Differential expression and activity of catechol-O-methyl transferase (COMT) in a generalist (Neotoma albigula) and juniper specialist (Neotoma stephensi) woodrat

Mammalian herbivores, particularly dietary specialists must have an efficient means to metabolize the high doses of plant secondary compounds they consume. We found previously that Neotoma stephensi, a juniper specialist, upregulated catechol-O-methyl transferase (COMT) mRNA almost seven fold in response to an ecologically relevant diet (70% juniper). To further investigate the relevance of this enzyme with respect to juniper metabolism, we compared the protein expression, activity and kinetics of the two forms of COMT, soluble (S-COMT) and membrane bound (MB-COMT), in the blood, kidneys and liver of N. stephensi on its natural juniper diet to that of N. stephensi fed an experimental diet of 70% juniper as well as a non-toxic control diet under laboratory conditions. In addition, we compared these results to that of Neotoma albigula, a generalist species, which consumes a diet of 25% juniper in the wild. The specialist consuming juniper under both field and laboratory conditions had increased S-COMT expression and activity in their livers and kidneys, and increased S-COMT activity in their blood compared to the specialist and generalist fed the control diet. The specialist showed expression and activity of S-COMT in their kidneys that was as high as or higher than that in their livers. The generalist had an elevated V_max for MB-COMT compared to the specialist that resulted in higher activity for MB-COMT than the specialist despite lower expression of MB-COMT in the generalist's livers and kidneys. This high activity MB-COMT may be in part responsible for differences in the behaviors of the generalist compared to the specialist. We conclude that S-COMT is important in the specialist's ability to consume high levels of juniper.     

Ultrastructure and significance of the transitory nephridia in Erpobdella octoculata (Hirudinea, Annelida)

In early developmental stages of Erpobdella octoculata two pairs of transitory nephridia occur which degenerate during the formation of the body segments. Because in the ground pattern of Annelida the first nephridia formed during ontogenesis are protonephridia, it can be assumed that the transitory nephridia of E. octoculata are homologous to the larval protonephridia (head kidneys) of Polychaeta. To test this hypothesis two cryptolarvae of E. octoculata were investigated ultrastructurally. Both pairs of transitory nephridia are serially arranged to either side of the midgut vestigium. Each organ consists of a coiled duct that opens separately to the exterior by an intraepidermal nephridiopore cell. The duct is percellular and formed by seventeen cells. Adluminal adherens and septate junctions connect all duct cells; the most proximal duct cell completely encloses the terminal end of the duct lumen. A filtration structure characteristic for protonephridia is lacking. Additionally, the entire organ lacks an inner ciliation. Morphologically and ultrastructurally the transitory nephridia of E. octoculata show far reaching congruencies with the segmental metanephridia in different species of the Hirudinea. These congruencies support the assumption that formation of transitory nephridia and definitive metanephridia in Hirudinea depends on the same genetic information. The same inherited information is assumed to cause the development of larval head kidneys and subsequently formed nephridia in different species of the Polychaeta. Thus, the presumed identical fate of a segmentally repeated nephridial anlage supports the hypothesis of a homology between the transitory nephridia in Hirudinea species and the protonephridial head kidneys in the ground pattern of the Polychaeta. We, therefore, assume that functional constraints lead to a modification of the protonephridial head kidneys in Hirudinea and explain ultrastructural differences between the transitory nephridia in Hirudinea and the protonephridia in Polychaeta. Accepted: 11 December 2000     

The pathogenicity, localization, and cyst structure of echinostomatid metacercariae (Trematoda) infecting the kidneys of the frogs Rana clamitans and Rana pipiens

Light and scanning electron microscopy were used to examine the localization and pathogenicity of echinostomatid metacercariae infecting the kidneys of leopard frogs, Rana pipiens, and green frogs, Rana clamitans. Cysts occurred predominantly in the ventrolateral renal cortex, and at least some were confined to the lumen of the Bowman's capsules. Each vermiform metacercarial body was enclosed by a spherical cyst wall that had a uniform thickness. The wall was composed of a homogeneous material containing basic and keratinlike proteins, with sulfated acid mucopolysaccharides on the outer surface. Most cysts were enclosed by a fibrous capsule of host origin, or were surrounded by an inflammatory focus. Fibrosis was always focal, but its degree varied between individual hosts and between different cysts within the same host. Some heavily encapsulated cysts were darkened and contained disintegrating worms. In heavily infected kidneys, confluence of fibrotic or inflammatory foci resulted in the displacement of functional renal tissue. These data suggest that infection by echinostomatids may impair renal function and that the host's response affects parasite viability.     

