These molecules are relevant humoral mediators of pathologic and physiologic responses and can be classified into several classes (i.e., interleukins, interferons, tumor necrosis factors, growth factors, colony-stimulating factors, and chemokines). Cytokines may trigger different cellular responses with respect to
TNF-α
Significant attentions have been paid to the role of TNF-α in the setting of DN over the past few years. TNF-α is a pleiotropic inflammatory cytokine originally produced by monocyte/macrophage, although intrinsic renal cells, including endothelial, mesangial, glomerular, dendritic, and renal tubular cells, are also able to synthesize this cytokine [30], [31], [32], [33]. No significant correlation between serum and urinary concentrations of TNF-α was found, thus suggesting an intrarenal
Diabetic Nephropathy and Gene Polymorphisms of Cytokines
Approximately, only one-third to one-half of DM patients may develop DN [92]. Traditional metabolic and hemodynamic factors such as hypertension, poor glycemic control, and albuminuria are the main known risk factors for DN. However, these factors do not fully explain the interindividual variability in nephropathy development. It is suggested that genetic variations encoding the cytokines altering their function and/or expression may strongly affect the susceptibility to the initiation,
Diabetic Nephropathy and Therapeutic Strategies Involving Cytokines
Due to the pathogenic complexity of DN, providing diabetic patients protection from the development and progression of renal injury remains a challenge for physicians. Traditionally, DN is viewed as a result of interactions among metabolic and hemodynamic factors that activate diverse pathways leading to renal damage. Growing evidences have indicated that cytokines participate in the pathogenic process of DN; therefore, strategies modulating the cytokines may offer a new approach to the therapy
Conclusions
Developing ideal therapeutic agents that effectively blunt the development and progression of DN is an important issue for physicians. Together with traditional metabolic and hemodynamic risk factors, inflammation especially cytokines exert an important role in the pathogenic complexity of development and progression during DN process, though various cytokines contribute to DN differently. Genetic variations may also participate in the susceptibility to initiation, progression, and/or
References (134)
- et al.
End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions
Am. J. Kidney Dis.
(1999) - et al.
The cytokine network
Immunol. Today
(1989) - et al.
The expanding universe of T-cell subsets: Th1, Th2 and more
Immunol. Today
(1996) - et al.
Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy
Kidney Int.
(2003) - et al.
Deficiency of endothelial nitric-oxide synthase confers susceptibility to diabetic nephropathy in nephropathy-resistant inbred mice
Am. J. Pathol.
(2007) - et al.
The role of TNF-alpha in diabetic nephropathy: pathogenic and therapeutic implications
Cytokine Growth Factor Rev.
(2006) - et al.
Stimulated kidney tubular epithelial cells express membrane associated and secreted TNF alpha
Kidney Int.
(1991) - et al.
Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury
Kidney Int.
(2007) - et al.
Cisplatin-induced nephrotoxicity is mediated by tumor necrosis factor-alpha produced by renal parenchymal cells
Kidney Int.
(2007) - et al.
Inflammatory parameters are independently associated with urinary albumin in type 2 diabetes mellitus
Am. J. Kidney Dis.
(2003)
Tumor necrosis factor-alpha gene expression in diabetic nephropathy: relationship with urinary albumin excretion and effect of angiotensin-converting enzyme inhibition
Kidney Int.
Angiotensin III increases MCP-1 and activates NF-kappaB and AP-1 in cultured mesangial and mononuclear cells
Kidney Int.
Induction of reactive oxygen species from isolated rat glomeruli by protein kinase C activation and TNF-alpha stimulation, and effects of a phosphodiesterase inhibitor
Life Sci.
The functions of circulatory polymorphonuclear leukocytes in diabetic patients with and without diabetic triopathy
Life Sci.
Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy
Metabolism
Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration
Am. J. Kidney Dis.
Urinary and renal interstitial concentrations of TNF-alpha increase prior to the rise in albuminuria in diabetic rats
Kidney Int.
Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat renal mesangial cells
Biochem. Biophys. Res. Commun.
Leukocyte adhesion molecules and kidney diseases
Kidney Int.
Biological and clinical aspects of interleukin 6
Immunol. Today
Interleukin 6 is an autocrine growth factor for mesangial cells
Kidney Int.
Interleukin-6: an autocrine regulator of mesangial cell growth
Kidney Int.
Differential effect of IL-18 on endothelial cell apoptosis mediated by TNF-alpha and Fas (CD95)
Cytokine
Aberrant cytokines/chemokines production correlate with proteinuria in patients with overt diabetic nephropathy
Clin. Chim. Acta
Nephropathic complication of type-2 diabetes is following pattern of autoimmune diseases?
Diabetes Res. Clin. Pract.
Transcriptional activation of transforming growth factor-beta1 in mesangial cell culture by high glucose concentration
Kidney Int.
Regulation of transforming growth factor beta in diabetic nephropathy: implications for treatment
Semin. Nephrol.
Diabetic complications: a role for the prorenin-(pro)renin receptor-TGF-beta1 axis?
Mol. Cell. Endocrinol.
An interleukin 1B allele, which correlates with a high secretor phenotype, is associated with diabetic nephropathy
Cytokine
Diabetes and nephropathy
Curr. Opin. Nephrol. Hypertens.
