Osteopontin expression in progressive renal injury in remnant kidney: role of angiotensin II. (33/503)

BACKGROUND: Osteopontin (OPN) is a macrophage chemotactic and adhesion molecule and has been shown to play a role in glomerular and tubulointerstitial injury in several kidney disease models. METHODS: The present study examined whether OPN expression is involved in the progression of renal disease following subtotal (5/6) nephrectomy (STNx) in rats and whether angiotensin II (Ang II) mediates the up-regulation of renal OPN expression and macrophage accumulation in this model by administering valsartan, an Ang II type I (AT1) receptor antagonist, or ramipril, an angiotensin-converting enzyme (ACE) inhibitor. RESULTS: In normal and sham-operated rat kidneys, OPN was expressed in a few tubules (<5%) and was absent in glomeruli. Following STNx (weeks 2 to 16), there was substantial up-regulation of OPN mRNA and protein expression in glomeruli [2 to 12 cells/glomerular cross section (gcs)] and tubular epithelial cells (20 to 75% OPN+). The up-regulation of OPN expression was associated with macrophage accumulation within the kidney, severe proteinuria, loss of renal function, and severe histologic damage, including tubulitis and tubulointerstitial fibrosis (all P < 0.001). Treatment with either valsartan or ramipril completely abrogated the up-regulation of OPN mRNA and protein expression in glomeruli and tubules. The reduction in OPN expression was associated with a significant inhibition of macrophage accumulation and progressive renal injury (P < 0.001). CONCLUSION: An up-regulation of OPN expression may play a role in progressive renal injury following STNx. Inhibition of OPN expression may be one of the mechanisms by which Ang II blockade attenuated renal injury after renal ablation.  (+info)

Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. (34/503)

BACKGROUND: We previously described that monocyte chemoattractant protein-1 (MCP-1) plays an important role in progressive glomerular and interstitial damage in inflammatory renal diseases. However, the expression of MCP-1 in diabetic nephropathy remains to be investigated. METHODS: We examined whether locally expressed MCP-1 participates in human diabetic nephropathy via recruiting and activating monocytes/macrophages (Mphi). Urinary and serum MCP-1 levels were measured by enzyme-linked immunosorbent assay in 45 patients with diabetic nephropathy. The presence of MCP-1 in diseased kidneys was determined by immunohistochemical and in situ hybridization analyses. RESULTS: Urinary MCP-1 levels were significantly elevated in patients with diabetic nephrotic syndrome and advanced tubulointerstitial lesions. Moreover, urinary levels of MCP-1 were well correlated with the number of CD68-positive infiltrating cells in the interstitium. In contrast, serum MCP-1 levels remained similar to those of healthy volunteers. Furthermore, we detected the MCP-1-positive cells in the interstitium of diabetic nephropathy via both immunohistochemical and in situ hybridization analyses. CONCLUSION: These observations suggest that locally produced MCP-1 may be involved in the development of advanced diabetic nephropathy, especially in the formation of tubulointerstitial lesions possibly through Mphi recruitment and activation. Moreover, up-regulation of MCP-1 may be a common pathway involved in the progressive tubulointerstitial damage in diabetic nephropathy as well as inflammatory renal diseases.  (+info)

Expression of DNA topoisomerases in chronic proliferative kidney disease. (35/503)

