Changes In Tubular Cells Research Articles

Hypoxia preconditioning increases the ability of healthy but not diabetic rat-derived adipose stromal/stem cells (ASC) to improve histological lesions of streptozotocin-induced diabetic nephropathy

BackgroundMesenchymal stromal cells (MSC) have demonstrated ability to improve diabetic nephropathy (DN) in experimental models, as well as by improving kidney endogenous progenitor cells proliferation and differentiation. Many studies have demonstrated the effect of hypoxia on MSC improving their functionality but the potential enhancement of the nephroprotective properties of MSC cultured under low oxygen concentration has been explored in few studies, none of them in the context of DN. On the other hand, diabetes is associated with abnormalities in MSCs functionality. These findings related to the hypoxia preconditioning ability to enhance adipose-tissue derived-MSC (ASC) performance have led us to wonder if hypoxia could increase the known beneficial effect of normal ASC in DN and if it could correct the expected inability of diabetic rat-derived ASC to exert this effect in vivo. To answer these questions, in the present study we have used ASC from healthy and diabetic-induced rats, cultured under standard conditions or hypoxia preconditioned, in a DN rat model induced by streptozotocin (STZ). MethodsDiabetes was induced in Wistar-rats by 60 mg/kg streptozotocin (STZ) intraperitoneal injection. Fifteen days thereafter, five diabetic-induced rats and five healthy, previously injected with saline, were sacrificed and used as ASC donors . Both healthy and diabetic rat-derived ASC (cASC and dASC, respectively) were cultured under standard conditions (21%O2)(N) or were subjected to a 48 h conditioning period in hypoxia (3%O2)(H). Thus, four types of cells were generated depending on their origin (healthy or diabetic-induced rats) and the culture conditions(N or H):cASC-N, cASC-H, dASC-N and dASC-H. DN experimental study were carried out fifteen days after STZ induction of diabetes in fifty-two healthy rats. DN-induced-animals were randomly assigned to be injected with 200 µL saline as placebo or with 3 × 106 cASC-N, cASC-H, dASC-N or dASC-H, according to the study group. Serum glucose, urea and creatinine, and urine albumin levels were measured at 2-weeks intervals until day+ 45 after ND-induction.Animals were sacrificed and kidneys extracted for histopathological and transmission electron microcopy analysis ResultsNone of the four study groups that received cell treatment showed significant changes in serum glucose, urea and creatinine levels, urine albumin concentration and body weight compared to placebo ND-induced group. Interestingly, only the group that received cASC-H showed a reduction in glucose and creatinine levels although it did not reach statistical significance.All DN-induced groups treated with ASC reduced significantly renal lesions such as mesangial expansion, mesangiolysis, microaneurysms and acute tubular necrosis compared to ND-induced placebo group (p ≤ 0.05). Renal injuries such as clear tubular cell changes, thickening of tubular basement membrane, tubular cysts and interstitial fibrosis significantly showed reduction in ND-induced rats treated with cASC-H regarding to their received cASCN (p ≤ 0.05). Non statistical differences were observed in the improvement capacity of cASC and dASC culture under standard condition.However, hypoxia preconditioning reduces the presence of tubular cysts (p ≤ 0.01). ConclusionsHypoxia preconditioning enhances the ability of healthy rat-derived ASC to improve kidney injury in a rat model of DN. Moreover, diabetic-derived ASC exhibits a similar ability to healthy ASC which is clearly more than expected, but it is not significantly modified by hypoxia preconditioning.

POS-385 CXCR2 Plays a Role in Promoting Renal Fibrosis by Accelerating Tubular Cell Senescence

