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H D Humes

Publications and source records attributed to H D Humes.

At least 19 recordsLinked to original sources
PubMed1992

Interaction between growth factors and retinoic acid in the induction of kidney tubulogenesis in tissue culture.

Kidney tubulogenesis is the initial step in renal organogenesis. The precise molecular determinants of this pattern formation are presently unknown, although soluble factors, such as growth factors, and insoluble factors, such as extracellular matrix molecules, most likely play fundamental roles in this process. To define the molecular determinants of renal proximal tubule morphogenesis, primary cultures of rabbit renal proximal tubule cells in hormonally defined, serum-free media were treated with transforming growth factor-beta 1 (TGF-beta 1), epidermal growth factor (EGF), and the retinoid, all trans-retinoic acid (RA), singly or in combination. Utilizing phase contrast and light and transmission electron microscopy, the simultaneous administration of TGF-beta 1 (10 ng/ml), EGF (1 nM), and RA (0.1 nM) transformed a confluent monolayer of renal proximal tubule cells within 5 to 6 days into three-dimensional cell aggregates containing lumens within the interior of the cell clusters. The lumens were bordered by tubule cells possessing a polarized epithelial cell phenotype with extensive microvilli formation and tight junctional complexes along the luminal border. All three factors were necessary and sufficient to induce this phenotypic transformation. Further studies demonstrated that RA promoted the deposition of the A and B1 chains of laminin, a cell attachment protein of the basement membrane, in a small subset of proximal tubule cells in culture, as deduced by indirect immunofluorescent microscopy. Additional studies demonstrated that soluble purified laminin fully substituted for RA in this system to promote renal tubulogenesis when combined with TGF-beta 1 and EGF. These results demonstrate that the growth factors, TGF-beta 1 and EGF, and the retinoid, RA, promote tubulogenesis in adult renal proximal tubule cells in tissue culture in a manner reminiscent of inductive embryonic kidney morphogenesis. These observations define a coordinated interplay between growth factors and retinoids to induce pattern formation and morphogenesis. Furthermore, the demonstration of RA-induced laminin deposition as a critical event in this morphogenic process identifies laminin as a possible target protein for RA to act as a morphogen.

Animals↗
PubMed1992

Triiodothyronine enhances renal tubule cell replication by stimulating EGF receptor gene expression.

Thyroid hormone is known to accelerate renal function recovery following toxic acute renal failure. Because epidermal growth factor (EGF)-receptor activation is most likely critical in renal replicative repair, these studies were undertaken to assess whether triiodothyronine (T3), the most active form of thyroid hormone, may modulate EGF-induced renal proximal tubule cell proliferation by an effect on the EGF receptor. Rabbit renal proximal tubular cells were grown in primary culture and treated with or without T3 (0.1 or 1.0 nM) for 24 to 48 h. Compared with nontreated controls, T3 exposure led to significant increases in EGF-promoted DNA synthesis, as measured by [3H]thymidine incorporation, in renal tubule cells. Furthermore, T3 treatment resulted in increases in EGF receptor mRNA in proximal tubule cells compared with nontreated cells and was associated with elevated numbers of EGF receptors on the cell surface of proximal tubule cells. EGF binding studies demonstrated that T3 treatment had only modest effects on Kd values of both the high-affinity binding site (0.19 nM) and the low-affinity binding site (3.7 nM) but substantially increased the maximal number of high-affinity sites from 3.8 x 10(3) to 9.4 x 10(3) receptors/cell and the maximal number of low-affinity sites from 132 x 10(3) to 199 x 10(3) receptors/cell. These findings suggest that a T3 effect to increase EGF receptor gene expression with resulting increases in the number of cell surface EGF receptors on renal proximal tubule cells and a potentiated mitogenic response to EGF may be a mechanism for thyroid hormone to enhance renal function recovery following toxic acute renal failure.

Animals↗
PubMed1991

Calcium and acute renal failure.

