Ginkgo Biloba Extract EGB761 Ameliorates the Extracellular Matrix Accumulation and Mesenchymal Transformation of Renal Tubules in Diabetic Kidney Disease by Inhibiting Endoplasmic Reticulum Stress.

The study is aimed at investigating the effects of Ginkgo biloba extract EGB761 on renal tubular damage and endoplasmic reticulum stress (ERS) in diabetic kidney disease (DKD). A total of 50 C57BL/6 N mice were randomly divided into the normal group, DKD group, DKD+EGB761 group (36 mg/kg), and DKD+4-phenylbutyrate (4-PBA) group (1 g/kg). The DKD model was replicated by high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Renal tubular epithelial cells (HK-2) were divided into the control group, high-glucose group (30 mmol/L), EGB761 group (40 mg/L, 20 mg/L, 10 mg/L), TM group, and TM+4-PBA group. After 8 weeks of administration, expressions of serum creatinine (Scr), blood urea nitrogen (BUN), 24 h urinary protein (24 h Pro), fasting blood glucose (FBG), ß 2-microglobulin (ß 2-MG), and retinol binding protein 4 (RBP4) of mice were tested. The pathological changes of renal tissue were observed. The expressions of extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) markers α-smooth muscle actin (α-SMA), E-cadherin, fibronectin, and collagen IV, as well as the ERS markers GRP78 and ATF6, were tested by Western blot, qPCR, immunohistochemistry, or immunofluorescence. EGB761 could decrease the Scr, BUN, 24 h Pro, and FBG levels in the DKD group, alleviate renal pathological injury, decrease urine ß 2-MG, RBP4 levels, and decrease the expression of α-SMA, collagen IV, fibronectin, and GRP78, as well as ATF6, while increase the expression of E-cadherin. These findings demonstrate that EGB761 can improve renal function, reduce tubular injury, and ameliorate ECM accumulation and EMT in DKD kidney tubules, and the mechanism may be related to the inhibition of ERS.

Uric acid transporters BCRP and MRP4 involved in chickens uric acid excretion.

BACKGROUND: Breast cancer resistance protein (BCRP) and multidrug resistance protein 4 (MRP4) are involved in uric acid excretion in humans and mice. Despite evidence suggesting that renal proximal tubular epithelial cells participate in uric acid excretion in chickens, the roles of BCRP and MRP4 therein remain unclear. This study evaluated the relationship between BCRP and MRP4 expression and renal function in chickens. RESULTS: Sixty laying hens were randomly divided into four treatment groups: a control group (NC) fed a basal diet; a sulfonamide-treated group (SD) fed the basal diet and supplemented with sulfamonomethoxine sodium via drinking water (8 mg/L); a fish meal group (FM) fed the basal diet supplemented with 16% fishmeal; and a uric acid injection group (IU) fed the basal diet and intraperitoneally injected with uric acid (250 mg/kg body weight). The results showed that serum uric acid, creatinine, and blood urea nitrogen levels were significantly higher in the SD and IU, but not FM, than in the NC groups. Renal tubular epithelial cells in the SD and IU groups were damaged. Liver BCRP and MRP4 mRNA and protein levels were significantly decreased in the SD and IU groups, but slightly increased in the FM group. In the SD group, BCRP and MRP4 were significantly increased in the ileum and slightly increased in the kidney. In the FM group, BCRP and MRP4 were significantly increased in the kidney and slightly increased in the ileum. In the IU group, BCRP and MRP4 were significantly increased in the kidney and ileum. BCRP and MRP4 expression in the jejunum was not affected by the treatments. CONCLUSION: Together, these results demonstrate that BCRP and MRP4 are involved in renal and intestinal uric acid excretion in chickens and that BCRP is positively related to MRP4 expression. Further, impairment of renal function results in an increase in serum uric acid as well as a compensatory increase in BCRP and MRP4 in the ileum; however, under normal renal function, renal BCRP and MRP4 are the main regulators of uric acid excretion.