Renal fibrosis is the common pathologic feature for all kinds of chronic kidney diseases (CKD). The premature aging in renal tubular cells plays an important role in the progression of renal fibrosis. However, the underlying mechanisms of tubular senescence have not been elucidated. In this study, we explored the role of CXCR2 in tubular senescence. The expression of CXCR2 in the kidneys of various CKD animal models was assessed. Mitochondrial function, tubular cellular senescence, and renal fibrosis were analyzed in CXCR2-overexpressed or IL-8, a CXCR2 ligand-treated CKD mice and tubular cells. A siRNA strategy or specific inhibitor to CXCR2 was also adopted. CXCR2 was highly upregulated in various CKD models, and colocalized with the senescence-related protein p16INK4A. CXCR2 expression was level intimately correlated with the extent of renal fibrosis, mitochondrial dysfunction, and p16INK4A expression. Furthermore, ectopic expression of CXCR2 in unilateral ischemia-reperfusion injury (UIRI) and unilateral ureteral obstruction (UUO) induced further damage of mitochondrial function and exacerbated renal fibrosis. Activation of CXCR2 via the ligand, IL-8 binding exacerbated tubular senescence, and mitochondrial dysfunction which were evidenced by decrease in mitochondrial biogenesis-related transcription factors peroxisome proliferator-activated receptor-coactivator-1α (PGC-1α) and transcription factor A, mitochondrial (TFAM), increase in p16INK4Aexpression and senescence-associated β-galactosidase (SA-β-gal) activity in vivo and vitro. Conversely, SB225002, a specific inhibitor of CXCR2, repressed UUO-induced renal fibrosis and impeded senescence in cultured tubular epithelial cells. In UIRI mice, CXCR2-accelerated renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4A. Overexpression of CXCR2 remarkably downregulated expressional levels of PGC-1α and TFAM, but upregulated levels of senescence-related p16INK4A and γH2AX, and promoted fibrosis-related morphology changes in tubular cells. Thus, CXCR2 drives renal fibrosis through inducing tubular senescence. The underlying mechanism is related to its regulation on mitochondrial dynamic. Although the more specific signaling mechanisms need to be clarified, our study still provides an important clue showing CXCR2 as a potential target for the prevention and treatment of CKD.

MO063CHRONIC INTERSTITIAL NEPHRITIS IN AGRICULTURAL COMMUNITIES IS A TOXIN-INDUCED PROXIMAL TUBULAR NEPHROPATHY

Abstract Background and Aims 30 years after the detection of CINAC, there is no consensus on its etiology. Heat stress/dehydration and toxic exposure are the two most likely etiologies. There are no diagnostic criteria that can directly identify CINAC patients. Method Renal biopsies (RB) (18 Sri Lanka, 10 El Salvador, 1 India, 3 France) of patients with CINAC (CKD2-3) were examined by light (LM) and electron microscopy (EM) in comparison to RB of normal kidneys at implantation and 6 and 12 months of calcineurin inhibitor (CNI) therapy, transplant patients on CNI with indication biopsies (n=24), proteinuric nephropathies (n=15), light chain disease (n=4), cases on nephrotoxic drugs (lomustine, clomiphene, lithium, tenofovir, cisplatinum) and CKD of various causes (n=20). A rat study was conducted comparing histopathology of heat stress/dehydration with cyclosporine nephrotoxicity. Results In addition to previously described histopathological changes, there was a unique constellation of proximal tubular cell (PTC) findings: cellular/tubular atrophy, cell fragment shedding, weak to non-proliferative capacity of the PTC and dysmorphic lysosomes increased in size and number with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound “aggregates”. Identical renal lesions were observed in 55-80% of renal transplant protocol biopsies taken after 6 and 12 months of calcineurin inhibitor (CNI) therapy and in indication biopsies, in implantation biopsies the prevalence was 6%. Several cases of nephrotoxic drugs (lomustine, clomiphene, lithium) and a subset of patients with light chain disease, all conditions that can be linked to CNI, presented the same lesion. Control RBs (n=66) of normal kidney, toxic nephropathies (tenofovir, cisplatinum), and overt proteinuric patients of different etiology to some extent could demonstrate the tubular cell changes observed by LM, but not or very rarely those that were observed by EM. Rats treated with cyclosporine for 4 weeks developed similar PTC lysosomal alterations, absent in a dehydration group. Conclusion A sensitive constellation of renal PTC lesions was detected associated with CINAC and CNI nephrotoxicity in several countries, suggesting a common new paradigm where CINAC patients are experiencing a tubulotoxic mechanism similar to CNI nephrotoxicity, the latter also being known as a direct or suggested indirect effect of pesticides.

Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy

Almost 30 years after the detection of chronic interstitial nephritis in agricultural communities (CINAC) its etiology remains unknown. To help define this we examined 34 renal biopsies from Sri Lanka, El Salvador, India and France of patients with chronic kidney disease 2-3 and diagnosed with CINAC by light and electron microscopy. In addition to known histopathology, we identified a unique constellation of proximal tubular cell findings including large dysmorphic lysosomes with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound "aggregates". These aggregates associated with varying degrees of cellular/tubular atrophy, apparent cell fragment shedding and no-weak proximal tubular cell proliferative capacity. Identical lysosomal lesions, identifiable by electron microscopy, were observed in 9% of renal transplant implantation biopsies, but were more prevalent in six month (50%) and 12 month (67%) protocol biopsies and in indication biopsies (76%) of calcineurin inhibitor treated transplant patients. The phenotype was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine) and in some patients with light chain tubulopathy, all conditions that can be directly or indirectly linked to calcineurin pathway inhibition or modulation. One hundred biopsies of normal kidneys, drug/toxin induced nephropathies, and overt proteinuric patients of different etiologies to some extent could demonstrate the light microscopic proximal tubular cell changes, but rarely the electron microscopic lysosomal features. Rats treated with the calcineurin inhibitor cyclosporine for four weeks developed similar proximal tubular cell lysosomal alterations, which were absent in a dehydration group. Overall, the finding of an identical proximal tubular cell (lysosomal) lesion in CINAC and calcineurin inhibitor nephrotoxicity in different geographic regions suggests a common paradigm where CINAC patients undergo a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity.

Histopathological Changes and Antioxidant Enzymes Status in Oxidative Stress Induction Using Sodium arsenite in Rats

Introduction: Arsenic toxicity has posed troublesome health concerns in the world and many of the toxic effects of arsenic are related to its effect on oxidative stress. The aim of the present study is to evaluate histopathological and antioxidant enzymes changes in oxidative stress status induced by sodium arsenite in rats. Materials and Methods: All experiments were carried out in male Wistar rats. Animal were divided into 2 groups of eight animals in each: Rats consumed distilled water (control group). Group 2: Rats consumed a solution of sodium arsenite (100 ppm) daily (arsenic group). At the end of day 28 arsenic exposure, the enzyme level in rat liver and kidney tissues was measured using the assay kits. The remaining liver, kidney, and heart tissue were fixed in 10% neutral-buffered formalin and used for histological observation. Results: The results showed a significant decrease in values of glutathione peroxidase (GPx), superoxide dismutase (SOD), total antioxidant capacity (TAC) and catalase (CAT) in serum and tissue in kidney and liver rat (P < 0.05). But, malondialdehyde (MDA) levels were increased significantly (P < 0.05). Arsenic caused severe degenerative changes in tubular cells and acute tubular necrosis, hepatocyte cell degeneration, severe hemorrhage, and infiltration and formation of Kupffer cells nodules, fragmentation, and degeneration of muscle fibers with pyknotic nuclei in heart tissue. Conclusions: The finding of the present study revealed that the administration of Sodium arsenite caused significant oxidative stress, decreased antioxidant enzymes activity and severe tissue damage.

Unique proximal tubular cell injury and the development of acute kidney injury in adult patients with minimal change nephrotic syndrome

BackgroundAdult patients with minimal change nephrotic syndrome (MCNS) are often associated with acute kidney injury (AKI). To assess the mechanisms of AKI, we examined whether tubular cell injuries unique to MCNS patients exist.MethodsWe performed a retrospective analysis of clinical data and tubular cell changes using the immunohistochemical expression of vimentin as a marker of tubular injury and dedifferentiation at kidney biopsy in 37 adult MCNS patients. AKI was defined by the criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI.ResultsThirteen patients (35.1%) were designated with AKI at kidney biopsy. No significant differences in age, history of hypertension, chronic kidney disease, diuretics use, proteinuria, and serum albumin were noted between the AKI and non-AKI groups. Urinary N-acetyl-β-D-glucosaminidase (uNAG) and urinary alpha1-microglobulin (uA1MG) as markers of tubular injury were increased in both groups, but the levels were significantly increased in the AKI group compared with the non-AKI group. The incidence of vimentin-positive tubules was comparable between AKI (84.6%) and non-AKI (58.3%) groups, but vimentin-positive tubular area per interstitial area was significantly increased in the AKI group (19.8%) compared with the non-AKI group (6.8%) (p = 0.011). Vimentin-positive injured tubules with tubular simplification (loss of brush-border of the proximal tubule/dilated tubule with flattening of tubular epithelium) were observed in the vicinity of glomeruli in both groups, suggesting that the proximal convoluted tubules were specifically injured. Two patients exhibited relatively severe tubular injuries with vimentin positivity and required dialysis within 2 weeks after kidney biopsy. The percentage of the vimentin-positive tubular area was positively correlated with uNAG but not with uA1MG in the non-AKI group.ConclusionsProximal tubular injuries with increased uNAG exist in MCNS patients without renal dysfunction and were more severe in the AKI group than they were in the non-AKI group. The unique tubular injuries probably due to massive proteinuria might be a predisposing factor for the development of severe AKI in adult MCNS patients.