Tubular cell calcium concentration and content rise following acute renal injury induced by ischemic and toxic insults. Since calcium plays a critical role in many cell functions and the proximal tubule appears to be a major site of injury in acute renal failure, it is possible that cell calcium overload plays a direct role in the pathogenesis of acute renal failure. Tubular cell calcium overload has been associated with altered function at the level of the plasma membrane, mitochondria, endoplasmic reticulum and cytoskeleton. While there is evidence to support a role for calcium in acute renal injury, the importance of cell calcium overload needs to be further explored. Furthermore, alterations in extracellular calcium and mineral metabolism may be involved in some aspects of acute renal failure and recovery. Calcium channel blockers and other interventions designed to modulate calcium changes may have a role in the treatment of acute renal failure.

Acute Kidney Injury↗
PubMed1991

Effects of transforming growth factor-beta, transforming growth factor-alpha, and other growth factors on renal proximal tubule cells.

Transforming growth factor (TGF)-alpha, epidermal growth factor (EGF), and insulin-like growth factor-1 (IGF-1) addition to quiescent, confluent monolayers of rabbit renal proximal tubule cells in primary culture stimulated [3H]thymidine incorporation. TGF-alpha and EGF promoted a 14-fold rise in thymidine incorporation over control levels with half-maximal responses at 2 x 10(-9) M. IGF-1 only promoted a 4-fold rise in thymidine incorporation compared with control values with a half-maximal response of 10(-8) M. Platelet-derived growth factor alone did not stimulate [3H]thymidine incorporation and did not potentiate the effects of EGF or IGF-1 on DNA synthesis, suggesting that platelet-derived growth factor is neither a competence nor a progression growth factor for renal proximal tubule cells. TGF-beta inhibited both baseline and EGF-stimulated [3H]thymidine incorporation after 48 hours of exposure but enhanced EGF-stimulated DNA synthesis at 24 hours. Morphologic evaluation with phase contrast microscopy, scanning, and transmission electron microscopy demonstrated that TGF-beta promoted a dramatic phenotypic transformation of the epithelial monolayer with migration and adhesion of the cells to form solid clusters of adherent cells. Quantitative morphometry demonstrated that this transformation developed 24 hours after TGF-beta exposure, was nearing completion after 48 hours of TGF-beta treatment, and correlated to TGF-beta related inhibition of EGF-induced DNA synthesis (r = -0.82, p less than 0.01). These results demonstrate that EGF and TGF-alpha are the most potent growth promoters for renal proximal tubule cells. IGF-1 is only a modest growth promoter, whereas platelet-derived growth factor has no effect either as a competence or progressive growth factor. TGF-beta inhibited EGF-induced DNA synthesis but only after observable phenotypic transformation of the cells. The degree of TGF-beta promoted transformation on renal tubule cells was highly correlative to th e antiproliferative effect of TGF-beta, suggesting that similar molecular components which promote this phenotypic transformation may also be critical in the antiproliferative effect of TGF-beta.

Animals↗
PubMed1990

Epidermal growth factor accelerates renal repair in mercuric chloride nephrotoxicity.

Repair and recovery of ischemic or nephrotoxic acute renal failure (ARF) are dependent upon renal tubule cell regeneration. Because epidermal growth factor (EGF) is a potent growth promoter to renal tubule cells, experiments were undertaken to assess the effects of exogenous administration of EGF during the recovery phase of HgCl2-induced ARF. Rats were administered HgCl2 (5 mg/kg sc), and [3H]thymidine incorporation into renal tissue and blood urea nitrogen (BUN) and serum creatinine concentrations were measured at various times after toxin administration. EGF (20 microgram) was administered subcutaneously 2 or 4 h after HgCl2 injection. Exogenous EGF resulted in greater levels of renal [3H]thymidine incorporation into renal proximal tubule cells compared with those observed in nontreated animals at several time points in the first 48 h after toxic injury. Morphometric analysis of histoautoradiograph sections of renal tissue demonstrated that greater than 96% of labeled cells were tubular in all examined sections. This EGF-related acceleration in DNA synthesis was associated with significantly lower peak BUN and serum creatinine levels, averaging 213 +/- 23 and 6.54 +/- 0.72 (SE) mg/dl, respectively, at 3 days in EGF-treated nephrotoxic rats compared with peak levels of 359 +/- 40 and 9.92 +/- 1.67 mg/dl (P less than 0.001, n = 7-16) at 5 days in non-EGF-treated nephrotoxic rats. EGF treatment also was associated with a return to near normal BUN and serum creatinine levels approximately 4 days earlier than that observed in non-EGF-treated animals. These findings demonstrate that exogenous EGF accelerates the repair process of the kidney after a severe toxic insult.