Huaiqihuang Granules () reduce proteinuria by enhancing nephrin expression and regulating necrosis factor κB signaling pathway in adriamycin-induced nephropathy.

OBJECTIVE: To investigate the effects of Huaiqihuang Granules (, HQH), a mixture of Chinese herbs including Trametes robiniophila Murr, Fructus Lycii and Polygonatum sibiricum, on adriamycininduced nephropathy (ADRN) in rats and its underlying mechanisms. METHODS: Rats with ADRN were divided into four groups: the sham group, the model group (distilled water), the low-dose HQH-treated (2 g/kg) group, and the high-dose HQH-treated (4 g/kg) group. Body weight and 24-h urinary protein (Upro) were checked every week. After 5-week intervention, at the end of the study, the rats were sacrificed and blood samples were collected for examination of biochemical parameters, including glomerular morphological makers, podocyte shape, cellular apoptosis, expressions of nephrin, inflammatory and apoptosis markers. RESULTS: HQH ameliorated the rat's general status, proteinuria, renal morphological appearance and glomerulosclerosis. The decreased expression of nephrin in ADRN rats was increased by HQH, as well as the impaired podocyte foot process fusion. Cytosolic levels of p65 and inhibitor of nuclear factor κBα (IκBα) were decreased in ADRN rats, and recovered by the treatment of HQH. Consistently, the induced expression of tumor necrosis factor α (TNF-α), phosphorylated nuclear factor κB p65 (p-NFκB p65) and IκBα in ADRN were markedly suppressed by HQH. In addition, induction of Bax, cleaved caspase-3 and cytochrome C in ADRN rats were suppressed by HQH, indicating the amelioration of apoptosis. CONCLUSION: HQH could ameliorate renal impairments in ADRN rats by increasing nephrin expression, inhibiting NF-κB signaling pathway via the down-regulation of p-NF-κB p65 and p-IκBα, and suppression of glomerular and tubular apoptosis.

Clinical and pathological features of dense deposit disease in Chinese patients.

AIMS: Dense deposit disease (DDD) is a rare disease that has no universally effective treatment. Herein we explore the clinical and pathological features of DDD in Chinese patients and the therapeutic effect of Tripterygium wilfordii (TW). MATERIALS AND METHODS: Clinical and pathological data of 10 Chinese patients with biopsy-proved DDD were collected and analyzed retrospectively. RESULTS: The patients consisted of 6 males and 4 females. All of them had heavy proteinuria and microscopic hematuria. Gross hematuria, renal insufficiency, anemia, hypertension and low serum complement 3 (C3) occurred in 3, 3, 5, 6 and 8 cases, respectively. Under light microscopy (LM), 8 cases exhibited membranoproliferative glomerulonephritis (MPGN). Periodic acid-Schiff (PAS) stain disclosed intense PAS-positive bright ribbon-like thickening of glomerular basement membranes (GBM). Immunofluorescence mainly showed diffuse fine granular and short linear deposition of C3 along the glomerular capillary wall. Under electron microscopy, ribbon-like electrondense intramembranous deposits were identified in the lamina densa of the GBM, along the tubule basement membranes (TBM) and wall of Bowman's capsule. Before admission, 6 cases were treated with prednisone, cyclophosphamide and/or cyclosporin A with no response. Proteinuria in 8 cases who received TW during the course decreased at different degrees. CONCLUSIONS: The clinical and pathological features in DDD patients were various. The effect of TW in patients with DDD merits further investigation.

In vitro evaluation of the cytotoxic potential of alkylphenols from Ginkgo biloba L.