Renal tubular Notch signaling triggers a prosenescent state after acute kidney injury

The aging kidney has a diminished regenerative potential and an increased tendency to develop tubular atrophy and fibrosis after acute injury. In this study, we found that activation of tubular epithelial Notch1 signaling was prolonged in the aging kidney after ischemia/reperfusion (IR) damage. To analyze the consequences of sustained Notch activation, we generated mice with conditional inducible expression of Notch1 intracellular domain (NICD) in proximal tubules. NICD kidneys were analyzed 1 and 4 wk after renal IR. Conditional NICD expression was associated with aggravated tubular damage, a fibrotic phenotype, and the expression of cellular senescence markers p21 and p16(INK4a). In wild-type mice pharmacological inhibition of Notch using the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) improved tubulo-interstitial damage and antagonized the prosenescent pathway activation after IR. In vitro, activation of Notch signaling with delta-like-ligand-4 caused prosenescent changes in tubular cells while inhibition with DAPT attenuated these changes. In conclusion, our data suggest that sustained epithelial Notch activation after IR might contribute to the inferior outcome of old kidneys after injury. Sustained epithelial activation of Notch is associated with a prosenescent phenotype and maladaptive repair.

Polyol pathway and diabetic nephropathy revisited: Early tubular cell changes and glomerulopathy in diabetic mice overexpressing human aldose reductase.

Aims/Introduction: The polyol pathway has long been involved in the pathogenesis of diabetic nephropathy. It remains still unclear, however, how the polyol pathway is implicated in this process. We explored the effects of the enhanced polyol pathway on renocortical tubular cells and glomeruli in experimentally-induced diabetes. Transgenic mice (Tg) overexpressing human aldose reductase were made diabetic by streptozotocin and followed for 8 weeks. Renocortical pathology, expressions of tonicity-responsive enhancer binding protein (TonEBP) and carboxymethyllysine of advanced glycation end-products, were examined. Wild-type non-transgenic mice (Wt) were also made diabetic and served as controls. Diabetic Tg showed augmented expression of TonEBP in renocortical tubular cells with vacuolated degenerative changes. These structural changes were associated with pronounced deposition of carboxymethyllysine. There was a significant increase in kidney weight, glomerular size, and mesangial area in diabetic animals and there was a trend for more severe changes in these measures in diabetic transgenic mice compared with those in control diabetic mice. Treatment with aldose reductase inhibitor significantly prevented polyol accumulation, mesangial expansion and expressions of TonEBP and carboxymethyllysine in diabetic Tg, but its effects on the renal structure were equivocal in control diabetic Wt. Our findings suggest that tubuloglomerular change might contribute to early diabetic nephropathy under the influence of the enhanced polyol pathway. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00071.x, 2010).

Myoglobin Induces Vascular Cell Adhesion Molecule-1 Expression through c-Src Kinase-Activator Protein-1/Nuclear Factor-ĸB Pathways

