The induction of renal papillary necrosis in Gunn rats by analgesics and analgesic mixtures.

Homozygous members of the mutant Gunn strain of Wistar rats genetically lack the enzyme uridine diphosphate glucuronyl transferase. "High" and "low" dose gavage feeding for 18-34 days of an analgesic mixture containing aspirin, phenacetin and caffeine (APC) confirmed the previously reported susceptibility of these animals to analgesic induced renal papillary necrosis. Heterozygotes do not share the gross enzyme deficiency of homozygotes and, when treated with APC under identical conditions, failed to develop renal papillary necrosis. Groups of homozygotes were dosed by gavage with aspirin, phenacetin and paracetamol for 4 weeks. Renal papillary necrosis was produced by all 3 drugs, the lowest frequency of lesions occurring with phenacetin. It is postulated that the enzyme deficiency of homozygous Gunn rats influences the metabolism of analgesics to favour the excretion of nephrotoxic metabolites. The renal papillary necrosis appearing in these experiments is essentially an acute lesion, differing both in natural history and morphology from the renal papillary necrosis of analgesic nephropathy, suggesting that the pathogeneses of the experimental and human lesions differ.     

Spontaneous renal lesions in five rat strains

A survey of non-neoplastic and neoplastic renal lesions found in 5 rat strains, namely, ACI (August X Copenhagen Irish), A22807 (August), F344 (Fischer), M520 (Marshall), and OM (Osborne-Mendel) is given. The results from this survey indicate that the OM, M520, and ACI rat strains have major disadvantages for their use in long-term toxicology and carcinogenesis studies. Male OM rats had a high incidence of renovascular lesions which consisted of necrotizing arteritis or arteriolitis and intimal thickening of small arteries, and resembled renal lesions described in hypertensive rats and human patients. Predominant renal lesions in the M520 and ACI rat strains included extensive calculus formation at the pyramido-pelvic junction, which was often associated with proliferative pelvic transitional cell lesions and hydronephrosis. The ACI rat strain also had unilateral congenital renal agenesis in about 12% of the animals of either sex. Based on the spectrum of renal lesions observed in the 2 remaining rat strains, namely A28807 and F344, it is difficult to determine which one of the two should be preferred for long-term studies. The A28807 rat strain had less severe chronic renal disease than the F344 but had a higher incidence of pelvic transitional cell hyperplasia. The ultimate choice should be based on the spectrum, incidence, and severity of extra-renal lesions.     

Morphometry of the kidney in rat pups from uninephrectomized mothers

Background: The present study was designed to explore whether maternal renal dysfunction affects fetal kidney development and if the effects are lasting during the postnatal development. Methods: Kidneys of 1-day-old and 6-week-old pups from mothers which were uninephrectomized on day 5 of gestation were studied. Results: One day after birth, both the number of immature glomeruli and average volume of mature glomeruli of the neonates from uninephrectomized mothers were significantly larger than those from sham-operated mothers. Six weeks after birth, no significant differences in parameters of the kidney were observed between the pups from uninephrectomized and those from sham-operated mothers. Furthermore, blood urea nitrogen (BUN) concentration in adult female rats was determined at various days after uninephrectomy. BUN concentration in uninephrectomized rats was significantly higher than that in sham-operated ones. Conclusions: These results suggest that the fetal kidney development is accelerated by the elevated BUN level following maternal uninephrectomy and that the renotropic activity does not last during the postnatal developmental period. © 1994 Wiley-Liss, Inc.     

The morphology of serotonin-induced renal lesions in the rat

The progress of serotonin-induced renal lesions was studied over a period of 6 mth following a single intraperioneal injection of 40 mg/kg serotonin. The predominant lesion was ischaemic necrosis of tubules of patchy distribution. Parahilar areas were usually spared and a narrow subcapsular strip was less severely affected than deeper parts. The early tubular lesions appeared to be an accelerated form of the lesion of complete renal ischaemia. The necrotic tubules were soon relined by epithelium from surviving segments and became dilated. This phase of dilatation corresponded approximatly with the period of diuresis following serotonin injection and was followed by collapse and atrophy of tubules. Possible mechanisms concerned in the sequential appearance of tubular dilatation and collapse were discussed. Many collapsed tubules eventually atrophied and were associated with basement membrane thickening and round cell infiltration. Reflux of necrotic proximal tubule cytoplasm into glomerular capsular spaces occurred in the early stages of the lesion. This lesion is not specific for serotonin nephropathy and can be produced by allowing normal rat kidney to autolyse.     