Extracts from the leaves of Ginkgo biloba L. belong to the most widely used phytopharmaceuticals. In crude Ginkgo extracts, ginkgolic acids (GA) and related alkylphenols (e.g. cardanols and cardols) have been recognized as hazardous compounds with suspected cytotoxic, allergenic, mutagenic and carcinogenic properties. To further assess the cytotoxic potential of GA, their effect on the human keratinocyte cell line HaCaT and the rhesus monkey kidney tubular epithelial cell line LLC-MK(2) was investigated. The action of a defined mixture of GA on cell growth, viability and integrity was evaluated by the neutral red uptake assay as well as the release of lactate dehydrogenase (LDH) and acid phosphatase (ACP). Cell morphology was examined by electron microscopy. For comparison, the effect of the standardized Ginkgo extract EGb 761, which contains less than 5 ppm GA, was also investigated. Following incubation of cells with EGb 761, neutral red uptake was half-maximally inhibited at concentrations of 900 mg/l (HaCaT) and 1480 mg/ml (LLC-MK(2)). The corresponding IC(50)-values for the mixture of GA ranged between 22 mg/l (HaCaT) and 4.6 mg/l (LLC-MK(2)), respectively. In parallel to the inhibition of neutral red uptake, a concentration dependent release of LDH was observed when cells were incubated in the presence of GA (1-100 mg/l). In contrast, even at a concentration of 1800 mg/l EGb 761 did not cause release of LDH above controls. Since GA interacted with the assay for ACP, no index of lysosomal damage could be established by this method. Incubation of HaCaT cells with GA for 18 h increased the proportion of apoptotic cells from about 6% (control) to nearly 80% at concentrations of >or=30 mg/l. Electron microscopic analysis of HaCaT cells revealed a drug induced formation of myelinosomes possibly due to the inhibition of lysosomal enzymes, while morphological evaluation of LLC-MK(2) cells indicated that the cytotoxic activity of GA in these cells is primarily mediated by transformation of mitochondria, which is probably induced by uncoupling of oxidative phosphorylation.

Effectiveness of a traditional Chinese medicine, Wulingsan, in suppressing the development of nephrocalcinosis induced by a high phosphorus diet in young rats.

The development of nephrocalcinosis in rats fed a high phosphorus diet, and the effectiveness of the Chinese traditional medicine, Wulingsan, and its components (Poria, Alismatis Rhizoma, Atractylodis Rhizoma, Cinnamomi Ramus, Polyporus) in suppressing the development of calcinosis were studied. The rats were fed a high phosphorus diet (1.5% P) supplemented with Wulingsan or its individual components (0.5 g/kg body weight) as separate experimental groups for a 2-week period. Upon histological observation by light microscopy and electron microscopy, signs of nephrocalcinosis were observed in almost all areas of the kidney. Calculi, consisting mainly of needle-shaped crystals of hydroxyapatite, were observed in the proximal tubules, in the collecting ductal lumina, and in the mitochondria of the proximal tubular cells and the interstitial cells. X-ray microanalysis revealed that the calculi were composed of hydroxyapatite (Ca and P). In the group fed the diet supplemented with Wulingsan, the severity of calcinosis in the corticomedullary junction was only slight. In all groups fed individual components of Wulingsan, the severity of calcinosis was almost the same as that in the group fed the high phosphorus diet (1.5% P). Wulingsan suppressed the development of calcinosis in rats fed the high phosphorus diet supplemented with this Chinese medicine, whereas its individual components alone had no effect. The process of calcinosis and the mechanism responsible for the activity of this Chinese medicine in the suppression of calcinosis are discussed.

[A case of Sjögren's syndrome presenting with hypokalemic myopathy due to renal tubular acidosis].

A 37-year-old woman was admitted to our university hospital because of severe flaccid quadriplegia. Her laboratory data, lip biopsy and muscle biopsy findings were compatible with hypokalemic myopathy due to renal tubular acidosis(RTA) type I associated with primary Sjögren's syndrome. Kidney biopsy revealed chronic tubulointerstitial nephritis(TIN), consisting of focal mononuclear cell infiltration with tubulitis, interstitial fibrosis and tubular atrophy. Immunohistochemical analysis of the renal biopsy specimens showed that the infiltrating mononuclear cells were predominantly CD8+T cells, and CD68+ cells(macrophages), whereas CD4+ T cells were fewer in number. Following potassium administration and alkali therapy, hypokalemia and metabolic acidosis were ameliorated and limb palsy gradually subsided. Finally, RTA improved with prednisolon and short term cyclophosphamide treatment without supplemental potassium and alkali therapy.

