Identification and regulation of reticulon 4B (Nogo-B) in renal tubular epithelial cells.

Nogo-B is a member of the reticulon family of proteins that has been implicated in diverse forms of vascular injury. Although Nogo-B is expressed in renal tissues, its localization and function in the kidney have not been examined. Here, we report that Nogo-B is expressed specifically in the epithelial cells of the distal nephron segments in the murine kidney. After unilateral ureteral obstruction (UUO) and ischemia/reperfusion, Nogo-B gene and protein levels increased dramatically in the kidney. This increase was driven in part by injury-induced de novo expression in proximal tubules. Examination of Nogo-B immunostaining in human biopsy specimens from patients with acute tubular necrosis showed similar increases in Nogo-B in cortical tubules. Mice genetically deficient in Nogo-A/B were indistinguishable from wild-type (WT) mice based on histological appearance and serum analyses. After UUO, there was a significant delay in recruitment of macrophages to the kidney in the Nogo-A/B-deficient mice. However, measurements of fibrosis, inflammatory gene expression, and histological damage were not significantly different from WT mice. Thus, Nogo-B is highly expressed in murine kidneys in response to experimental injuries and may serve as a marker of diverse forms of renal injury in tissues from mice and humans. Furthermore, Nogo-B may regulate macrophage recruitment after UUO, although it does not greatly affect the degree of tissue injury or fibrosis in this model.

Necrosis papilar renal: el diagnóstico de un clásico en la era de la tomografía multidetector / Renal papillary necrosis: the diagnosis of a classic in the era of the multislice computed tomography

La necrosis papilar renal es una condición originada por múltiples factores, con consecuencias variadas incluyendo dentro de ellas el desarrollo de insuficiencia renal terminal y eventualmente la muerte. Su presentación en la pielografía de eliminación demuestra múltiples patrones de excavación papilar, que están muy bien descritos en la literatura clásica. Con el advenimiento de la urografía por tomografía computada multicorte, estos hallazgos han sido refinados, agregándose también nuevos signos, que incluyen, entre otros, la detección de cambios medulares precoces que podrían implicar, en un futuro cercano, un significativo cambio en la evolución y pronóstico de estos pacientes. En esta publicación hacemos una revisión y puesta al día de los aspectos imaginológicos de la necrosis papilar renal.

Renal papillary necrosis is a multifactorial entitiy that encompasses a wide range of consecuences, including end-stage renal impairment or even death. Its appearance on intravenous pyelography pictures reveals multiple patterns of papillary excavation, fairly well defined in traditional literature. With the advent of multislice computed tomography urography these findings have been refined and new radiological signs such as detection of early renal medullary changes, among others, have been added. The application of this imaging modality may translate into significant short-term improvements in the evolution and prognosis of these patients. This paper is intended to provide both a reviewing and an updating of renal papillary necrosis imaging issues.

Early pathophysiological features in canine renal papillary necrosis induced by nefiracetam.

To ascertain the early pathophysiological features in canine renal papillary necrosis (RPN) caused by the neurotransmission enhancer nefiracetam, male beagle dogs were orally administered nefiracetam at 300 mg/kg/day for 4 to 7 weeks in comparison with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), at 50 mg/kg/day for 5 weeks. During the dosing period, the animals were periodically subjected to laboratory tests, light-microscopic, immunohistochemical, and electron-microscopic examinations and/or cyclooxygenase (COX)-2 mRNA analysis. In laboratory tests, a decrease in urinary osmotic pressure and increases in urine volume and urinary lactate dehydrogenase (LDH) level were early biomarkers for detecting RPN. Light-microscopically, nefiracetam revealed epithelial swelling and degeneration in the papillary ducts in week 7, while ibuprofen displayed degeneration and necrosis in the papillary interstitium in week 5. In immunohistochemical staining with COX-2 antibody, nefiracetam elicited a positive reaction within interstitial cells around the affected epithelial cells in the papillary ducts (upper papilla) in week 7, and ibuprofen positively reacted within interstitial cells adjacent to the degenerative and/or necrotic lesions in week 5. Ultrastructurally, nefiracetam exhibited reductions of intracellular interdigitation and infoldings of epithelial cells in the papillary ducts, whereas ibuprofen showed no changes in the identical portions. Thus, the early morphological change in the papilla brought about by nefiracetam was quite different from that elicited by ibuprofen. By the renal papillary COX-2 mRNA expression analysis, nefiracetam exceedingly decreased its expression in week 4, but markedly increased it in week 7, suggesting an induction of COX-2 mRNA by renal papillary lesions. These results demonstrate that the epithelial cell in the papillary ducts is the primary target site for the onset of RPN evoked by nefiracetam.

