Glomerular Basement Membrane

RPS19 (ribosomal protein S19), a component of the 40S small ribosomal subunit, has recently been identified to bind the pro-inflammatory cytokine macrophage MIF (migration inhibitory factor). In vitro experiments identify RPS19 as the first endogenous MIF inhibitor by blocking the binding of MIF to its receptor CD74 and MIF functions on monocyte adherence to endothelial cells. In the present study, we sought to establish whether recombinant RPS19 can exert anti-inflammatory effects in a mouse model of anti-GBM (glomerular basement membrane) GN (glomerulonephritis) in which MIF is known to play an important role. Accelerated anti-GBM GN was induced in C57BL/6J mice by immunization with sheep IgG followed 5 days later by administration of sheep anti-mouse GBM serum. Groups of eight mice were treated once daily by intraperitoneal injection with 6 mg of RPS19/kg of body weight or an irrelevant control protein (human secretoglobin 2A1), or received no treatment, from day 0 until being ki...

Background. In small vessel vasculitis and its renal- limited form, idiopathic crescentic glomerulonephritis, renal damage is characterized by pauci-immune necro- tizing crescentic glomerulonephritis (CGN) without histological evidence of immunoglobulin (Ig) deposi- tion. In some patients, however, significant amounts of immune deposits may be detected. Therefore, we evaluated the clinical significance of these immune deposits in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune

Vascular endothelial growth factor, which is critical for blood vessel formation, is regulated by hypoxia inducible transcription factors (HIFs). A component of the E3 ubiquitin ligase complex, von Hippel-Lindau (VHL) facilitates oxygen-dependent polyubiquitination and proteasomal degradation of HIFα subunits. Hypothesizing that deletion of podocyte VHL would result in HIFα hyperstabilization, we crossed podocin promoter-Cre transgenic mice, which express Cre recombinase in podocytes beginning at the capillary loop stage of glomerular development, with floxed VHL mice. Vascular patterning and glomerular development appeared unaltered in progeny lacking podocyte VHL. However, urinalysis showed increased albumin excretion by 4 weeks when compared with wild-type littermates with several sever cases (>1000 μg/ml). Many glomerular ultrastructural changes were seen in mutants, including focal subendothelial delamination and widespread podocyte foot process broadening, and glomerular basement membranes (GBMs) were significantly thicker in 16-week-old mutants compared with controls. Moreover, immunoelectron microscopy showed ectopic deposition of collagen α1α2α1(IV) in GBM humps beneath podocytes. Significant increases in the number of Ki-67-positive mesangial cells were also found, but glomerular WT1 expression was significantly decreased, signifying podocyte death and/or de-differentiation. Indeed, expression profiling of mutant glomeruli suggested a negative regulatory feedback loop involving the HIFα prolyl hydroxylase, Egln3. In addition, the brain oxygen-binding protein, Neuroglobin, was induced in mutant podocytes. We conclude that podocyte VHL is required for normal maintenance of podocytes, GBM composition and ultrastructure, and glomerular barrier properties.

Summary Mac-1 ( a m b 2 ), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fc g receptors to facilitate immune complex (IC)-stimulated polymorphonuclear neutro- phil (PMN) functions. To investigate the relevance of Mac-1-Fc g R interactions in IC-medi- ated injury in vivo, we induced a model of Fc-dependent anti-glomerular basement membrane (GBM) nephritis

An association between low nephron number and subsequent development of hypertension in later life has been demonstrated. The underlying pathomechanisms are unknown, but glomerular and postglomerular changes have been discussed. We investigated whether such changes are already present in prehypertensive “glial cell line-derived neurotrophic growth factor” heterozygous mice (GDNF+/−) with lower nephron number. Twenty-six-week-old mice [22 GDNF+/−, 29 C57B6 wild-type control (wt)] were used for in vivo experiments with intra-arterial and tail cuff blood pressure measurements. After perfusion fixation, kidneys were investigated with morphological, morphometric, stereological, and immunohistochemical techniques and TaqMan PCR analysis. As expected at this age, blood pressure was comparable between GDNF+/− and wt. Nephron number per kidney was significantly lower in GDNF+/− than in wt (−32.8%, P < 0.005), and mean glomerular volume was significantly higher (+49.5%, P < 0.001). Rena...

Immunoglobulin A nephropathy (IgAN) is associated with mucosal IgA defect. Probiotics regulate specific and innate immunity. We evaluated the effect of Saccharomyces boulardii on experimental IgAN in mice. Four groups of BALB/c mice (eight for each) were formed. Group 1 was immunized by oral poliovirus vaccine (OPV) at 0, 14, and 28 days. Group 2 was also given S. boulardii in addition to OPV. Group 3 was given only S. boulardii, whereas group 4 received no treatment. At week 6, after urine and serum samples were obtained for urinalysis and serum creatinine and IgA measurements, all animals were sacrificed to get their kidneys for histopathological evaluation. Urinalysis and serum creatinine levels were normal in all groups. Serum IgA level was increased only in group 1. Whereas group 1 had mesangial proliferation, histology was normal in the other groups. Predominant IgA deposition was universal in group 1, whereas it was either not present or minimal in other groups. Three mice in group 1 also had C3 deposition, which was absent in other groups. Electron microscopy revealed mesangial proliferation, matrix expansion, focal glomerular basement membrane thickening and electron-dense deposits in group 1 only, whereas the other groups were normal. In conclusion, enteral S. boulardii prevented OPV-induced IgAN in mice.

The glomerular filtration barrier prevents large serum proteins from being lost into the urine. It is not known, however, why the filter does not routinely clog with large proteins that enter the glomerular basement membrane (GBM). Here, we provide evidence that an active transport mechanism exists to remove immunoglobulins that accumulate at the filtration barrier. We found that FcRn, an IgG and albumin transport receptor, is expressed in podocytes and functions to internalize IgG from the GBM. Mice lacking FcRn accumulated IgG in the GBM as they aged, and tracer studies showed delayed clearance of IgG from the kidneys of FcRn-deficient mice. Supporting a role for this pathway in disease, saturating the clearance mechanism potentiated the pathogenicity of nephrotoxic sera. These studies support the idea that podocytes play an active role in removing proteins from the GBM and suggest that genetic or acquired impairment of the clearance machinery is likely to be a common mechanism pr...

Intrauterine growth restriction (IUGR) can reduce glomerutar number and increase blood pressure in rats. The aim of this study was to assess the effects of maternal undernutrition during late gestation on-glomerutar ultrastructure in adult rat offspring. Timed pregnant Sprague-Dawley rats were used. Control dams received regular food throughout pregnancy, while experimental dams received 50% of control food intake from days 15-21 of gestation. GLomerular ultrastructure was quantified in male offspring at 16 weeks of age. The ultrastructure of the filtration apparatus in the IUGR rat glomeruli was indistinguishable from that in the control rat glomeruli. The relative volumes of the glomerulus occupied by podocytes, capillaries, and mesangium, and the thickness of the glomerular basement membrane (GBM), and width of the filtration slit were comparable between control and IUGR rats. These results indicate that glomerular ultrastructure is not affected by maternal undernutrition and sug...

For the purpose of studying renal side effects induced by anticancer drugs, we inspected glomerular damage as well as tubular damage of patients with anticancer chemotherapy. Thirty patients medicated with anticancer drugs, which are known to have nephrotoxic side effects were enrolled in this study. 17 of the patients were male and 13 female with a median age of 44.