Contribution of Proteinuria to Progressive Renal Injury: Consequences of Tubular Uptake of Fatty Acid Bearing Albumin

Thomas, Mark; Schreiner, George F.

doi:10.1159/000168653

Cited by 112 publications

(63 citation statements)

References 58 publications

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“…Studies using these models have suggested that the proteinuria itself could induce the progressive interstitial injury, and several hypotheses have been proposed as potential mechanisms of proteinuria-induced tubulointerstitial injury. These include direct tubulotoxicity of high protein concentrations (18) or that specific proteins such as growth factors, lipoproteins (19,20), transferrin (21), or activated complement components (22, 23) may be damaging. Recent studies have emphasized the role of the MAC.…”

Section: Discussionmentioning

confidence: 99%

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Turnberg

Lewis

Moss

et al. 2006

The Journal of Immunology

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Adriamycin nephropathy is a model of focal segmental glomerulosclerosis, characterized by proteinuria and progressive glomerulosclerosis and tubulointerstitial damage. In this study, we examined the role of complement in the etiology of adriamycin nephropathy in mice. We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls. C3 deposition occurred in the glomeruli of wild-type mice as early as 48 h following a single i.v. injection of adriamycin. C3-deficient mice developed significantly less proteinuria and less podocyte injury at day 3 postadriamycin than controls, suggesting that complement is important in mediating the early podocyte injury. At later time points, C3-deficient mice were protected from glomerulosclerosis, tubulointerstitial injury, and renal dysfunction. Factor D-deficient mice were also protected from renal disease, confirming the importance of alternative pathway activation in this model. In contrast, C1q-deficient mice developed similar disease to controls, indicating that the complement cascade was not activated via the classical pathway. CD59-deficient mice, which lack adequate control of C5b-9 formation, developed significantly worse histological and functional markers of renal disease than controls. Interestingly, although more C9 deposited in glomeruli of CD59-deficient mice than controls, in neither group was tubulointerstitial C9 staining apparent. We have demonstrated for the first time that alternative pathway activation of complement plays an important role in mediating the initial glomerular damage in this in vivo model of focal segmental glomerulosclerosis. Lack of CD59, which regulates the membrane attack complex, led to greater glomerular and tubulointerstitial injury.

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Section: Discussionmentioning

confidence: 99%

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Turnberg

Lewis

Moss

et al. 2006

The Journal of Immunology

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“…Several experiments showed that this results in tubulointerstitial inflammation and fibrosis (130 -133). The mechanisms are likely related to FFA lipotoxicity, and the release of nonpolar lipids by proximal tubular cells which attract macrophages and promote inflammation and apoptosis (130,132). PPAR-␥ has been shown to mediate FFA-induced apoptosis (134).…”