Acute Kidney Injury↗
PubMed1990

Comparison of toxicity of radiocontrast agents to renal tubule cells in vitro.

We have previously reported that radiocontrast agents induce direct renal tubule cell toxicity in vitro. The observed toxic effects were markedly potentiated by concomitant hypoxia. In addition, we have reported that the ionic radiocontrast agent diatrizoic acid is more toxic than the nonionic radiocontrast agent iopamidol in this system. Using suspensions enriched in rabbit renal proximal tubule segments, we compared the direct toxicities of the ionic dimeric ioxaglic acid to the nonionic monomeric compound iopamidol. Toxicity was assessed by comparing tubule potassium and calcium content, ATP levels, and respiratory rates after exposure to clinically achievable concentrations of radiocontrast agents. Ioxaglate (25 mM) produced significant declines in tubule cation content and respiratory rate with 30 min of hypoxia followed by 60 min of reoxygenation compared to molar-equivalent concentrations of iopamidol under similar conditions. Meglumine, a cationic compound frequently present in ionic contrast agent solutions, and ioxaglate tubule toxicity was additive. Iopamidol and ioxaglate exhibited similar tubule cell toxicity when comparison was based on iodine content. These experimental results suggest that the intrinsic nephrotoxic potential of ioxaglic acid is greater than that of iopamidol on a molar basis, but that the nephrotoxic potential of the two radiocontrast agents is similar when comparison is based upon iodine content.

Adenosine Triphosphate↗
PubMed1989

The role of free fatty acids in hypoxia-induced injury to renal proximal tubule cells.

Phospholipase activation with resulting phospholipid breakdown and lipid byproduct accumulation may play a critical role in hypoxic cell injury. To explore this role, mildly hypoxic rabbit renal proximal tubules (PT) in suspension were treated in vitro with exogenous phospholipase A2 (PLA2). This treatment produced severe tubule cell injury measured by alterations in tubule cation homeostasis, respiratory rates, and adenosine nucleotide metabolism. This injury was associated with loss of the major membrane phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), with accumulation of lipid byproducts, lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), and free fatty acids (FFA). Addition of fatty acid-free bovine serum albumin (BSA) to PTs reduced markedly FFA levels and improved significantly derangements in metabolic parameters of hypoxic PTs treated with exogenous PLA2, suggesting that FFA accumulation was a critical factor in this injury process. Effects of increasing durations of hypoxia (30, 45, and 60 min) with or without reoxygenation recovery demonstrated increased FFA levels, especially polyunsaturated FFA, which correlated better with the degree of hypoxic injury than alterations in membrane phospholipid and lysophospholipid levels. PTs undergoing hypoxia and reoxygenation recovery exposed to BSA were not protected. Although 60 min of hypoxia with 60 min reoxygenation produced accumulation of FFA to levels nearly identical to those seen in hypoxic PTs treated with exogenous PLA2 and BSA, with a similar distribution of various FFA species, hypoxia/reoxygenation produced a more severe degree of cell injury than that observed with hypoxia plus exogenous PLA and BSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure.