High-dose 7-hydromethotrexate: acute toxicity and lethality in a rat model.

To elucidate mechanisms for methotrexate (MTX)-induced renal and hepatic toxicity, we investigated the acute effects of bolus plus continuous infusion of up to 0.4 g/kg 7-hydroxymethotrexate (7-OH-MTX) in the rat. We demonstrate for the first time in any species the occurrence of acute lethal toxicity within a few hours after 7-OH-MTX administration. Serum concentrations of 7-OH-MTX measured at the time of death were 1.4 mM (mean), about one-half of those achieved in some patients after infusion of high-dose MTX (HD-MTX) in the clinic. The data suggest an approximate LD50 (the dose lethal to 50% of the study population) of 0.3 g/kg and a steep dose/lethality curve for 7-OH-MTX. Moreover, acute renal and hepatic toxicity occurred as evidenced by severe morphological findings and increased serum levels of creatinine and liver transaminases. In all rats subjected to continuous infusion of 7-OH-MTX, yellow microscopic precipitations were apparent in the kidney tubules. Crystallization was also seen in bile ducts of the liver in some of the rats. These results further support that the formation of 7-OH-MTX is disadvantageous and that reported attempts to prevent its formation during MTX treatment are warranted.

Citrinin produces acute adverse changes in renal function and ultrastructure in pentobarbital-anesthetized dogs without concomitant reductions in [potassium]plasma.

Citrinin's nephrotoxicity was examined in pentobarbital-anesthetized dogs under conditions that minimized or avoided significant changes in a number of its actions that could indirectly and adversely affect renal function and ultrastructure, such as, (i) major acute reductions in blood pressure and renal blood flow and, (ii) emesis and diarrhea that could lead to dehydration and electrolyte imbalances, especially hypokalemia. Slow intravenous injection of 20 mumol citrinin/kg to pentobarbital-anesthetized dogs did not induce any alterations in renal tissue ultrastructure or in any of the 23 whole blood, plasma or renal function parameters that were monitored over a 6-h post-citrinin period. On the other hand, 80 mumol citrinin/kg produced significant increases in the hematocrit and in the renal excretion rates of protein and glucose; modest reductions were noted in CIN, RBF and excretion rate of inorganic phosphorus. In addition, 80 mumol citrinin/kg induced ultrastructural lesions in the cells of the S2 proximal tubular segment, the thick ascending limb, the distal convoluted tubule and the collecting ducts. The glomeruli, S1 and S3 cells of the proximal tubule and the thin descending and ascending limbs of Henle's loop were unaffected by both citrinin doses. The location and nature of the adverse ultrastructural lesions were most likely the result of the direct actions of citrinin (or a citrinin metabolite) since the effects of citrinin that could lead to indirect adverse renal effects were totally avoided or greatly minimized.

Effects of ethanol on urinary acidification and on gluconeogenesis by isolated renal tubules.

Class I alcohol dehydrogenase (ADH) is present in the kidney of rats. Rats fed an alcohol-containing diet long-term had higher urinary pH and reduced titratable acidity compared with pair-fed controls; rates of ammonium excretion were unchanged. The effects of ethanol on the metabolism of isolated renal tubules were then studied. Gluconeogenesis from lactate, pyruvate, or glutamine was not inhibited by 10 mmol/L ethanol during 30- or 60-minute incubations, although there was a trend toward increased lactate/pyruvate ratios at 30 minutes in the presence of ethanol. When the medium was also supplemented with oleate, glucose synthesis from most substrates was decreased, and the addition of ethanol inhibited glucose synthesis dramatically. This interaction between oleate and ethanol was not abolished by 4-methylpyrazole, an inhibitor of ADH. This effect of ethanol was highly dependent on the concentration of oleate present in the medium and was not observed with palmitate or decanoate; the inhibition was reversed by increasing the medium concentration of albumin. We conclude that ethanol may mildly perturb the redox state of isolated kidney tubules without inhibiting glucose synthesis, and that ethanol and oleate interact to inhibit renal gluconeogenesis by a mechanism highly dependent on the fatty acid concentration. The mechanism by which ethanol in the diet reduces renal acid excretion remains unknown.