Clinical practice. Nephropathy in patients with type 2 diabetes
N. Engl. J. Med.
Diabetic nephropathy in type 2 diabetes prevention and patient management
J. Am. Soc. Nephrol.
Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy
Diabetologia
Diabetic nephropathy: diagnosis, prevention, and treatment
Diabetes Care
New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology
Eur. J. Clin. Invest.
Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS)
Circulation
Association between C-reactive protein and features of the metabolic syndrome: a population-based study
Diabetes Care
NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X
Diabetologia
The role of inflammatory cytokines in diabetic nephropathy
J. Am. Soc. Nephrol.
Pathogenic perspectives for the role of inflammation in diabetic nephropathy
Clin. Sci. (Lond.)
Inflammation and diabetic nephropathy
Curr. Diab. Rep.
Role of inflammation in diabetic complications
Nephrol. Dial. Transplant.
Functional diversity of helper T lymphocytes
Nature
Interleukin-17 and type 17 helper T cells
N. Engl. J. Med.
Role of high glucose-induced nuclear factor-kappaB activation in monocyte chemoattractant protein-1 expression by mesangial cells
J. Am. Soc. Nephrol.
Attenuation of mouse mesangial cell contractility by high glucose and mannitol: involvement of protein kinase C and focal adhesion kinase
J. Biomed. Sci.
Advanced glycation end products and the kidney
Am. J. Physiol. Renal Physiol.
Clinical review: the role of advanced glycation end products in progression and complications of diabetes
J. Clin. Endocrinol. Metab.
Interactions between angiotensin II and NF-kappaB-dependent pathways in modulating macrophage infiltration in experimental diabetic nephropathy
J. Am. Soc. Nephrol.
Role of inflammation in diabetic nephropathy
Curr. Diabetes Rev.
Cited by (39)
Ophiopogonin D suppresses TGF-β1-mediated metastatic behavior of MDA-MB-231 breast carcinoma cells via regulating ITGB1/FAK/Src/AKT/β-catenin/MMP-9 signaling axis
2020, Toxicology in VitroCitation Excerpt :Limiting these key nodes may effectively reduce the possibility of cancer metastasis. Transforming growth factor beta-1 (TGF-β1) is a multifunctional fibrogenic cytokine that regulates various aspects of physiological and pathological responses, including stimulating synthesis of regulator of ECM and inhibiting matrix degradation process (Wu et al., 2012). Several studies have reported that TGF-β1 can promote fibrosis and suppress the host immune system, and fibrosis and dysregulated immune responses are also a feature of cancer (Lodyga and Hinz, 2020).
Exosomes from high glucose-treated macrophages activate macrophages and induce inflammatory responses via NF-κB signaling pathway in vitro and in vivo
2020, International ImmunopharmacologyCitation Excerpt :In addition, elevated TNF-α and IL-1β in kidney is known to decrease the glomerular filtration rate whereas the improvement of IL-6 expression level is known to increase ECM synthesis [32]. Over-expression of IL-6 is also associated with increased rates of urinary albumin excretion [33]. TGF-β1 is an important fibrogenic cytokine, which could mediate glomerular sclerosis and tubulointerstitial fibrosis by improving ECM synthesis [34].
Lycium chinense leaves extract ameliorates diabetic nephropathy by suppressing hyperglycemia mediated renal oxidative stress and inflammation
2018, Biomedicine and PharmacotherapyCitation Excerpt :Reactive oxygen species induced inflammation can stimulate increase in the expression of different pro-inflammatory mediators via the activation of NF-κB pathway, thus damaging the endothelial cells [46]. Previous studies have implicated pro-inflammatory cytokines as mediators of alterations in renal function and kidney injury which is effected via several mechanistic pathways [43,47]. In addition, the release of pro-inflammatory cytokines in diabetic nephropathy can stimulate the infiltration of macrophages which in turn damages glomerular tissue leading to the occurrence of excessive levels of protein in the urine [43].
Danshen injection ameliorates STZ-induced diabetic nephropathy in association with suppression of oxidative stress, pro-inflammatory factors and fibrosis
2016, International ImmunopharmacologyCitation Excerpt :Since all of these pro-inflammatory cytokines could promote macrophage infiltration to exacerbate inflammatory insults and damage glomerular tissue causing proteinuria in STZ-induced diabetic rats [6]. Furthermore, increased TNF-α and IL-1β in kidney is known to increase superoxide dismutase expression and reduce the glomerular filtration rate whereas increased IL-6 levels are known to alter endothelial permeability, induce proliferation, and increase some extracellular matrix (ECM) proteins expression [33,34]. All of these aspects are contribute to lead real dysfunction.
The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment
2016, CytokineCitation Excerpt :It potentiates TNF-α production by mononuclear and mesenchymal cells [70]. Moreover, it upregulates inducible nitric oxide (NO) synthase, chemokines such as CXCL8, CXCL5 and CCL20 [71] and cyclooxygenase (COX)-2 expression [72]. It is also suggested that IL-18 up-regulates the expression of intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and matrix metalloproteinases-1, -9, and -13 in endothelial cells and synovial fibroblasts [73,74].