To determine the timing and location of renal cell regeneration after ischemic injury to the kidney and to assess whether exogenous epidermal growth factor (EGF) enhances this regenerative repair process to accelerate recovery of renal function, experiments were undertaken in rats undergoing 30 min of bilateral renal artery clamp ischemia followed by reperfusion for varying time intervals. Renal cell regeneration, as reflected by incorporation of radiolabeled thymidine within the kidney, began between 24 to 48 h and reached a peak at 72 h after renal ischemia. As demonstrated by histoautoradiography, renal thymidine incorporation was essentially confined to tubule cells. Morphometric analysis of histoautoradiograph sections of renal tissue demonstrated that the majority of labeled cells were found in renal cortex, but some labeled cells were also located in the inner stripe of the outer medulla, suggesting that injury to medullary thick ascending limbs also occurs in this ischemic model. Exogenous EGF administration produced increases in renal thymidine incorporation compared with non-treated animals at 24, 48, and 72 h after ischemic injury. This accelerated DNA replicative process was associated with significantly lower peak blood urea nitrogen (BUN) and serum creatinine levels, averaging 63 +/- 20 and 3.1 +/- 0.4 mg/dl in EGF-treated ischemic rats compared with 149 +/- 20 and 5.1 +/- 0.1 mg/dl, respectively, in nontreated ischemic rats, and was also associated with a return to near normal BUN and serum creatinine levels in EGF-treated animals approximately 4 d earlier than that observed in nontreated animals. This report is the first demonstration that EGF accelerates the repair process of a visceral organ after an injurious insult.

Acute Kidney Injury↗
PubMed1988

Interactions of cyclosporine with renal proximal tubule cells and cellular membranes.

Cyclosporine-induced nephrotoxicity is a limiting factor in the clinical use of cyclosporine. Since the manner in which cyclosporine interacts with proximal tubule cells and their membranes may provide insight into the cellular pathophysiology of cyclosporine toxicity, experiments were undertaken to characterize the interactions of cyclosporine with proximal tubule cells, renal brush border membranes, and renal cortical mitochondria. Cyclosporine bound to isolated rat renal brush border membranes in a saturable manner with a Kd of 0.38 microM and an nmax of 0.33 nmoles/mg protein. Scatchard analysis suggested that the interaction of cyclosporine at low concentrations with brush border membranes was consistent with a partitioning process rather than binding to a specific membrane component. Cyclosporine inhibited rat renal cortical mitochondrial respiration in a dose-dependent manner, with 8 microM as a threshold dose. This inhibitory effect was greater for respiration supported by succinate than pyruvate-malate. TMPD-ascorbate-supported respiration was unaffected. Suspensions of rabbit renal proximal tubule segments were incubated in vitro with 0.5-500 microM 3H-cyclosporine to measure the kinetics of cyclosporine uptake. Uptake was rapid (80% after 10 min) and saturable at 100 microM, with 9 nmoles cyclosporine/mg protein accumulated. Incubation of suspensions of enriched in rabbit renal proximal tubule segments with 10 microM cyclosporine in vitro for 2 hr with or without 22.5 min of hypoxia, or for 16 hr without hypoxia, had no effect on a variety of quantitative metabolic parameters of cell injury, including basal and uncoupled tubule respiratory rates and tubule K+, Ca++ and adenine nucleotide levels. These results demonstrate that cyclosporine interacts with critical renal membrane components at low concentrations but this interaction does not result in proximal renal tubular cell injury acutely in vitro.

Adenosine Triphosphate↗
PubMed1988

Glutathione protects against exogenous oxidant injury to rabbit renal proximal tubules.