[Cordyceps sinensis in protection of the kidney from cyclosporine A nephrotoxicity].

To explore the protective effect of cordyceps sinensis (CS) on cyclosporine A nephro-toxicity (CsA-Nx) and the possible mechanism, we studied the kidney changes induced by CsA in rats by light microscopy (LM), electronic microscopy (EM) and morphometrical analysis. At the 15th day after receiving CsA, prominent vacuolation and necrosis were noted microscopically in proximal tubular cells and mitochondria swelling electronmicroscopically. Morphometrical study showed that the epithelial areas of both proximal and distal tubules in the CS group were larger than those of the control group. There were obvious vacuolation (90%) and necrosis in proximal tubular cells at different stages of chronic CsA-Nx. Interstitial edema with mild fibrosis was observed. Mitochondria abnormality was seen electronmicroscopically. Morphometrical analysis showed that the epithelial cell areas of tubules and glomeruli were smaller in the CsA group than those in the CS group. Both acute and chronic experiments showed that CS could protect the kidney from CsA-Nx and ameliorate the glomerular and interstitial injuries.

A 90-day continuous vapor inhalation toxicity study of JP-8 jet fuel followed by 20 or 21 months of recovery in Fischer 344 rats and C57BL/6 mice.

The kerosene-type jet fuel, JP-8, consists of a complex mixture of aliphatic and aromatic hydrocarbons. Because of the utility of JP-8, studies have been conducted to identify the potential long-term consequence of occupational inhalation exposure. Fischer 344 rats and C57BL/6 mice of both sexes were exposed to JP-8 vapors at 0, 500, and 1,000 mg/m3 on a continuous basis for 90 days, then followed by recovery until approximately 24 months of age. Occurrence of necrotizing dermatitis associated with fighting resulted in an increase in mortality in mice (male greater than female) during the 2 week to 9 month post-exposure recovery period. The male rat kidney developed a reversible ultrastructural increase in size and propensity for crystalloid changes of phagolysosomal proteinic reabsorption droplets in the proximal convoluted tubular epithelium. A specific triad of persisting light microscopic renal lesions occurred but functional change was limited to a decrease in urine concentration compared to controls that persisted throughout the recovery period. The response is comparable to the chronic effect of lifetime exposure of the male rat to unleaded gasoline, d-limonene, and p-dichlorobenzene, except for the absence of tubular tumorigenesis. The active toxicologic response presumably must occur over a greater proportion of the male rat's life span for the tumor component of this male rat hydrocarbon nephropathy syndrome. The predictiveness for humans must be questioned, since the pathologic response to JP-8 involved only one tissue in one sex of one species, and since the male rat response appears to be linked to an inherent renal protein peculiarity.

[Electron microscopic observation of the effects of Rhodiola kirilowii (Regel.) Maxim. in preventing damage of the rat viscera by a hypoxic high altitude environment].

This paper has shown that the pathologic damages done to rat's viscera due to hypoxic environment of altitude can be reduced significantly by oral administrations of Shengmaiyin, Danshen-Chuanxiong mixture and Rhodiola kirilowii. Shengmaiyin that maintains interior substances in the plate layer bodies proves more effective than Danshen-Chuanxiong mixture, while the latter excels in preventing capillary contraction, thus improving blood circulation. Rhodiola kirilowii has the effects of both Shengmaiyin and Danshen-Chuanxiong mixtures.

31P-NMR spectroscopy and ultrastructural studies on nephrotoxicity of cyclosporine A.