BACKGROUND: Circulating autoantibodies to human topoisomerases have been reported in glomerular kidney disease associated with scleroderma and systemic lupus erythematosus. However, limited information is available about the expression of topoisomerases in the kidney under normal and pathological conditions. METHODS: The expression of DNA topoisomerases I and IIalpha was studied by immunohistochemistry on archival biopsies from 70 patients with chronic renal diseases. Normal kidney tissue was examined for comparison. Topoisomerase I was detected by means of monoclonal antibody (mAb) C21, and topoisomerase IIalpha was detected by means of mAb Ki-S4. In addition, mAb Ki-M1p was used to assess the density of monocytic infiltrates. All parameters were assessed in a semiquantitative manner. RESULTS: Glomerular topoisomerase IIalpha levels were increased in mesangial proliferative glomerulonephritis (MPGN), rapidly progressive glomerulonephritis (RPGN), and lupus nephritis (LN) and were reduced in membranous glomerulonephritis (MGN), chronic transplant nephropathy (CTN), and tubulointerstitial nephritis (TIN). Tubular epithelia displayed high topoisomerase IIalpha levels in mesangiocapillary glomerulonephritis (MCGN), RPGN, TIN, miscellaneous entities (MISC) and LN, and displayed low levels in MPGN and CTN. Topoisomerase I expression was high in the glomeruli of focal segmental glomerulosclerosis (FSGS), MCGN, and RPGN and was extreme in LN, whereas it was strikingly diminished in the glomeruli of MGN, CTN, and TIN. Almost all conditions displayed lower tubular topoisomerase I levels than normal kidney, except for LN, in which the enzyme content was markedly increased. Increased glomerular monocytic infiltrates were found in FSGS, MCGN, RPGN, TIN, and LN, and tubulointerstitial Ki-M1p+ cells were seen at high numbers in MCGN, RPGN, TIN, MISC, and LN. The expression of the topoisomerases I and IIalpha was significantly correlated; also, topoisomerases showed a positive association with the density of monocytic infiltrates. The parameter profiles exhibited significant differences between distinct types of chronic renal disease. CONCLUSION: Topoisomerase IIalpha expression is tightly linked to cell cycling, and topoisomerase I is likely a reflection of gene transcription. Rapidly progressing glomerular disease therefore appears to be accompanied by active mesangial cell proliferation and increased metabolic activity in glomerular cells. The correlation with inflammatory infiltrates is likely to reflect a positive feedback mechanism involving cytokines, growth factors, and adhesion molecules. Assessment of topoisomerases may therefore be of diagnostic help and might allow prognostic predictions. Provided that our observations are supported by clinicopathological follow-up studies, one might envisage the use of topoisomerase inhibitors in the therapy of chronic proliferative renal disease refractory to current treatment protocols.  (+info)

A paradoxical severe decrease in serum HDL-cholesterol after treatment with a fibrate. (36/503)

There have been a handful of reports in the literature of a paradoxical decrease in serum high density lipoprotein (HDL)-cholesterol in patients on fibrate drugs. The reason for this decline in cardioprotective HDL-cholesterol is not known and may have potential deleterious effects on the patient. This report describes a decrease in serum HDL-cholesterol in a patient on both simvastatin and bezafibrate. This patient also developed abnormal renal function, probably interstitial nephritis. In addition, the literature of fibrate induced serum HDL-cholesterol decline is reviewed and possible mechanisms for this phenomenon discussed.  (+info)

Acute renal failure: unusual complication of Epstein-Barr virus-induced infectious mononucleosis. (37/503)

A 17-year-old boy with juvenile rheumatoid arthritis presented with jaundice, confusion, hemolytic anemia, thrombocytopenia, and acute renal failure secondary to titer-confirmed acute Epstein-Barr virus (EBV). Renal biopsy specimen revealed interstitial nephritis with an inflammatory infiltrate composed of cytotoxic/suppressor T cells, and interstitial mononuclear cell nuclei expressed EBV encoded RNA-1 (EBER-1) mRNA. Methylprednisolone treatment resulted in rapid improvement.  (+info)

Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. (38/503)

BACKGROUND: Unilateral ureteral obstruction (UUO) is characterized by progressive renal atrophy, renal interstitial fibrosis, an increase in renal transforming growth factor-beta (TGF-beta), and renal tubular apoptosis. The present study was undertaken to determine the effect of a monoclonal antibody to TGF-beta (1D11) in UUO. METHODS: Mechanical stretch was applied to tubular epithelial cells (NRK-52E) by a computer-assisted system. Three doses of 1D11 (either 0.5, 2, or 4 mg/rat) were administered to rats one day prior to UUO and every two days thereafter, and kidneys were harvested at day 13. Fibrosis was assessed by measuring tissue hydroxyproline and mRNA for collagen and fibronectin. Apoptosis was assessed with the terminal deoxy transferase uridine triphosphate nick end-labeling assay. TGF-beta levels were determined by bioassay. Western blot and immunostaining were used to identify proliferating cell nuclear antigen (PCNA), p53, bcl-2, and inducible nitric oxide synthase (iNOS). RESULTS: Stretch significantly induced apoptosis in NRK-52E cells, which was accompanied by an increased release of TGF-beta; 1D11 (10 microg/mL) totally inhibited stretch-induced apoptosis. Control obstructed kidney contained 20-fold higher TGF-beta as compared with its unobstructed kidney; 1D11 neutralized tissue TGF-beta of the obstructed kidney. Control obstructed kidney exhibited significantly more fibrosis and tubular apoptosis than its unobstructed counterpart, which was blunted by 1D11. In contrast, 1D11 significantly increased tubular proliferation. p53 immunostaining was localized to renal tubular nuclei of control obstructed kidney and was diminished by 1D11. In contrast, bcl-2 was up-regulated in the 1D11-treated obstructed kidney. Total NOS activity and iNOS activity of the obstructed kidney were increased by 1D11 treatment. CONCLUSION: The present study strongly suggests that an antibody to TGF-beta is a promising agent to prevent renal tubular fibrosis and apoptosis in UUO.  (+info)