Glutathione, comprising a major portion of cellular nonprotein thiols, plays a central role in a diverse group of cell metabolic functions. Glutathione and related enzyme systems have been shown to protect against both toxin and oxidant-induced injury in several organ systems. The role of glutathione in protecting renal epithelia against oxidant stress has not been investigated previously. We report here the response of enriched, isolated rabbit renal proximal tubule segments to oxidant stress induced by tert-butyl hydroperoxide. In addition, the effects of glutathione depletion by various biochemical means and of exogenous glutathione supplementation on the response of tubule segments to tert-butyl hydroperoxide exposure are described. Depletion of cell glutathione by several distinct methods potentiates oxidant-induced injury. Augmentation of cellular glutathione affords significant protection against exogenous oxidant stress. The protective effect of glutathione may reside in its ability, in conjunction with glutathione peroxidase, to arrest the propagation of lipid peroxidation and, therefore, to minimize alterations in plasma membrane permeability. The results of this study do not exclude the possibility that glutathione prevents tert-butyl hydroperoxide induced oxidation of critical sulfhydryl groups of catalytic or structural proteins associated with control of cell cation homeostasis. These results confirm the important role of glutathione in protecting renal tubular epithelia against oxidant stress.

Adenosine Triphosphate↗
PubMed1988

Importance of adenosine triphosphate in phospholipase A2-induced rabbit renal proximal tubule cell injury.

The pathogenesis of ischemic renal tubular cell injury involves a complex interaction of different processes, including membrane phospholipid alterations and depletion of high-energy phosphate stores. To assess the role of membrane phospholipid changes due to activation of phospholipases in renal tubule cell injury, suspensions enriched in rabbit renal proximal tubule segments were incubated with exogenous phospholipase A2 (PLA2). Exogenous PLA2 did not produce any significant change in various metabolic parameters reflective of cell injury in control nonhypoxic preparations despite a significant decrease in phosphatidylethanolamine (PE) and moderate increases in lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). In contrast, exogenous PLA2 treatment of hypoxic tubules resulted in a severe degree of cell injury, as demonstrated by marked declines in tubule K+ and ATP contents and significant decreases in tubule uncoupled respiratory rates, and was associated with significant phospholipid alterations, including marked declines in phosphatidylcholine (PC) and PE and significant rises in LPC, LPE, and free fatty acids (FFA). The injurious metabolic effects of exogenous PLA2 on hypoxic tubules were reversed by addition of ATP-MgCl2 to the tubules. The protective effect of ATP-MgCl2 was associated with increases in tubule PC and PE contents and declines in LPC, LPE, and FFA contents. These experiments thus indicate that an increase in exogenous PLA2 activity produces renal proximal tubule cell injury when cell ATP levels decline, at which point phospholipid resynthesis cannot keep pace with phospholipid degradation with resulting depletion of phospholipids and accumulation of lipid by-products. High-energy phosphate store depletion appears to be an important condition for exogenous PLA2 activity to induce renal tubule cell injury.

Adenosine Triphosphate↗
PubMed1988

Comparison of the toxicity of the radiocontrast agents, iopamidol and diatrizoate, to rabbit renal proximal tubule cells in vitro.

Radiographic contrast agent-induced acute renal failure is an increasingly recognized clinical event. Multiple factors have been implicated in its development. Recent experiments have demonstrated that sodium diatrizoate, a common ionic radiocontrast agent, is moderately toxic to proximal tubule cells in vitro, and that this toxicity is enhanced by hypoxia. In this study, we compare toxicities of the nonionic radiocontrast agent, iopamidol, and the commonly used ionic contrast agent, diatrizoate. Suspensions enriched in proximal tubule segments were exposed for 82.5 min to 10 or 25 mM diatrizoate or 10 or 25 mM iopamidol with or without 22.5 min or 30 min of hypoxia. Cell viability parameters, including basal and uncoupled respiratory rates, tubule cell potassium and calcium levels and cell ATP content were measured. No consistent differences in tubule viability parameters were observed between tubule suspensions exposed to 10 mM concentrations of the radiocontrast agents during either oxygenated or hypoxic conditions. Under oxygenated conditions, both 25 mM iopamidol and diatrizoate exposure produced greater metabolic alterations in renal tubules than control conditions, but the effects were not statistically significant. With concomitant hypoxia, the alterations after 25 mM diatrizoate exposure were significantly greater than those seen after exposure to 25 mM iopamidol. Iopamidol had less of a detrimental effect on renal tubule potassium content and both basal and uncoupled respiratory rates than that of diatrizoate under these conditions. Thus, diatrizoate is more toxic to rabbit renal proximal tubule cells than iopamidol in vitro, and this difference in toxicity is enhanced by hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1988

