Aki Ishida

Up-Regulation of Galectin-3 in Acute Renal Failure of the Rat

Galectin-3, a multifunctional beta-galactoside-binding lectin, is known to participate in development, oncogenesis, cell-to-cell attachment, and inflammation. We studied to determine whether galectin-3 is associated with cell injury and regeneration in two types of acute renal failure (ARF), namely ischemic and toxic ARF. In ischemia/reperfusion renal injury in rats (bilateral renal pedicles clamped for 40 minutes), galectin-3 mRNA began to increase at 2 hours and extended by 6.2-fold at 48 hours (P: < 0.01 versus normal control rats), and then decreased by 28 days after injury. In addition, a significant negative correlation between galectin-3 mRNA expression and serum reciprocal creatinine was shown at 48 hours after injury (n = 13, r = -0.94, P: < 0.0001). In folic acid-induced ARF, galectin-3 mRNA was found to be up-regulated at 2 hours after injury and increased levels continued until at least 7 days post-injury. In immunohistochemistry, at 2 hours following reperfusion, galectin-3 began to develop in proximal convoluted tubules. From 6 hours up to 48 hours, galectin-3 was also found in proximal straight tubules, distal tubules, thick ascending limbs, and collecting ducts. In later stages of regeneration, galectin-3 expressions were found in macrophages. In conclusion, we demonstrated that galectin-3 expressions were markedly up-regulated in both ischemic and toxic types of ARF. Galectin-3 may play an important role in acute tubular injury and the following regeneration stage.

Glomerular proliferating cell kinetics in acute post-streptococcal glomerulonephritis (APSGN)

To investigate the time sequence of glomerular cell proliferation in acute human glomerulonephritis, renal biopsy tissues were examined from 15 acute post‐streptococcal glomerulonephritis (APSGN) patients (who were biopsied 1–31 days after onset), using an immunoperoxidase technique with monoclonal antibodies against proliferating cell nuclear antigen (PCNA) and various cell surface markers. Few, if any, PCNA+ cells were observed in normal glomeruli, but many cells were positive for PCNA in the acute phase of APSGN. Glomerular PCNA+ cells were observed either within glomerular tufts, or lining Bowmans capsule (parietal epithelial cells); the number of positive cells tended to decrease exponentially as the disease duration increased (r=−0·91, P<0·0001). PCNA+ cells within glomerular tufts were further identified by double immunostaining. PCNA was not found in PMN or T cells, but a small proportion of macrophages were PCNA+. Most of the remaining PCNA+ cells were resident glomerular cells; the proportion of PCNA+ endothelial cells (CD31+) was over 80 per cent in the early phase, but as the disease continued the proportion of mesangial cells (α‐smooth muscle actin+) increased to about half of the total PCNA+ cells within the tuft. These data indicate that the hypercellular glomeruli in APSGN are due not only to immune cell infiltration, but also to resident glomerular cell proliferation, probably induced by locally produced growth factors.

Angiotensin II receptor blockade limits kidney injury in two-kidney, one-clip Goldblatt hypertensive rats with special reference to phenotypic changes

Recent evidence indicates that tubulointerstitial injury plays an important role in hypertensive kidney injury and that phenotypic changes contribute to this pathology. Moreover, angiotensin II is known to be actively involved in the pathogenesis of progressive kidney injury induced by hypertension. The present study was undertaken to see the effect of a newly developed angiotensin II type I receptor (AT1 receptor) antagonist on hypertension-induced kidney injury and to determine the contribution of phenotypic changes to morphologic alterations. Two-kidney, one-clip (2K1C), Goldblatt hypertensive rats (n = 27) were made by clipping the left renal artery. These animals were orally administered 57G709 (a selective non-peptide AT1 receptor antagonist)(10 mg/kg/day), captopril (20 mg/kg/day), or vehicle alone for 23 days beginning 4 weeks after clipping. In the non-clipped kidney of vehicle-treated 2K1 C rats, marked tubulointerstitial injury as well as glomerular sclerosis and/or hyalinosis was found in association with phenotypic changes, as shown by the neoexpression of vimentin in periglomeruli, perivascular walls, distal tubuli, and injured interstitium. Renin expression was markedly suppressed in the non-clipped kidneys of vehicle-treated 2K1C rats as compared with renin expression in normotensive control kidneys of sham-operated rats. Both 57G709 and captopril markedly ameliorated hypertensive kidney injury as reflected by the glomerular sclerosing index and by the tubulointerstitial index as determined by the point-counting method, and this improvement was accompanied by a significant decrease in blood pressure, urinary protein excretion, kidney/body weight ratio, and heart/body weight ratio. In addition, the vimentin neoexpression mentioned above was also suppressed with an inhibition of angiotensin II. These results suggest that in 2K1C Goldblatt hypertensive kidney injury, the AT1 receptor antagonist 57G709 exerts a potent renal protective effect associated with the inhibition of phenotypic changes.

