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Graft versus host disease-dependent renal dysfunction after hematopoietic stem cell transplantation.CEN Case Reports Nov 2014Nephropathy is an important complication in hematopoietic stem cell transplantation (HSCT) wherein multifactorial causes, i.e., radiation, drug toxicity, graft versus...
Nephropathy is an important complication in hematopoietic stem cell transplantation (HSCT) wherein multifactorial causes, i.e., radiation, drug toxicity, graft versus host disease (GVHD), are thought to contribute renal dysfunction. Here, we report a 10-year-old boy with high-risk acute myelocytic leukemia and severe but partially reversible renal dysfunction. The patient initially received umbilical cord blood transplantation (UCBT) with CY 120 mg/kg and kidney unshielded 12 Gy of total body irradiation. After the leukemic relapse, he received allogenic bone marrow transplantation (BMT) 270 days after the first transplantation. Two months later, his renal function started to deteriorate and urinary protein increased gradually to 1 g/day. Four months after BMT, by the symptoms of severe GVHD, the dose of tacrolimus, utilized to avoid GVHD, was increased although his serum Cre level elevated to 2.97 mg/dL. Serum Cre level improved to 2.0 mg/dL paralleled with GVHD improvement. Renal histological findings showed severe interstitial edema, features of thrombotic microangiopathy (TMA), and C4d deposition along the glomerular capillaries and peritubular capillaries. We suggested that control of GVHD had benefitted to ameliorate renal function of the patient. Treatment for GVHD improved renal dysfunction and TMA of our patients. Moreover, renal biopsy was powerful to elucidate the exact origin of renal dysfunction after HSCT.
PubMed: 28509199
DOI: 10.1007/s13730-014-0118-1 -
PloS One 2014Indoxyl sulfate is a uremic toxin and a ligand of the aryl-hydrocarbon receptor (AhR), a transcriptional regulator. Elevated serum indoxyl sulfate levels may contribute...
Indoxyl sulfate is a uremic toxin and a ligand of the aryl-hydrocarbon receptor (AhR), a transcriptional regulator. Elevated serum indoxyl sulfate levels may contribute to progressive kidney disease and associated vascular disease. We asked whether indoxyl sulfate injures podocytes in vivo and in vitro. Mice exposed to indoxyl sulfate for 8 w exhibited prominent tubulointerstitial lesions with vascular damage. Indoxyl sulfate-exposed mice with microalbuminuria showed ischemic changes, while more severely affected mice showed increased mesangial matrix, segmental solidification, and mesangiolysis. In normal mouse kidneys, AhR was predominantly localized to the podocyte nuclei. In mice exposed to indoxyl sulfate for 2 h, isolated glomeruli manifested increased Cyp1a1 expression, indicating AhR activation. After 8 w of indoxyl sulfate, podocytes showed foot process effacement, cytoplasmic vacuoles, and a focal granular and wrinkled pattern of podocin and synaptopodin expression. Furthermore, vimentin and AhR expression in the glomerulus was increased in the indoxyl sulfate-exposed glomeruli compared to controls. Glomerular expression of characteristic podocyte mRNAs was decreased, including Actn4, Cd2ap, Myh9, Nphs1, Nphs2, Podxl, Synpo, and Wt1. In vitro, immortalized-mouse podocytes exhibited AhR nuclear translocation beginning 30 min after 1 mM indoxyl sulfate exposure, and there was increased phospho-Rac1/Cdc42 at 2 h. After exposure to indoxyl sulfate for 24 h, mouse podocytes exhibited a pro-inflammatory phenotype, perturbed actin cytoskeleton, decreased expression of podocyte-specific genes, and decreased cell viability. In immortalized human podocytes, indoxyl sulfate treatment caused cell injury, decreased mRNA expression of podocyte-specific proteins, as well as integrins, collagens, cytoskeletal proteins, and bone morphogenetic proteins, and increased cytokine and chemokine expression. We propose that basal levels of AhR activity regulate podocyte function under normal conditions, and that increased activation of podocyte AhR by indoxyl sulfate contributes to progressive glomerular injury.
Topics: Animals; Indican; Kidney; Ligands; Mice; Mice, Inbred C57BL; Podocytes; Receptors, Aryl Hydrocarbon
PubMed: 25244654
DOI: 10.1371/journal.pone.0108448 -
Journal of Lipid Research Oct 2014Lipoprotein glomerulopathy (LPG) is a renal disease often accompanied by dyslipidemia and increased serum apoE levels. apoESendai (Arg145Pro), a rare mutant based on the...