Glomerular epithelial cell lesions in rat renal isografts

Visceral glomerular epithelial cell lesions--microvillus formation, loss of foot processes, osmiophilic inclusion droplets, balloon-like malformation of cell processes, degeneration, necrosis, and loss of cell processes from capillary basement membranes--are found in rat renal isografts 1 mth after transplantation. The lesions, which are most readily recognized in perfusion-fixed material, are essentially focal, affecting neither all glomeruli, nor all cells in any glomerulus, bear no relation to the degree of interstitial nephritis in the graft, and are associated with albuminuria and with focal capillary sclerosis in some glomeruli. They are not restricted to renal isografts but are found in aging rats, in different experimental models of glomerular disease and in clinical glomerular disorders, again in association with proteinuria and glomerulosclerosis. It is therefore proposed that glomerular epithelial cell damage increases capillary permeability and impairs maintenance of the integrity of the capillary wall, leading to proteinuria and focal glomerulosclerosis.     

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.     

Role of afferent renal nerves in renal adaptation to sodium restriction in uninephrectomized rats

In the present study we examined the role of the afferent renal nerves in the control of ipsilateral renal adaptation to sodium restriction. Uninephrectomized rats were subjected to selective renal deafferentation or sham operation, instrumented with catheters and housed in metabolism cages to collect urine in 90 min fractions. Only sodium deficient food (0.03% Na⁺) was allowed. Water and sodium excretion were stabilized via a continuous 48 h infusion (1.25 ml h^-1) of a Ringer's solution. During this period water, sodium and potassium excretion were similar in renal deafferented and sham operated rats. Then, the infusion was exchanged for a modified Ringer's solution, in which the sodium ion was replaced by the choline ion. Measurements were performed over 24 h. During the choline Cl infusion, urine flow increased similarly in renal deafferented and sham-operated rats. In both groups of rats, sodium excretion decreased within 24 h by more than 95 %, whereas potassium excretion stayed constant. Sodium loss was higher in renal deafferented rats only in the first 90 min period after the exchange of the infusions. These results indicate that afferent renal nerves are not necessary in ipsilateral renal adaptation during 24 h sodium restriction, but may play a modulatory role in correcting transient changes in ipsilateral renal excretory function.     

Experimental pyelonephritis and papillary necrosis in the Gunn rat

Homozygous and heterozygous female Gunn rats show increased susceptibility to experimental urinary infection. The strain develops pyelonephritis after intravesical inoculation of Proteus mirabilis in numbers which fail to induce the lesion in albino rats, and severe pyelonephritis is frequently complicated by papillary necrosis. The basis for this enhanced susceptibility has not been defined, but the occurrence of the phenomenon in both homozygous and heterozygous rats indicates that it is not caused primarily by high plasma levels of unconjugated bilirubin or by the deposition of bilirubin in the tip of the renal papilla. The increased susceptibility of the homozygous Gunn rat to ascending urinary tract infection provides supporting evidence for the suggestion that infection may complicate the natural history of experimental analgesic nephropathy in this strain and is relevant to the clinical association of analgesic nephropathy and urinary infection.     

Reactive oxygen species mediate compensatory glomerular hypertrophy in rat uninephrectomized kidney

Hyperfiltration in glomeruli is the most common pathway to progressive renal dysfunction. Moreover, reduction of renal mass by unilateral nephrectomy results in an immediate increase in glomerular flow to the remnant kidney, followed by compensatory glomerular hypertrophy. Reactive oxygen species (ROS) are involved in renal hypertrophic responses; however, the role of ROS in compensatory glomerular hypertrophy remains unclear. Therefore, this role was investigated in the present study. Wistar rats were randomly placed into two groups: uninephrectomized rats (Nx) and uninephrectomized rats treated with tempol (Nx + TP). The glomerular volume increased in the Nx 1 week after surgery, but was significantly suppressed in the Nx + TP. Levels of phospho-Akt and phospho-ribosomal protein S6, which are critical for cell growth and hypertrophy, were markedly increased in the glomeruli of the Nx, while tempol treatment almost abolished the activation of these proteins. These results suggest that ROS have important roles in compensatory hypertrophy in glomeruli. M. Ozeki and H. Nagasu have contributed equally to this study.     