Background/Aims: It is not clear whether a sublethal dose of myoglobin induces some pathophysiological changes in tubular cells, potentially affecting tubular injury or tubular regeneration. We investigated the effect of a low dose of myoglobin on vascular cell adhesion molecule-1 (VCAM-1) expression and elucidated the underlying signaling pathways. We further examined the effect of losartan and simvastatin on myoglobin-induced VCAM-1 expression and the signaling pathways. Methods: Activation of nuclear factor (NF)-ĸB and activator protein (AP)-1 was assessed by electrophoretic mobility shift assay. Phosphorylation of protein kinases was examined by Western blot analysis. VCAM-1 mRNA and protein were measured by Northern blot analysis and cell ELISA. Results: A sublethal dose of myoglobin (100 µg/ml) induced VCAM-1 expression via activation of AP-1 and NF-ĸB, which was mediated through activation of c-Src kinase, followed by mitogen-activated protein kinases (p38, ERK 1/2, JNK-1) and the IĸB kinase – IĸB-α. Inhibitors of protein kinase C and tyrosine kinase, antioxidants and intracellular calcium chelator suppressed myoglobin-induced activation of c-Src kinase. Losartan and simvastatin suppressed myoglobin-induced VCAM-1 expression via inhibition of c-Src kinase. Conclusion: VCAM-1 expression via c-Src kinase-AP-1/NF-ĸB pathways might be one of the possible mechanisms linking myoglobin to tubular injury. Losartan and simvastatin might be beneficial in attenuating myoglobin-induced tubular injury.

BK Virus–Associated Nephropathy in a Patient With AIDS

The BK virus is a ubiquitous member of the group of human polyoma viruses that commonly is reactivated in the setting of immunosuppression related to renal transplantation, which results in tubulointerstitial nephritis and allograft dysfunction. BK virus-associated nephropathy occurring in association with human immunodeficiency virus infection and acquired immunodeficiency syndrome (AIDS) was reported only rarely. We describe the case of a 43-year-old man with AIDS presenting with nonoliguric renal failure. The renal biopsy specimen showed tubulointerstitial nephritis and renal tubular cell changes consistent with BK viral inclusions. Results of in situ hybridization for BK viral DNA were positive and showed tubular cell intranuclear inclusions. To our knowledge, this represents the third case of AIDS-associated BK virus-associated nephropathy diagnosed by means of biopsy.

Generation and Evolution of Atubular Glomeruli in the Progression of Renal Disorders

Functional nephrons can be lost through a process of glomerulotubular disconnection. Progressive development of atubular glomeruli seems to play a major role in a number of renal disorders, including glomerular diseases, ascribed to injury to the glomerulotubular junction as a result of proteinuria; however, formation of atubular glomeruli is even more common in tubulointerstitial disorders, such as obstructive nephropathy. Toxic nephropathy is also associated with the formation of atubular glomeruli, suggesting susceptibility of the glomerulotubular junction to toxic injury. Narrowing or other abnormalities of the glomerulotubular junction are described as precursors of glomerulotubular disconnection. Cystinosis represents a dramatic example of progressive injury to the glomerulotubular junction, with formation of the "swan-neck deformity" following degenerative tubular cell changes attributable to apoptosis. Significant numbers of atubular glomeruli have been reported in chronic pyelonephritis and renal allograft rejection; this suggests interstitial inflammation as a stimulus for the formation of atubular glomeruli. Because of difficulties in morphologic recognition, it is likely that glomerulotubular disconnection is an underappreciated mechanism in the progression of renal disease. A better understanding of the vulnerability of the glomerulotubular junction and its protection from injury should lead to better strategies for preserving renal function in many nephropathies.

The Effect of Angiotensin II Receptor Blockade on an End-Stage Renal Failure Model of Type 2 Diabetes

The effect of olmesartan medoxomil (OLM), an angiotensin II receptor blocker (ARB), on advanced nephropathy and mortality was evaluated in Zucker Diabetic Fatty (ZDF) rats, a type 2 diabetes model. OLM was administered from 36 weeks of age, when the animals developed advanced proteinuria. OLM effectively suppressed the progression of proteinuria. The ZDF rats started to die at 50 weeks of age, which was accompanied by abrupt increase in blood urea nitrogen, suggesting that the cause of death was renal insufficiency. OLM suppressed increases in blood urea nitrogen and increased the survival rate of the ZDF rats. The histological examination revealed that the renal damage was ameliorated by OLM. The macrophage infiltration and monocyte chemoattractant protein-1 (MCP-1) expression was increased in the glomeruli and tubulointerstitium of the ZDF rat kidneys, and the increase was lessened by OLM. In a separate study, albumin increased MCP-1 release from cultured tubular epithelial cells. These results suggest that protein leakage from the glomeruli stimulates MCP-1 production in tubular cells and that MCP-1 released into the interstitial space induces macrophage infiltration and inflammation. It is conceivable that the beneficial actions of ARB on diabetic nephropathy are, at least in part, due to decrease of proteinuria and the subsequent reduction of inflammatory changes in tubular cells.