Juxtaglomerular cell tumor with retroperitoneal fibrosis and secondary immune-complex glomerulonephritis: A possible contribution of the renin angiotensin system to renal fibrosis

We present a case of a 25-year-old woman with a renin-secreting juxtaglomerular cell tumor, retroperitoneal fibrosis associated with glomerular hypertrophy, glomerulonephritis, and marked tubulointerstitial alterations. Myofibroblasts, as shown by positive immunostaining for alpha-smooth muscle actin, were found along with transforming growth factor-beta (TGF-beta) in the interstitium of the tumor-free kidney. Regarding the pathogenesis of renal fibrosis and glomerular hypertrophy, this case may provide evidence not only experimentally but also clinically that the renin-angiotensin system plays an important role because angiotensin II is known to induce renal fibrosis associated with increased TGF-beta and the appearance of myofibroblasts.

Differential Effect of Nephrectomy on Renal Expressions of IGF-I and IGFBPs mRNA in Selective Growth Hormone-Deficient Rats

It is known that growth hormone (GH) contributes to glomerulosclerosis and that this probably occurs via insulin-like growth factor-I (IGF-I). However, the manner by which GH and nephrectomy (Nx) alter IGF-binding protein (IGFBP) mRNA in the kidney has not been fully explained. The effects of GH on renal IGF-I and IGFBP-1, 2, 3, 4, and 5 following Nx were examined in spontaneous dwarf rats (SDRs) which have a complete and specific lack of GH among pituitary hormones. In normal Sprague-Dawley rats (SDs), Nx resulted in significant decreases in levels of IGFBP-1 mRNA and IGFBP-5 mRNA to 62.7 ± 4.9 and 56.5 ± 5.0% those of sham-operated kidneys, respectively. Nx did not alter the IGF-I mRNA level in SDs. The levels of IGFBP-2, IGFBP-3, and IGFBP-4 mRNAs were likewise unchanged following nephrectomy. In SDRs, Nx significantly decreased the levels of IGFBP-1, IGFBP-4, and IGFBP-5 mRNA, to 57 ± 2.6, 46 ± 12, and 64 ± 8.1% of sham-operated animals. However, Nx did not alter the levels of IGF-I, IGFBP-2, and IGFBP-3 mRNA. GH injections of nephrectomized SDRs fully normalized the decreased IGFBP-4 mRNA levels, whereas levels of IGFBP-1 and IGFBP-5 mRNA were not reversed. The altered expression of IGFBP-4 mRNA following Nx of SDRs compared to that of SDs appears highly significant since it is known that, unlike SDs, glomerulosclerosis does not fully develop in SDRs following renal ablation. The change in the IGFBP-4 mRNA level might be related to the development of glomerulosclerosis in SDs.

Two cases of necrotizing crescentic glomerulonephritis with skin lesions

Two cases of rapidly progressive glomerulonephritis (RPGN) with skin vasculitis-associated anti-neutrophil cytoplasmic antibody (ANCA) are examined. Both cases showed purpura on the lower legs on admission and subsequently revealed renal or pulmonary vasculitis. One case responded positively to oral prednisolone alone, but the other case showed high ANCA titer and renal—pulmonary vasculitis. We discuss the diversity of clinical symptoms and the titer of antibody-associated vasculitis.