Potentiation of aminoglycoside nephrotoxicity by vitamin-D-induced hypercalcemia.

The effect of 1,25(OH)2 vitamin D3-induced hypercalcemia on the course of aminoglycoside nephrotoxicity in the rat was studied. Daily gentamicin, 100 mg/kg body weight, was administered subcutaneously concomitant with 1,25(OH)2 vitamin D3, 50 ng s.c. to male Sprague-Dawley rats. This group was compared to rats injected with gentamicin alone, 1,25(OH)2 vitamin D3 alone, and an ethanol vehicle as a control. Structural and functional parameters of acute renal failure were assessed following 4, 6 and 7 days of treatment. Severe morphologic evidence of tubular injury was documented on day 6 in the group injected with gentamicin and 1,25(OH)2 vitamin D3. Correlative functional and metabolic evidence of tubular cell deterioration occurred in this group on day 7 as represented by an elevated blood urea nitrogen (BUN), 198 +/- 14 mg/dl (p less than 0.001 compared to all other groups), a heightened mean renal cortical homogenate calcium, 1,028.3 +/- 304.8 nmol/mg protein (p less than 0.05 or better compared to all other groups), and significantly increased mean cortical mitochondrial calcium content, 796.3 +/- 116.5 nmol/mg protein (p less than 0.01 in relation to all other groups). Elevated total serum calcium to a level of 11.9 +/- 0.2 mg/dl (p less than 0.001 compared to control group) developed in the gentamicin/1,25(OH)2 vitamin D3 group on day 4, 2 days prior to pronounced structural damage, and continued to be elevated through day 7. No difference in serum phosphorus levels, however, developed between control and gentamicin-plus-vitamin-D-treated animals except on day 7 when severe renal failure developed in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Cyclosporine effects on isolated membranes, proximal tubule cells, and interstitium of the kidney.

The pathogenesis of renal cell injury is a complex interplay among derangements in subcellular membrane function and mediators of injurious processes. Plasma and subcellular membrane injury and the resulting membrane dysfunction appear especially important. As detailed previously in this report, Cs, an extremely lipophilic compound, has the ability to bind to renal brush border membranes, interact with mitochondrial membranes resulting in multiple sites of dysfunction, and accumulate in high concentrations in renal proximal tubule cells. In spite of these interactions, Cs could not be shown to be directly toxic in vitro to proximal tubule cells. Thus, from these experiments, it is difficult to conclude that Cs-induced acute renal failure observed in vivo is due to a direct tubular toxic effect, even though Cs has the capability to interact with critical renal membranes at low concentrations. The majority of present evidence, therefore, does not suggest a toxic effect of Cs on renal epithelial cells. Instead, the acute effect of Cs to produce a decline in renal excretory function appears to be due to a fall in renal blood flow. On the other hand, the chronic effect of Cs to produce a decline in renal excretory function appears to be due to an effect of this agent to induce interstitial fibrosis. In this regard, recent findings summarized in this report demonstrate that Cs produces (over ten days) a higher than normal collagen content, as measured by hydroxyproline levels, in the kidney. In addition, this increase in collagen content with Cs treatment was associated with a significant increase in proliferation of cells in the renal interstitium, as determined by 3H-thymidine incorporation into DNA. This increase in DNA incorporation after Cs was not observed in other organs, including liver, spleen, or heart. Histologic assessment of these proliferating cells revealed them to be mononuclear. Cell surface markers also demonstrated an increase in LCA positive cells in the renal interstitium. These results, therefore, suggest a readily demonstrable effect of Cs on the renal interstitium. The relationship between Cs dosage and interstitial cell proliferation as well as the relationship between Cs-induced renal perfusion alterations and this interstitial proliferative process mandates further investigation.