Serotonin (5-HT1A-receptor) agonist-induced collecting duct vacuolation and renal papillary necrosis in the rat.

General anxiety in humans is treated with azaspirodecanedions, which act through a reduction of serotonin transmission. Ipsapirone also represents a serotonin (5-HT1A) receptor agonist and was under development as an anxiolytic drug. Histopathologic evaluation of animal experiments revealed cellular swelling and/or vacuolation of renal papillary and medullary collecting duct (MCD) epithelium in rats but not in dogs or mice. The changes ensued already after 1 wk of dosing and were first localized in the inner MCDs. Longer treatment periods showed that these changes proceeded from proximal to distal, approaching the papillary collecting ducts. The changes were most likely the result of altered hemodynamics in the papillary tip. Swelling resulted in partial or total papillary necrosis in some cases. Furthermore, rats treated with ipsapirone showed a sharp and transient rise in urinary endothelin excretion. Concomitantly, urinary PGE2 levels were elevated. In contrast, no elevated levels of endothelin were detected in urine samples of patients from a volunteer study, leading to the conclusion that the human kidney is not susceptible to the ipsapirone-induced alterations seen in the collecting ducts of rats.

Renal papillary necrosis and urinary protein alterations induced in Fischer-344 rats by D-ormaplatin.

D-ormaplatin (previously called tetraplatin) produced dose-related renal papillary necrosis when given intravenously to Fischer-344 rats at doses of 2, 4, and 9 mg/kg. The lesions were most severe at 4 days postdosing and had repaired by day 9 in the 2- and 4-mg/kg dose groups. Blood urea nitrogen and the N-acetyl-beta-glucosaminidase (NAG): creatinine ratio were slightly elevated at day 4 while creatinine clearance was decreased. Body weight was reduced in a dose-related manner while kidney weights increased. Total protein excretion in male and female rats was elevated at day 4 postdosing. The evaluation of urinary proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed an increase, primarily in high molecular weight proteins at 4 days postdosing, indicating an increase in glomerular filtration of albumin and transferrin. The morphologic appearance of the glomeruli was normal by light microscopy. At day 4 postdosing, alpha 1-microglobulin was elevated. This correlated with an increase in the NAG: creatinine ratio also seen at this time and the morphologic appearance of the kidney, indicating that the proximal tubules were affected but were not a major site of toxicity. Although the change in urinary proteins occurred at the same time as morphologic alterations in the renal papilla, these findings were not considered to be related. SDS-PAGE provided a useful method for detecting and localizing renal toxicity when used in conjunction with morphologic and clinical chemistry methods.