Experimental infection of Physa heterostropha, Helisoma trivolvis, and Biomphalaria glabrata (Gastropoda) with Echinostoma revolutum (Trematoda) Cercariae

Gross and histologic studies were done on laboratory-raised Physa heterostropha, Helisoma trivolvis, and Biomphalaria glabrata snails exposed individually to 100 cercariae of Echinostoma revolutum. Cercariae showed a predisposition for the kidneys of snails. They entered the nephridiopore, migrated up the tubular kidney, and encysted in the saccular kidney within 2 hr. Considerably more cysts were in the kidney of B. glabrata at 24 hr than in H. trivolvis or P. heterostropha kidneys. Encysted metacercariae were not infective to domestic chicks at 2 hr, but were infective by 4 hr. Biomphalaria glabrata exposed to about 1,000 cercariae/snail and necropsied either 10 or 16 wk postexposure contained 300-500 cysts/kidney; about one-half the cysts were viable and infective to chicks. Biomphalaria glabrata is an excellent second intermediate host for the laboratory propagation of E. revolutum.     

Angiotensin II in epitheloid (renin containing) cells of rat kidney

The PAP-method was used for immunocytochemical investigations with antisera against angiotensin (ang) I, ang II and renin in kidneys of rats and mice. In 14 rats, ang II was found in the media of the afferent arteriole - both in the region of the JGA and upstream until the interlobular artery. Serial sections alternately reacted for ang II and renin revealed that the octapeptide is contained in the well known renin positive epitheloid cells of the afferent arteriole and, beyond that, together with renin probably in the same "specific" granules. Fixation conditions were critical for the visualization of immunoreactivity With ang I antisera, comparable in terms of titer and affinity to the ang II antisera, specific immunoreactivity could not be found in the kidneys of rats. With horse radish peroxidase and ferritin as tracers it could be shown that the epitheloid cells of the JGA have the ability to pinocytize and incorporate macromolecules into their granules. It is suggested that ang II is taken up by these cells through the same route, Intracellular generation of ang II appears unlikely as an explanation. Functionally the selective uptake of ang II by epitheloid cells might be a specific process, possibly connected with the negative feedback of the octapeptide on renin secretion. Negative results in mice may be explained by a small uptake or more rapid degradation of ang II by the epitheloid cells.     

The effects of age,sex, and zinc status on the accumulation of (copper,zinc)-metallothionein in rat kidneys

A study has been made of the distribution of copper in the kidneys of growing rats. Renal copper concentrations increased steadily with age and were greater in female than in male animals. Most of the copper was present as (copper, zinc)-metallothionein and two forms of this protein were isolated and characterized from the kidneys of mature female rats. That copper metabolism in kidneys is subject to hormonal influence was indicated by a reduction in the concentrations of copper and (copper, zinc)-metallothionein in ovariectomized rats and by an increase in their concentrations after the administration of progesterone. Concentrations of renal (copper, zinc)-metallothionein were less in zinc-deficient than in zinc-adequate rats during pregnancy and after progesterone administration.     

Comparative studies of body mass,body measurements and organ weights of wild-derived and laboratory golden hamsters (Mesocricetus auratus)

All laboratory golden hamsters originate from a sibling pairing back in 1930. To investigate possible differences between domesticated and wild conspecifics, descendants of both strains were maintained under standardized laboratory conditions individually and in unisexual groups. Body mass and food consumption were monitored from birth to 22 weeks of age. The animals were subsequently sacrificed, and body measurements and body composition were analysed. In addition, the absolute and relative masses of different organs were measured. Laboratory hamsters gained more body mass through higher food consumption. However, they did not get fatter, since relative fat values were the same for both strains. Body measurements revealed only minor differences (in body and ear lengths). As deducible from the body mass, the organs (spleen, kidneys, adrenal glands, testes, epididymis and ovaries) were seen to be heavier in laboratory hamsters. Furthermore, with the exception of the kidneys, the same went for the relative values. There were distinct sexual specific differences in both strains only for body fat ( male symbol male symbol upward arrow ) and adrenal glands ( male symbol male symbol upward arrow ). In females, group housing induced an elevated level of aggression. In general, these housing conditions led to social stress symptoms, such as heavier adrenal glands. Additionally, spleen, kidneys, ovaries, body length and mass, body water and body fat were increased in group-housed hamsters. In conclusion, no major differences between laboratory and wild-derived hamsters were observed.     

Effects of losartan on expression of monocyte chemoattractant protein-1 (MCP-1) in hyperuricemic nephropathy rats

Abstract

The monocyte chemoattractant protein-1 (MCP-1) plays an important role in the pathogenesis of progression of renal failure. This is based on the observations done both in various animal models of renal damage and in different types of human renal disease. During the development of non-infectious kidney stones, crystals are formed and deposited on the kidneys and the kidneys are surrounded by monocytes/macrophages. We have proposed that in response to crystal exposure, renal epithelial cells produce chemokines, which attract the monocytes/macrophages to the sites of crystal deposition. In this study, we investigated the expression of MCP-1 protein by SD rats exposed to oxonic acid (OA). Our study showed that hyperuricemia accelerates renal progression via a mechanism linked to high MCP-1 which may mediate the inflammation reaction of renal diseases induced by hyperuricemia. Losartan may retard the progression of advanced renal dysfunction, and the mechanism was partly due to blocking of renal inflammation induced by the uric acid. Because the number of experiments performed here is very few, results must be confirmed by more extensive studies with a larger sample size.     