Early diabetes mellitus stimulates proximal tubule renin mRNA expression in the rat. (39/503)

BACKGROUND: Enhanced intrarenal angiotensin II (Ang II) activity may contribute to diabetic nephropathy. The proximal tubule is a proposed site of significant intrarenal Ang II production. We determined the effect of early diabetes on mRNA expression of components of the proximal tubule renin-angiotensin system. METHODS: Three groups of male Sprague-Dawley rats were studied after two weeks: (1) control (C), (2) streptozotocin-induced diabetes (STZ), and (3) STZ-induced diabetes, with normoglycemia maintained by insulin implants (STZ-I). Competitive reverse transcription-polymerase chain reaction was used to assay mRNA for renin, angiotensinogen, and angiotensin-converting enzyme in suspensions of proximal tubules; plasma and kidney levels of Ang II were measured by radioimmunoassay, and Western analysis of Ang II subtype 1 (AT1) receptors was performed. RESULTS: STZ rats tended to have increased plasma and intrarenal levels of Ang II compared with C and STZ-I rats. In proximal tubules, mRNA for renin was significantly increased in STZ rats, with reversal to control values in STZ-I rats (C, 2432 +/- 437 vs. STZ, 5688 +/- 890 fg/0.25 microg RNA, P < 0.05 vs. C, N = 9, vs. STZ-I, 1676 +/- 376 fg/0.25 microg RNA, P = NS vs. C). In STZ rats, the AT1 receptor antagonist losartan caused a further fivefold increase in proximal tubule renin mRNA, associated with proximal tubular renin immunostaining. STZ had no significant effect on mRNA expression for angiotensinogen or angiotensin-converting enzyme in proximal tubules. By Western blot analysis, cortical and proximal tubule AT1 receptor protein expression was significantly decreased in STZ rats. CONCLUSIONS: These data suggest activation of the proximal tubule renin-angiotensin system in early STZ diabetes, mediated at least partly by enhanced expression of renin mRNA. Increased local production of Ang II could contribute to tubulointerstitial injury in this model.  (+info)

Genetically modified bone marrow-derived vehicle cells site specifically deliver an anti-inflammatory cytokine to inflamed interstitium of obstructive nephropathy. (40/503)

In this study, we used genetically modified bone marrow-derived CD11b(+)CD18(+) vehicle cells to deliver IL-1 receptor antagonist (IL-1ra) for treatment of inflamed renal interstitium in an animal model of unilateral ureteral obstruction (UUO). Vehicle cells that expressed the ICAM-1 ligands, CD11b and CD18, were obtained from bone marrow cells of DBA/2j mice and adenovirally transduced with the IL-1ra gene or glucocerebrosidase (GC) gene ex vivo. In kidneys treated to develop UUO, levels of ICAM-1, IL-1 beta, and IL-1R expression increased within 3 days compared with contralateral untreated kidneys in the same mice. Similarly, the macrophage infiltration in the cortical interstitium increased after 3 days in UUO kidneys, but not untreated kidneys. After UUO developed, DBA/2j mice were injected i.v. with either IL-1ra(+) vehicle cells (IL-1ra-treated mice) or GC(+) vehicle cells (GC-treated mice) at 24 h after UUO. Six days after the injection of these vehicle cells, marked increase of CD11b(+) IL-1ra(+) vehicle cells was observed in the ICAM-1-positive interstitium of UUO kidneys from IL-1ra-treated mice. In contrast, no CD11b(+) IL-1ra(+) cells appeared in ICAM-1-negative contralateral kidneys from these mice. Furthermore, the infiltration of macrophages (p < 0.001), expression of ICAM-1 (p < 0.005), and presence of alpha-smooth muscle actin (p = 0.005) in the interstitium of UUO kidneys were significantly decreased in IL-1ra-treated mice compared with GC-treated mice. These findings suggest that IL-1 may contribute to the development of renal interstitial injury and that our method can deliver a functioning gene encoding an antiinflammatory cytokine gene specifically at that site by interacting with local adhesion molecules.  (+info)