Histological assessment of the kidneys of these mice shows severe tubulointerstitial inflammation, with marked infiltration by T and B lymphocytes and macrophages (Fig. 3).23 CD4+ and CD8+ cell numbers increase in cortex and medulla of Adriamycin-affected kidneys, but not in spleen, suggesting

a direct role of these selleckchem cells in modulating renal injury. However, studies in severe combined immunodeficient (SCID) mice (inbred BALB/c mice that lack lymphocytes) have demonstrated that structural and functional injury induced by Adriamycin does not require lymphocytes but can be modulated by the presence or absence of specific subpopulations. Renal injury develops in mice with doses of Adriamycin approximately half (5.3 mg/kg) that of wild-type BALB/c mice (9.8–10.4 mg/kg), suggesting that while lymphocytes are not essential, it is likely that a subpopulation of these cells protects against the development of renal injury. Further evidence for this comes from adoptive transfer studies of FoxP3 expressing CD4+CD25+ T cells, which protect against renal injury in AN,24 consistent with the exacerbation of renal injury by depletion of CD4+ T cells.25 BAY 80-6946 cell line The pattern of renal injury in SCID mice is similar to that in wild-type BALB/c mice. Macrophage infiltration is prominent in the tubulointerstitium but not in glomeruli (Fig. 4). Depletion

and reconstitution studies suggest a pivotal role of pro- and anti-inflammatory macrophages in the pathogenesis of Adriamycin-induced kidney injury.26–28 Adriamycin induces renal injury in the fetus as well as the mother. When Adriamycin is administered intraperitoneally 4 weeks prior to pregnancy, kidneys from the fetus show increased amounts of PAS-positive mesangial matrix, glomerulosclerosis, tubular injury and dilatation.29 Pregnant rats given Adriamycin 2 weeks prior

to pregnancy develop more severe proteinuria and higher blood pressure compared with non-pregnant rats, in association with an elevated ratio of thromboxane B2 (vasoconstrictor) to prostaglandin F1α (vasodilator) Edoxaban synthesis, changes which normalize post-pregnancy in a manner analogous to human pre-eclampsia.30,31 In contrast, repeated pregnancies after the induction of AN are associated with persistent glomerular damage post-partum.32 Adriamycin administration early in gestation (days 7 to 9 of rat pregnancy), induces anomalies in urinary tract development, the most common being bilateral megaureters with hypoplastic bladder.33 We and others have examined the effect of various immunologic interventions in AN, which have enabled a greater understanding of the immune mechanisms underlying chronic proteinuric renal disease associated with tubulointerstitial fibrosis. Macrophages and lymphocytes are heterogeneous populations containing cells that act to promote or reduce inflammation and fibrosis (see review by Lee et al.34).