NMR-spectroscopy and electron microscopy were applied in order to find out whether nephrotoxic effects of cyclosporine A in combination with ischaemia on rat kidney are of significance for the energy metabolism of the organ. CSA was administered in daily doses of 15 mg/kg rat over 20 days. Use was made of the particular advantage of 31P-NMR-spectroscopy to follow up the dynamics of high-energy phosphate concentrations in the same tissue. Ultrastructural changes were observed in the region of the proximal tubule. Some mitochondria showed degenerative changes, others increased density of cristae. The total number of mitochondria was increased. This observation together with the coexistence of vacuolarly degenerated mitochondria and mitochondria with increased activity after CSA treatment is interpreted as expression of a compensatory mechanism that keeps constant the totality of high-energy phosphates despite damage to some mitochondria.

Renal blood flow, glomerular filtration rate, and renal morphology in cyclosporine-induced acute renal failure in Munich-Wistar rats.

The mechanism of clinical cyclosporine nephrotoxicity has remained unclear. We have established an animal model of cyclosporine-induced acute renal failure in the male Munich-Wistar rat by giving four daily doses of parenteral cyclosporine 60 mg/kg intraperitoneally (IP). In this model, 20 minutes of bilateral renal ischemia preceding the first cyclosporine dose did not significantly increase the renal failure, but did increase mortality (65% v 17%), which was due in part to the CNS effect of cyclosporine. Pair-fed and pair-watered vehicle and saline controls were used. The renal morphologic changes induced by the castor oil vehicle of the commercial parenteral cyclosporine solution were quantitatively similar to those induced by cyclosporine, although the severity of the changes by light microscopy was considerably less in the vehicle-treated groups. However, by electron microscopy, pale lipid vacuoles were seen only in the cyclosporine-treated groups, whereas dense alterations in lysosomes and dilated endoplasmic reticulum were also seen in other groups. Renal blood flow determined by electromagnetic flow probe showed a significant decline during 2 hours after a single IP injection of cyclosporine (6.6 +/- 0.4 to 5.0 +/- 0.6 mL/min). A similar decline was seen following injection of the castor oil vehicle of the commercial cyclosporine parenteral preparation (6.6 +/- 0.5 to 5.1 +/- 0.5 mL/min), but not after an injection of a similar volume of mineral oil (6.7 +/- 0.3 to 6.3 +/- 0.2 mL/min). These studies suggest that brief renal ischemia does not increase cyclosporine nephrotoxicity significantly in this rat model.(ABSTRACT TRUNCATED AT 250 WORDS)

Methyl mercury and selenium interaction in relation to mouse kidney gamma-glutamyltranspeptidase, ultrastructure, and function.

The effects of methyl mercury (CH3Hg) and selenium (Se) on renal ultrastructure were investigated and correlated to changes in renal gamma-glutamyl transpeptidase (gamma-GTPase) activity, mercury (Hg) accumulation, and renal function (serum creatinine and urea nitrogen). Three experimental protocols were used to investigate CH3Hg and Se interactions of both Se-sufficient and Se-deficient mice involving ip injection of the following administered alone or in combination: CH3Hg (4.0 mg/kg) and Se (0.16 mg/kg) daily for 7 days, CH3Hg (1.0 mg/kg) and Se (0.08 mg/kg) daily for 20 days, and a single acute dose of CH3Hg (8.0 mg/kg). Acivicin (12 to 50 mg/kg), an antitumor glutamine antagonist, was also used as a highly effective specific inhibitor of the gamma-GTPase. Our results show that CH3Hg administered to Se-deficient mice for 7 or 20 days resulted in significant (p less than or equal to 0.05) but only moderate inhibition (20%) of gamma-GTPase activity and extensive renal ultrastructural damage. Acivicin-treated mice had significant inhibition of gamma-GTPase activity (80%) following a single injection while ultrastructural damage was substantial only after several days of administration. These results may indicate different modes of action of acivicin and CH3Hg. Acivicin inhibited gamma-GTPase prior to renal damage while CH3Hg produced greater pathological effects with only moderate gamma-GTPase inhibition. Renal damage from acute and chronic CH3Hg toxicity occurred after distinct neurological signs were present. Selenium administered to Se-deficient mice ameliorated both the neurotoxic effects and nephrotoxic action of CH3Hg. While Se and CH3Hg treatments caused some of the same ultrastructural pathology as the treatment with CH3Hg alone (cytoplasmic vacuolation, increased lysosomal profile, mitochondrial swelling, and extrusion of cellular masses into the tubular lumen), degeneration was not as extensive. Although the total doses administered during both the 7- and the 20-day studies were similar, mice from the chronic 20-day study showed greater ultrastructural pathological effects from CH3Hg. The primary effects of CH3Hg appeared to be on the lysosomal system, while acivicin exerted its effects on the mitochondrial and endoplasmic reticulum systems. The accumulation studies on Hg suggest that dietary Se may have only an initial protective effect against Hg accumulation in the kidney while injected Se offers longer protection.(ABSTRACT TRUNCATED AT 400 WORDS)