Later complications on diabetic patients: nephropathies in necropsy material

The purpose of the present study was to analyze in detail the kidney lesions of diabetic patients. Revision of the histopathologic aspects of this nephropathy was performed, seeking to approach the pathophysiology of its formation. In 200 consecutive necropsies of cadavers of diabetic patients examined at the Pathology Department of the Medical School of the Säo Paulo University, some degree of nephropathy was found in 158 cases. The slides from parffin sections of these cases were reviewed according to a morphologic protocol previously established. Diffuse, nodular and mixed glomerulosclerosis were encountered in 42.2 per cent, 21.5 per cent and 5.7 per cent respectively. Subvcapsular drop and exudative lesion appeared in 12,7 per cent and 15.2 per cent of the cases. We also encoutered arteriosclerosis in 81.6 per cent, arteriolosclerosis in 88.6 per cent, necrotizing papillitis in 11.4 per cent and acute and chronic pyelonephritis in 23.4 per cent and 20.9 per cent respectively. We concluded that glomerular and vascular hyalin alterations were the most frequent findings in diabetic patients

Sequential study of the chronic nephrotoxicity induced by dietary administration of ethoxyquin in Fischer 344 rats.

Groups of 3-week-old male and female Fischer 344 rats were administered 0.5% ethoxyquin-containing diet for varying periods of time, ranging from 4 weeks up to 18 months, to assess renal histopathology. The primary lesion observed was renal papillary necrosis in the male rat, commencing as interstitial degeneration of the papillary tip by 4 weeks exposure, and reaching a complete form of papillary necrosis by 24 weeks. The papillary necrosis in male rats was consistently accompanied by active pyelonephritis affecting the cortex, and urothelial hyperplasia in the renal pelvis. A marked sex difference was evident in that female rats developed papillary change at a later stage than males and the lesion never progressed beyond interstitial degeneration. A further sex difference associated with ethoxyquin treatment was the increasing cellular accumulation of lipofuscin-related pigment involving proximal tubules in female rats. Spontaneous chronic progressive nephropathy (CPN) was exacerbated by ethoxyquin in both males and females, but more so in the former. Proximal tubule hyperplasia was most frequently observed in ethoxyquin-treated males at the later sampling times. In all cases, such proliferative lesions were associated either with pyelonephritis or with the most advanced stages of CPN. Contrary to a previous report, there was no evidence that ethoxyquin directly induced preneoplastic renal tubule hyperplasia.

Spontaneous papillary necrosis in the heterozygous Gunn rat.

Spontaneous papillary necrosis develops in aging heterozygous non-jaundiced Gunn rats. The lesion is situated in the subapical or mid papilla and in its earliest stages is manifest by the appearance of amorphous material in the interstitial space. This is seen in plastic-embedded sections taken from rats 6 months old. In its later stages, the accumulation of amorphous material is accompanied by loss of interstitial cells and cyst formation, but there is no associated inflammatory reaction. The largest lesions are found in the oldest rats, but even in these animals the macroscopic appearance of the papilla is normal. Similar papillary changes were not found in albino or homozygous Gunn rats, but in aging albino rats there was loss of papillary interstitial cells without accumulation of amorphous material.

Co-carcinogenic effect of retinyl acetate on forestomach carcinogenesis of male F344 rats induced with butylated hydroxyanisole.

The potential modifying effect of retinyl acetate (RA) on butylated hydroxyanisole (BHA)-induced rat forestomach tumorigenesis was examined. Male F344 rats, 5 weeks of age, were maintained on diet containing 1% or 2% BHA by weight and simultaneously on drinking water supplemented with RA at various concentrations (w/v) for 52 weeks. In groups given 2% BHA, although marked hyperplastic changes of the forestomach epithelium were observed in all animals, co-administration of 0.25% RA significantly (P less than 0.05) increased the incidence of forestomach tumors (squamous cell papilloma and carcinoma) to 60% (9/15, 2 rats with carcinoma) from 15% (3/20, one rat with carcinoma) in the group given RA-free water. In rats given 1% BHA, RA co-administered at a dose of 0.05, 0.1, 0.2 or 0.25% showed a dose-dependent enhancing effect on the development of the BHA-induced epithelial hyperplasia. Tumors, all papillomas, were induced in 3 rats (17%) with 0.25% RA and in one rat (10%) with 0.05% RA co-administration. RA alone did not induce hyperplastic changes in the forestomach. These findings indicate that RA acted as a co-carcinogen in the BHA forestomach carcinogenesis of the rat.