Section: Role Of Albumin-saturated Fatty Acidsmentioning

confidence: 99%

Obesity and Obesity-Initiated Metabolic Syndrome

Wahba

Mak

2007

Clinical Journal of the American Society of Nephrology

461

343

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There is an epidemic of obesity and the metabolic syndrome in the United States and across the world. Both entities are associated with high mortality, mainly as a result of cardiovascular disease. The epidemic of obesity has been paralleled by an increase in the incidence of chronic kidney disease (CKD). Several recent epidemiologic studies have shown that obesity and the metabolic syndrome are independent predictors of CKD. In addition to diabetes and hypertension, several other mechanisms have been postulated to initiate and maintain kidney injury in patients with obesity and the metabolic syndrome. This article reviews the recent epidemiologic data linking obesity and the metabolic syndrome to CKD and summarizes the potential mechanisms of renal injury in this setting, with a focus on the role of inflammation, lipotoxicity, and hemodynamic factors. Potential preventive and therapeutic modalities based on the limited evidence available are discussed.Clin , and the increase occurred for both men and women and for all age groups (2). Since then, the trend for increased prevalence has continued, particularly for adolescents and men (1). Obesity is also on the rise in other industrialized countries (3-5). The metabolic syndrome, previously known as syndrome X and a major consequence of obesity, is also on the rise (6). According to the Third National Health and Nutrition Examination Survey (NHANES III), the prevalence of the metabolic syndrome in the United States is 23% in those who are 20 yr or older and Ͼ40% in those who are 60 yr or older (7). According to the Third Adult Treatment Panel of the National Cholesterol Education Program, the metabolic syndrome is defined as the presence of at least three of the following criteria, with or without diabetes: Central obesity (waist circumference in men Ͼ102 cm and in women Ͼ88 cm), hypertriglyceridemia (Ն150 mg/dl), low HDL cholesterol (men Ͻ40 mg/dl, women Ͻ50 mg/dl), elevated fasting glucose (Ͼ110 mg/dl), and hypertension (Ն130/85 mmHg) (8). A central feature of the metabolic syndrome is insulin resistance, which results in hyperglycemia and hyperinsulinemia, and eventually leads to the development of diabetes (9). Central obesity is the most important predisposing factor for insulin resistance (9). Chronic inflammation is another feature of the metabolic syndrome, which, together with insulin resistance, results in complex metabolic derangements that contribute to the pathogenesis of hypertension, lipoprotein abnormalities, atherosclerosis, coronary artery disease, and other organ dysfunction (10,11). Both obesity and the metabolic syndrome are associated with high mortality, mainly related to cardiovascular disease (12,13). Overweight, obesity, and the metabolic syndrome have recently emerged as strong independent risk factors for chronic kidney disease (CKD) and ESRD. This article reviews the epidemiology of CKD in relationship to obesity and the metabolic syndrome and the possible mechanisms of renal injury that is caused by obesity and obesity-initiated metab...

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“…This process not only impairs function in the individual cell but also reduces cell mass via apoptosis in multiple organs, each with important functional consequences. Lipotoxicity in proximal tubular cells-with its associated tubulointerstitial inflammation-is now a recognized consequence of heavy proteinuria as a result of accumulation of excess albumin-bound FFA (146,147). However, no studies have systematically addressed whether FFA lipotoxicity afflicts renal cell types in obesity-initiated metabolic syndrome, particularly in the absence of (or independent of) proteinuria.…”

Section: Renal Lipotoxicity?mentioning

confidence: 99%

Obesity-Initiated Metabolic Syndrome and the Kidney

Bagby

2004

Journal of the American Society of Nephrology

230

183

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Metabolic syndrome, originally described in 1988 as "syndrome X" by Reaven et al. (1), has evolved in our collective thinking from a vague association of common chronic disease states to a formally defined cluster of clinical traits with adverse impact on cardiovascular risk (2). The cause is incompletely understood but represents a complex interaction among genetic, environmental, and metabolic factors, clearly including diet (3,4) and level of physical activity (4,5). These abnormalities are mediated by-and interconnected by-complex pathways that affect energy homeostasis at cellular, organ, and whole-body levels. This review focuses on obesity-initiated metabolic syndrome, first to provide a pathogenetic overview of extrarenal metabolic derangements; second to consider predisposing conditions shaped by genetic or environmental factors, including growth constraints in utero; and finally to consider the impact of metabolic syndrome on the kidney in its prediabetic phase. The pathogenesis of hypertension in the context of metabolic syndrome is considered separately in this series. Similarly, central nervous system pathways that contribute to disordered energy homeostasis is addressed in detail by others. The mechanisms of irreversible renal injury from hypertension and overt diabetes are well documented and are beyond the scope of this review; nonetheless, they loom large in the long-term renal future of the patient with metabolic syndrome. The current worldwide epidemic of obesity-initiated metabolic syndrome, with its potential for renal damage, mandates our commitment to early renal protection in the obese and to vigorous prevention of obesity in both pediatric and adult populations.

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Contribution of Proteinuria to Progressive Renal Injury: Consequences of Tubular Uptake of Fatty Acid Bearing Albumin

Cited by 112 publications

References 58 publications

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Obesity and Obesity-Initiated Metabolic Syndrome

Obesity-Initiated Metabolic Syndrome and the Kidney

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