Animals↗
PubMed1987

Direct toxic effect of the radiocontrast agent diatrizoate on renal proximal tubule cells.

The pathophysiology of radiocontrast agent-induced acute renal failure is presently unclear. To test for a possible direct deleterious effect of diatrizoate, a commonly used radiocontrast agent, on renal tubule cells, suspensions enriched in rabbit proximal tubule segments were incubated with sodium diatrizoate. After these manipulations, a variety of well-established metabolic parameters to quantitate the extent of cell injury were measured. Diatrizoate sodium (25 mM) produced significant declines in tubule K+, ATP, and total adenine nucleotide (TAN) contents, significant decreases in tubule basal and uncoupled respiratory rates, and a significant increase in tubule Ca2+ content, demonstrating the development of cell injury induced by diatrizoate. These effects were dose related and were progressive with increasing incubation time from 97.5 to 157.5 min. The effects of N-methylglucosamine (meglumine) on renal tubule cell viability was also evaluated. Meglumine is a low molecular weight amino-substituted cationic compound and is commonly added to radiocontrast dye solutions. Meglumine (25 mM) had significant effects to lower tubule K+ content and to decrease both tubule basal and uncoupled respiratory rates. These alterations were slightly additive to diatrizoate in that meglumine diatrizoate produced greater alterations in tubule-metabolic parameters compared to diatrizoate sodium. A period of 22.5 min of hypoxia also caused deleterious changes in each of these quantitative indices of cell viability, and diatrizoate potentiated the degree of hypoxia-induced cell injury. These results demonstrate that the radiocontrast agent, diatrizoate, is directly toxic to renal proximal tubule cells. Meglumine, a cation added to diatrizoate containing radiocontrast solutions, also had a moderate toxic effect on renal epithelial cells and added to the toxicity of diatrizoate. Diatrizoate also aggravated the degree of cell injury induced by a 22.5-min period of hypoxia. These experiments thus provide evidence for a direct toxic effect of diatrizoate on proximal renal tubule cells which was additive to hypoxic cell injury.

Animals↗
PubMed1987

Alterations in renal structure and function in a rat model of cyclosporine nephrotoxicity.

Adult male Sprague-Dawley rats maintained on a low sodium diet were administered 100 mg of cyclosporine per kg b.wt. per day s.c. for 4 to 10 days. Serum urea nitrogen was significantly elevated by day 4 and continued to rise, whereas serum creatinine was not elevated above control until day 10. Morphologic examination of perfusion-fixed kidneys from cyclosporine-treated rats revealed focal areas of tubular atrophy and interstitial fibrosis in the outer cortex and a generalized increase in interstitial cells in the outer medulla. No areas of acute tubular necrosis were identified. The effect of this dose of cyclosporine on renal hemodynamics was examined in conscious restrained rats. Renal blood flow, measured by microsphere injection, was 70% of control after four daily doses and remained near this level after eight daily doses. The glomerular filtration rate, measured by iodothalamate clearance, was 70% of control after four doses but fell to 34% of control after eight doses. [3H]Thymidine incorporation into renal DNA was used as a sensitive index of renal cell proliferation after cyclosporine administration (100 mg/kg/day). [3H]Thymidine incorporation was increased over control 3-fold in the outer cortex, 7-fold in the inner cortex and 11-fold in the medullary-papillary regions of the kidney after eight daily doses of cyclosporine. Histoautoradiographic examination of renal sections revealed an increase in the number of labeled nuclei in all three regions of the kidney from rats treated with cyclosporine. Morphometric analysis demonstrated that the majority of proliferating cells were located in the interstitium and not in renal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