CyA-mediated renal interstitial and vascular lesions in the rat under low-sodium diet

Nephrotoxicity of CyA was analyzed histologically in rats fed a low-sodium diet. CyA was subcutaneously administered daily at a dose of 15 mg/kg for 10 or 35 days with or without prior uninephrectomy (UNT) in male Sprague-Dawley rats receiving a low-sodium diet (0.03% sodium). CyA-administered rats showed impaired renal function as well as tubulo-interstitial lesions, such as edema, tubular basement membrane changes, and tubular atrophy, in the cortex, especially in the subcapsular portion, within 10 days. On day 35, the tubulo-interstitial lesions were advanced with mild focal interstitial fibrosis. These lesions were mild in the UNT group compared to the non-UNT group. Immunohistochemically, CyA treatment caused an increase in number of renin-positive cells in the afferent arteriolar wall at juxtaglomerular area. These cells lost the expression of calponin, which is a marker of mature smooth muscle cells. In addition, in afferent arterioles and interlobular arteries, electron-dense fibrous bodies were found in the smooth muscle cells on days 10 and 35. Immunoelectron microscopically, these bodies showed scattered positive staining for calponin and alpha-actinin, were negative or only peripherally positive for alpha-SMA and vimentin, and were completely negative for desmin. This study revealed that CyA could cause interstitial lesions starting in the subcapsular portion of the renal cortex and vascular lesions of the preglomerular artery. Increases in number of renin granules and formation of cytoplasmic fibrous bodies in smooth muscle cells could be the forerunner of severe arteriolar wall damage.     

Caffeine potentiation of mefenamic acid-induced lesions in the rat renal medulla.

The effect of caffeine given in combination with mefenamic acid on the renal medulla was examined. Sprague-Dawley rats were divided into four groups and gavage fed either vehicle suspension (control), mefenamic acid, mefenamic acid+caffeine or caffeine only for 4 months. Renal tissue taken from the corticomedullary junction was processed for electron microscopy. Ultrathin sections were cut after identification of vasa rectae on survey sections. On subsequent morphometric analysis, percentage interstitial tissue was calculated from the total area of vasa recta less the non-interstitial tissue. The median percentage of interstitial tissue in the mefenamic acid and caffeine group was 41 (range 33-50; n = 15) compared with 34 (20-48; n = 20) in mefenamic acid (P less than 0.01), 29 (15-42; n = 15) in caffeine only (P less than 0.001) and 32 (20-46; n = 18) in vehicle-treated animals (P less than 0.001). There were no significant differences between mefenamic acid alone and vehicle or caffeine-only groups or between caffeine-only and vehicle-treated controls. This suggests that caffeine potentiates the effect of the non-steroidal anti-inflammatory drug, mefenamic acid, on the rat renal medulla, resulting in a quantitative increase in the interstitial tissue between adjacent afferent and efferent vasa recta.     

Reaction to electrical shock after cerebellar lesions in the rat

The reactivity to electrical shock of control animals and animals with lesions of the cerebellar cortex was compared. At current levels above 200 μA no differences could be found between the groups. At threshold levels animals with lesions of the vermis showed the first measureable response to shock at significantly higher current levels than animals of the other two groups. The findings lend further support to the concept of a functional differentiation between the cerebellar cortex of the vermis and the hemispheres.     

Expression of nestin after renal transplantation in the rat

Chronic allograft injury (CAI) limits the long‐term success of renal transplantation. Nestin is a marker of progenitor cells, which probably contribute to its pathogenesis. We hypothesize that nestin is induced by ischemia/reperfusion injury and acute rejection, main risk factors for CAI. Syngeneic renal transplantation was performed in Lewis rats and allogeneic transplantation in the Fischer 344 to Lewis strain combination, which results in reversible acute rejection and in CAI in the long‐run. The Dark Agouti to Lewis rat strain combination was used to study fatal acute rejection. In untreated kidneys, nestin immunoreactivity was detected in glomeruli and in very few interstitial or microvascular cells. Syngeneic transplantation induced nestin expression within 4 days, which decreased until day 9 and returned to control levels on day 42. Nestin expression was strong during acute rejection and still detected during the pathogenesis of CAI on day 42. Nestin‐positive cells were identified as endothelial cells and interstitial fibroblast‐like cells co‐expressing alpha‐smooth muscle actin. A sub‐population of them expressed proliferating cell nuclear antigen. In conclusion, nestin is induced in renal grafts by ischemia/reperfusion injury and acute rejection. It is expressed by proliferating myofibroblasts and endothelial cells and probably contributes to the pathogenesis of CAI.