Background. End-stage renal disease (ESRD) results in increased susceptibility to infections, impaired response to vaccination and diffuse B-cell lymphopenia. However, the precise nature and mechanism of ESRD-induced B-cell lymphopenia remains unclear. Therefore, we studied the distribution of major B-cell subsets, B-cell growth, differentiation and survival factors, IL-7 and BAFF, and their receptors in 21 haemodialysis patients and 21 controls.Methods. Innate B1 cells (CD19+, CD5+), conventional B2 cells (CD19+, CD5−), newly formed transitional B cells (CD19+, CD10+, CD27−), naïve B cells (CD19+, CD27−) and memory B cells (CD19+, CD27+) and BAFF receptor were quantified by flow cytometry. Plasma IL-7, BAFF, IL-6, TNF-α and IL-10 were measured by ELISA.Results. The ESRD group exhibited significant reductions of all B-cell subpopulations except for transitional B cells that were less severely affected. No significant difference was found in B-cell apoptosis between the ESRD and control groups. Moreover, plasma IL-7 and BAFF levels were elevated in ESRD patients, therefore excluding their deficiencies as a possible culprit. However, BAFF receptor expression was significantly reduced in transitional but not mature B cells in the ESRD group. Interestingly, B-cell activation with the TLR9 agonist resulted in significantly greater production of IL-6 and TNF alpha but not IL-10 in the ESRD group.Conclusions. Thus, despite elevation of B-cell growth, differentiation and survival factors, ESRD patients exhibited diffuse reduction of B-cell subpopulations. This was associated with the down-regulation of BAFF receptor in transitional B cells. The latter can, in part, contribute to B-cell lymphopenia by promoting resistance to the biological actions of BAFF that is a potent B-cell differentiation and survival factor.

Background-Severe obesity can result in proteinuria and progressive glomerulosclerosis in humans and experimental animals. The associated renal disease is ameliorated by weight reduction and/or blockade of the renin-angiotensin system. Various growth factors, cytokines, and lipid mediators are implicated in the pathogenesis of renal disease. To explore the possible involvement of these mediators in obesity-induced renal disease, we examined the expression of key enzymes of arachidonate metabolism and inflammatory genes in untreated and losartan-treated obese Zucker rats, a model of obesity, insulin resistance, and renal injury. Methods and Results-Seven-week-old male obese Zucker rats were randomized to losartan-treated (100 mg/L drinking H 2 O) and untreated groups, with lean Zucker rats as controls. After 4 months, RNA and protein were obtained from renal cortical tissue for relative reverse transcription-polymerase chain reaction, Western blots, and immunohistochemistry. Compared with the lean controls, obese Zucker rats showed significant glomerular matrix expansion and increased mRNA expression of the extracellular matrix protein fibronectin, inflammatory mediators interleukin-6 and monocyte chemoattractant protein-1, and 2 major enzymes of arachidonate metabolism, namely, 12/15-lipoxygenase and cyclooxygenase-2. This was associated with significant increases in p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase activities and marked upregulation of angiotensin II type 1 receptor (AT1R) mRNA and protein expression. These abnormalities and the associated glomerulopathy and proteinuria were prevented by administration of the AT1R blocker losartan. Conclusions-These findings indicate that obesity-induced glomerulopathy is associated with upregulation of key inflammatory mediators. These events are associated with and perhaps in part due to upregulation of AT1R, as evidenced by their reversal with AT1R blocker treatment.

Mitochondria are the major source of superoxide (O(2)(-)) in the aerobic organisms. O(2)(-) produced by the mitochondria is converted to hydrogen peroxide by mitochondrial superoxide dismutase (SOD2). Mice with complete SOD2 deficiency (SOD2(-/-)) exhibit dilated cardiomyopathy and fatty liver leading to neonatal mortality, whereas mice with partial SOD2 deficiency (SOD2(+/-)) show evidence of O(2)(-)-induced mitochondrial damage resembling cell senescence. Since earlier studies have provided compelling evidence for the role of oxidative stress and tubulointerstitial inflammation in the pathogenesis of hypertension, we tested the hypothesis that partial SOD2 deficiency may result in hypertension. Wild-type (SOD2(+/+)) and partial SOD2-deficient (SOD2(+/-)) mice had similar blood pressures at 6-7 mo of age, but at 2 yr SOD2(+/-) mice had higher blood pressure. Oxidative stress, renal interstitial T-cell and macrophage infiltration, tubular damage, and glomerular sclerosis were all significantly increased in 2-yr-old SOD2(+/-) mice. High-salt diet induced hypertension in 6-mo-old SOD2-deficient mice but not in wild-type mice. In conclusion, partial SOD2 deficiency results in oxidative stress and renal interstitial inflammation, changes compatible with accelerated renal senescence and salt-sensitive hypertension. These findings are consistent with the pattern described in numerous other models of salt-sensitive hypertension and resemble that commonly seen in elderly humans.