Morphologic changes in tubular cells from in situ kidneys following experimental hypothermia and rewarming

Although renal failure may occur following rewarming from deep accidental hypothermia, this subject has received little attention in experimental hypothermia and clinical case reports. In order to explore the integrity of hypothermic and posthypothermic renal morphology we used an experimental animal model of accidental hypothermia where the heart supports the circulation throughout cooling and rewarming without accompanying cardioplegia or ischemia. Ultrastructural changes in renal tubular cells from three groups of pentobarbital anesthetized Wistar rats: 1) controls (n=6) maintained at 37 degrees C for 4 h, 2) hypothermic rats (n=6) core-cooled and maintained at 15-13 degrees C for 4 h, and 3) rewarmed rats (n=10), were studied as a sensitive indicator of renal damage. Electron micrographs (EM) from hypothermic kidneys showed rounded up mitochondria with loss of contrast. These changes were observed in several though not all of the biopsies, but they were found in all kidneys. Areas exhibiting focal tubular necrosis were seen on most EM from three of these kidneys. EM from rewarmed kidneys showed alterations of mitochondrial ultrastructure with similarities to those observed after hypothermia, but in general the changes were more prominent. Extracellular edema, intracellular edema, swelling of mitochondria, margination of chromatin, necrosis of single tubular cells, and disrupting necrotic debris into tubular lumen could be found in micrographs from 7 of the 10 kidneys examined. Rewarming from experimental hypothermia, without episodes of ischemia or hypoxia, thus induces ultrastructural changes in renal tubular cells similar to changes observed in acute tubular necrosis, associated with renal failure.

Human immunodeficiency virus and IgA nephropathy

Summary: IgA nephropathy (IgAN) in human immunodeficiency virus (HIV)‐infected patients has been described with increasing frequency. In contrast to HIV‐associated nephropathy, with collapsing variant of focal and segmental glomerulosclerosis and prominent tubular cell changes, a disorder which is more common in black persons, IgAN is a disease mainly of white patients. Most are asymptomatic carriers of HIV although few have acquired immunodeficiency syndrome (AIDS) or ARC at the time the renal disorder is discovered. The clinical manifestations are generally of haematuria, sometimes with proteinuria. In some patients, the finding of IgA reactive with anti‐HIV IgG or IgM in circulating immune complexes and in glomerular eluates strongly suggests this glomerulopathy to be an HIV‐associated immune complex disorder. Because of the demographic factors, IgAN may evolve to be an important renal lesion in HIV infection.

Reversible changes of tubular cell and basement membrane in drug-induced renal cystic disease

To delineate changes in the development and regression of renal cystic disease, sequential studies were done in rats fed 2-amino-4,5-diphenyl thiazole (DPT). Kidneys were perfusion fixed with either aldehyde fixative alone or with the addition of ruthenium red (RR). Tissues were processed for light and electron microscopy. Light microscopy sections were stained with alcian blue and eosin and hematoxylin. Initially, cellular proliferation and, later, cystic transformation of collecting tubules were observed. The structural changes in tubular cells preceded alterations in the basement membrane and consisted of an increase in smooth and rough endoplasmic reticulum and free polyribosomes, prominence of Golgi complexes, and an increased number of lysosomes. These findings are suggestive of changes in the biosynthetic, secretory, and degradative mechanisms of the cell. With time, the tubular basement membranes became progressively thicker and laminated with concomitant loss of alcian-blue- and RR-staining. When DPT-treated animals with renal cystic disease were placed on a normal diet, tubular cell and basement membrane morphology and alcian-blue- and RR-staining returned to normal and cystic changes regressed. These findings are compatible with altered synthesis and degradation of tubular basement membranes in this model of cystic disease.

Lithium-induced nephropathy in rat. Light and electron microscopic studies.

Lithium carbonate was used intraperitoneally to produce an experimental model of renal lesion in Wistar rats. When injected in smaller doses it resulted in proximal tubule cell damage, whereas higher doses produced both proximal and distal tubular cell changes followed by a progressive glomerular lesion. It has also been demonstrated that smaller doses of lithium carbonate, in the presence of serum sickness, resulted in a severe progressive glomerulo-nephritis and proximal tubule cell damage. The probable underlying mechanism responsible for the glomerular and tubular lesions is also discussed.