The electron density of light and dark lysosomes in the proximal convoluted tubule of the rat kidney.

The present paper deals with the electron density of the lysosomal matrices in the renal proximal-convoluted-tubule cells of Wistar rats (20-60 days of age). Its purpose was to determine which physicochemical factors influence the electron density of lysosomes, and how their electron density is affected by various methods of fixation.--3 types of lysosomes can be distinguished in the proximal-convoluted-tubule cell; namely light, intermediate and dark lysosomes, which have an electron density lower, equal to or higher than the surrounding cytoplasm. All 3 types of lysosomes were invariably present after all methods of fixation tested. Light, intermediate and dark lysosomes differ in several respects. Staining intensity with uranyl acetate, lead citrate and potassium permanganate, osmiophilia, basophilia (in semithin sections) and --probably most importantly--the physical mass density of the lysosomal matrix are all low in light lysosomes, higher in intermediate lysosomes and highest in dark lysosomes. Light, intermediate and dark lysosomes of the proximal convoluted tubule do not form discrete classes, but one continuous spectrum of lysosomes of increasing electron density.

Effect of potassium depletion on tubular morphology in gentamicin-induced acute renal failure in dogs.

Potassium deprivation has recently been reported to potentiate the degree of functional impairment in a gentamicin-induced model of acute renal failure. The present study investigated the effects of two different states of potassium homeostasis on the development of cellular injury in the early stage of gentamicin nephrotoxicity in dogs. Gentamicin (15 mg. per kg. intramuscularly twice daily) was administered for 4 and 7 days to potassium-depleted or potassium-supplemented animals. The results show that potassium supplementation markedly lessens the severity of pathologic alterations induced by gentamicin. In both groups of animals, the S1 and S2 segments of the proximal tubule were the most consistently damaged regions of of the nephron. Potassium-supplemented dogs had a significantly higher number of normal proximal tubule cells than did the animals deprived of potassium and viewed 7 days after gentamicin treatment (77.3 versus 36.9 per cent; p less than 0.025). The degree of total injury to the proximal tubule was significantly higher in potassium-depleted animals than in those supplemented with potassium (59.9 versus 21.9 per cent; p less than 0.05). Only those dogs depleted of potassium prior to the administration of gentamicin had a markedly elevated plasma creatinine level of proximal tubular injury and functional impairment (r = 0.81; p less than 0.005). Potassium supplementation appears to lessen the extent of structural alterations seen in this model of gentamicin-induced acute renal failure in dogs.

Renal changes in selenium-exposed fish.

A group of green sunfish was collected from a selenium-rich lake and compared with a similar group collected from a control lake upstream in the same drainage system in east Texas. Since the level of selenium in kidneys of these fish was relatively high (averaging 11 ppm on a fresh weight basis), histopathological and ultrastructural data were collected. Kidneys from fish from the selenium-rich lake showed proliferative glomerulonephritis and hematuria as well as vacuolation and necrosis of cells of the convoluted tubules.