Cholesterol feeding accentuates the cyclosporine-induced elevation of renal plasminogen activator inhibitor type 1

Cholesterol feeding accentuates the cyclosporine-induced elevation of renal plasminogen activator inhibitor type 1. Long-term cyclosporine (CsA) therapy is accompanied by the occurrence of hypercholesterolemia and renal interstitial fibrosis. The present study investigates the effect of dietary cholesterol on CsA-induced lipid disturbances in the rat and on CsA nephrotoxicity. Since plasminogen activator inhibitor type 1 (PAI-1) is a major inhibitor of matrix degradation and elevated plasma PAI-1 levels are reported to be associated with increased low-density lipoprotein (LDL) cholesterol, PAI-1 was examined in the kidneys of rats fed a sodium-deficient diet, with or without cholesterol. After nine weeks, both diet groups were subdivided into a CsA-treated group and a vehicle-treated group. Although cholesterol feeding significantly aggravated CsA-induced renal function impairment, CsA-induced histological lesions were comparable in both diet groups. Cholesterol feeding significantly decreased high-density lipoprotein (HDL) cholesterol irrespective of the treatment, while CsA treatment significantly elevated serum triglycerides irrespective of the diet. Cholesterol feeding alone did not increase the number of infiltrating cells in the renal interstitium. In contrast, in both diet groups CsA treatment caused a significant influx of macrophages, while combined treatment with CsA and cholesterol additionally elevated the number of T-helper cells in the cortex. In all rats, PAI-1 immunostain-ing was found mainly in intracellular vesicles (lysosomes) in proximal tubules, which stained most intensely in fibrotic areas of kidneys from CsA-treated rats. Cholesterol feeding enhanced the CsA-induced elevation of renal PAI-1 immunostaining to a significant level. These results show that, although serum creatinine, PAI-1 staining and cell influx were significantly increased in the cholesterol-fed CsA-treated group compared to the other groups, renal CsA-induced histological lesions were not influenced by cholesterol feeding after short-term (3 weeks) CsA administration. To what extent the more pronounced proximal tubular PAI-1 (inhibitor of matrix degradation) immunostaining in fibrotic areas in the cortex of cholesterol-fed CsA-treated rats contributes to the progression of CsA-induced renal fibrosis remains to be determined

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

EGF and TGF-α in the human kidney: Identification of octopal cells in the collecting duct

EGF and TGF-α in the human kidney: Identification of octopal cells in the collecting duct. Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α) are well-known mitogens expressed in the kidney. Their human renal cell origin has not been conclusively identified. The distribution of EGF and TGF-α was investigated immunohistochemically in the adult human kidney in comparison with the monkey and rodent kidney. In humans, as in the monkey, two variants of EGF immunoreactivity were detected. One was present along the apical cell surfaces and diffusely in the cytoplasm of the thick ascending limb (TAL), co-localizing with Tamm-Horsfall protein, and in the distal convoluted tubule (DCT). The other occurred as overall membranous staining in the connecting tubule and cortical collecting duct (CD), and mainly as basal staining in the rest of the CD. The EGF stained cells in the cortical and outer medullary CD reached a diameter of 40 µ and were identified as intercalated or dark cells; they displayed a peculiar octopus-like shape, bearing long lateral extensions that stretched underneath and between 20 surrounding smaller negative cells. Cytoplasmic TGF-α staining appeared in the DCT and decreased further on. In conclusion: (1) the normal human distal nephron displayed EGF and TGF-α immunoreactivity in a partly complementary segmental and subcellular distribution pattern, partly differing from that in rodents. (2) EGF immunostaining revealed the presence of long lateral projections on CD intercalated cells; this peculiar morphology suggests a modulatory role within the CD epithelium, possibly involving the EGF immunoreactivity on their surface