Lipoprotein glomerulopathy (LPG) is a renal disease often accompanied by dyslipidemia and increased serum apoE levels. apoESendai (Arg145Pro), a rare mutant based on the apoE3 sequence carrying an apoE2 charge, causes LPG in humans and transgenic mice, but its effects on the artery wall are unknown. Macrophage expression of apoESendai may also directly influence renal and arterial homeostasis. We investigated the effects of macrophage-expressed apoESendai in apoE(-/-) mice with or without LDL receptor (LDLR). Murine bone marrow transduced to express apoE2, apoE3, or apoESendai was transplanted into lethally irradiated mice. Macrophage apoESendai expression reduced aortic lesion size and inflammation by 32 and 28%, respectively, compared with apoE2 in apoE(-/-) recipients. No differences in lesion size or inflammation were found between apoESendai and apoE3 in apoE(-/-) recipients. Macrophage apoESendai expression also reduced aortic lesion size by 18% and inflammation by 29% compared with apoE2 in apoE(-/-)/LDLR(-/-) recipients. Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE(-/-)/LDLR(-/-) mice expressing apoESendai. Thus, macrophage expression of apoESendai protects against atherosclerosis while causing lipoprotein glomerulopathy. This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.
Topics: Animals; Apolipoproteins E; Atherosclerosis; Glomerular Mesangium; Hyperlipidemias; Inflammation; Kidney Diseases; Macrophages; Mice; Mice, Knockout; Receptors, LDL
PubMed: 25183802
DOI: 10.1194/jlr.M049874 -
Journal of the American Society of... Jan 2015Mesangial cell injury has a major role in many CKDs. Because renin-positive precursor cells give rise to mesangial cells during nephrogenesis, this study tested the...
Mesangial cell injury has a major role in many CKDs. Because renin-positive precursor cells give rise to mesangial cells during nephrogenesis, this study tested the hypothesis that the same phenomenon contributes to glomerular regeneration after murine experimental mesangial injury. Mesangiolysis was induced by administration of an anti-mesangial cell serum in combination with LPS. In enhanced green fluorescent protein-reporter mice with constitutively labeled renin lineage cells, the size of the enhanced green fluorescent protein-positive area in the glomerular tufts increased after mesangial injury. Furthermore, we generated a novel Tet-on inducible triple-transgenic LacZ reporter line that allowed selective labeling of renin cells along renal afferent arterioles of adult mice. Although no intraglomerular LacZ expression was detected in healthy mice, about two-thirds of the glomerular tufts became LacZ positive during the regenerative phase after severe mesangial injury. Intraglomerular renin descendant LacZ-expressing cells colocalized with mesangial cell markers α8-integrin and PDGF receptor-β but not with endothelial, podocyte, or parietal epithelial cell markers. In contrast with LacZ-positive cells in the afferent arterioles, LacZ-positive cells in the glomerular tuft did not express renin. These data demonstrate that extraglomerular renin lineage cells represent a major source of repopulating cells for reconstitution of the intraglomerular mesangium after injury.
Topics: Animals; Animals, Genetically Modified; Cell Lineage; Doxycycline; Enalapril; Female; Genes, Reporter; Glomerular Mesangium; Green Fluorescent Proteins; Imaging, Three-Dimensional; Kidney; Kidney Glomerulus; Lac Operon; Lipopolysaccharides; Male; Mice; Mice, Transgenic; Renin; Stem Cells
PubMed: 24904091
DOI: 10.1681/ASN.2014030265 -
Journal of the American Society of... Aug 2014VEGF-A and nitric oxide are essential for glomerular filtration barrier homeostasis and are dysregulated in diabetic nephropathy. Here, we examined the effect of excess...
VEGF-A and nitric oxide are essential for glomerular filtration barrier homeostasis and are dysregulated in diabetic nephropathy. Here, we examined the effect of excess podocyte VEGF-A on the renal phenotype of endothelial nitric oxide synthase (eNOS) knockout mice. Podocyte-specific VEGF(164) gain of function in eNOS(-/-) mice resulted in nodular glomerulosclerosis, mesangiolysis, microaneurysms, and arteriolar hyalinosis associated with massive proteinuria and renal failure in the absence of diabetic milieu or hypertension. In contrast, podocyte-specific VEGF(164) gain of function in wild-type mice resulted in less pronounced albuminuria and increased creatinine clearance. Transmission electron microscopy revealed glomerular basement membrane thickening and podocyte effacement in eNOS(-/-) mice with podocyte-specific VEGF(164) gain of function. Furthermore, glomerular nodules overexpressed collagen IV and laminin extensively. Biotin-switch and proximity ligation assays demonstrated that podocyte-specific VEGF(164) gain of function decreased glomerular S-nitrosylation of laminin in eNOS(-/-) mice. In addition, treatment with VEGF-A decreased S-nitrosylated laminin in cultured podocytes. Collectively, these data indicate that excess glomerular VEGF-A and eNOS deficiency is necessary and sufficient to induce Kimmelstiel-Wilson-like nodular glomerulosclerosis in mice through a process that involves deposition of laminin and collagen IV and de-nitrosylation of laminin.
Topics: Animals; Cell Culture Techniques; Collagen Type IV; Diabetic Nephropathies; Glomerular Basement Membrane; Laminin; Mice; Mice, Knockout; Nitric Oxide Synthase Type III; Podocytes; Proteinuria; Renal Insufficiency; Vascular Endothelial Growth Factor A
PubMed: 24578128
DOI: 10.1681/ASN.2013070752