Renal tubulointerstitial injury is characterized by inflammatory cell infiltrate; however, the stimuli for leukocyte recruitment are not fully understood. IL-8 is a potent chemokine produced by proximal tubular epithelial cells (PTECs). Whether nephrotic proteins stimulate tubular IL-8 expression remains unknown. Acute exposure of human PTECs to albumin induced IL-8 gene and protein expression time-and dose-dependently. Apical albumin predominantly stimulated basolateral IL-8 secretion. Electrophoretic mobility shift assay demonstrated nuclear translocation of NF-κB, and the p65/p50 subunits were activated. NF-κB activation and IL-8 secretion were attenuated by the NF-κB inhibitors pyrrolidine dithiocarbamate and cell-permeable peptide. Albumin upregulated intracellular reactive oxygen species (ROS) generation, while exogenous H 2 O 2 stimulated NF-κB translocation and IL-8 secretion. Albumin-induced ROS generation, NF-κB activation, and IL-8 secretion were endocytosis-and PKC-dependent as these downstream events were abrogated by the PI3K inhibitors LY294002 and wortmannin, and the PKC inhibitors GF109203X and staurosporin, respectively. In vivo, IL-8 mRNA expression was localized by in situ hybridization to the proximal tubules in nephrotic kidney tissues. The intensity of IL-8 immunostaining was higher in nephrotic than non-nephrotic subjects. In conclusion, albumin is a strong stimulus for tubular IL-8 expression, which occurs via NF-κB-dependent pathways through PKC activation and ROS generation.

Aldehyde dehydrogenase (ALDH) activity is used to define normal hematopoietic stem cell (HSC), but its link to leukemic stem cells (LSC) in acute myeloid leukemia (AML) is currently unknown. We hypothesize that ALDH activity in AML might be correlated with the presence of LSC. Fifty-eight bone marrow (BM) samples were collected from AML (n ¼ 43), acute lymphoblastic leukemia (ALL) (n ¼ 8) and normal cases (n ¼ 7). In 14 AML cases, a high SSC lo ALDH br cell population was identified (ALDH þ AML) (median: 14.89%, range: 5.65-48.01%), with the majority of the SSC lo ALDH br cells coexpressing CD34 þ . In another 29 cases, there was undetectable (n ¼ 23) or rare (p5%) (n ¼ 6) SSC lo ALDH br population (ALDH À AML). Among other clinicopathologic variables, ALDH þ AML was significantly associated with adverse cytogenetic abnormalities. CD34 þ BM cells from ALDH þ AML engrafted significantly better in NOD/ SCID mice (ALDH þ AML: injected bone 21.1179.07%; uninjected bone 1.5270.75% vs ALDH À AML: injected bone 1.7771.66% (P ¼ 0.05); uninjected bone 0.2370.23% (P ¼ 0.03)) with the engrafting cells showing molecular and cytogenetic aberrations identical to the original clones. Normal BM contained a small SSC lo ALDH br population (median: 2.92%, range: 0.92-5.79%), but none of the ALL cases showed this fraction. In conclusion, SSC lo ALDH br cells in ALDH þ AML might denote primitive LSC and confer an inferior prognosis in patients.

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In selected patients with IgAN, MMF is effective in lowering proteinuria and ameliorating some of the putative pathogenetic abnormalities.