Tissue-type Plasminogen Activator (tPA) Promotes M1 Macrophage Survival through p90 Ribosomal S6 Kinase (RSK) and p38 Mitogen-activated Protein Kinase (MAPK) Pathway

Macrophage accumulation is one of the hallmarks of progressive kidney disease. Resting macrophages have a finite lifespan, but become resistant to apoptosis in response to pathogenic cues, whereas the underlying mechanism remains unknown. Tissue-type plasminogen activator (tPA), a protease up-regulated in the kidneys with chronic injury, has been shown to promote macrophage accumulation and renal inflammation. We hypothesized that tPA may be the endogenous factor that promotes macrophage survival and extends their lifespan that leads to their accumulation in the injured kidneys. We examined the role of tPA in macrophage survival, and found that tPA protected macrophages from both staurosporine and H₂O₂-induced apoptosis. tPA promoted the survival of both resting and lipopolysaccharide- or interferon-γ-induced M1 macrophages, but failed to do so in the interleukin 4 (IL4)-induced M2 macrophages. In the kidneys with unilateral ureteral obstruction, there were significantly more apoptotic M1 macrophages in tPA-deficient mice than their wild-type counterparts, and obstruction-induced M1 macrophages accumulation and M1 chemokine expression were markedly reduced in these knock-out mice. The cytoprotective effect of tPA required its receptor, LDL receptor-related protein-1 (LRP-1). tPA induced the phosphorylation of Erk1/2, p90 ribosomal S6 kinase (RSK), and p38 in a temporal order. The tPA-mediated macrophage survival was eliminated by PD98059, BI-D1870, or sc68376, the specific inhibitors for Erk1/2, p90RSK, or p38, respectively. Thus, it is clear that tPA promoted M1 macrophage survival through its receptor LRP-1-mediated novel signaling cascade involving Erk1/2, p90RSK, and p38, which leads to the accumulation of these cells in the injured kidneys.     

Prenatal treatment of mosaic mice (Atp7a mo-ms) mouse model for Menkes disease, with copper combined by dimethyldithiocarbamate (DMDTC)

Menkes disease is a fatal neurodegenerative disorder in infants caused by mutations in the gene ATP7A which encodes a copper (Cu) transporter. Defects in ATP7A lead to accumulated copper in the small intestine and kidneys and to copper deficiencies in the brain and the liver. The copper level in the kidney in postnatal copper-treated Menkes patients may reach toxic levels. The mouse model, mosaic Atp7a (mo-ms) recapitulates the Menkes phenotype and die about 15.75±1.5 days of age. In the present study we found that prenatal treatment of mosaic murine fetuses throughout gestation days 7, 11, 15 and 18 with a combination of CuCl(2) (50 mg/kg) and dimethyldithiocarbamate (DMDTC) (280 mg/kg) leads to an increase in survival to about 76±25.3 days, whereas treatment with CuCl(2) alone (50 mg/kg) only leads to survival for about 21 days ±5 days. These copper-DMDTC treated mutants showed an improved locomotor activity performance and a gain in body mass. In contrast to treatment with CuCl(2) alone, a significant increase in the amount of copper was observed in the brain after prenatal copper-DMDTC treatment as well as a decrease in the amount of accumulated copper in the kidney, both leading towards a normalization of the copper level. Although copper-DMDTC prenatal treatment only leads to a small increase in the sub-normal copper concentration in the liver and to an increase of copper in the already overloaded small intestine, the combined results suggest that prenatal copper-DMDTC treatment also should be considered for humans.     

Differential expression of ABC transporters (MDR1, MRP1, BCRP) in developing human embryos

Three ABC transporters (MDR1, MRP1, BCRP), belonging to the family of multidrug resistance (MDR) proteins, play a crucial role in the protection mechanisms during embryogenesis and mediate drug resistance in cancer cells. The distribution of these transporters in the series of human embryonal/fetal intestine, liver and kidneys of various stages of intrauterine development (IUD) by indirect two-step immunohistochemical method was investigated. The organ- and age-specific expression patterns of these transporters were depicted and compared with the expression in adult organs. The evaluation of intestine and liver samples demonstrate differences in expression pattern of ABC transporters during IUD. On the contrary, in kidneys the age-specific localization was not observed. However, the increasing positivity from the kidney surface towards deeper, more differentiated parts was found. Hopefully, our study may contribute to elucidation of the role of multidrug resistance (MDR) pathways during IUD in man.     

Complex estrogenic regulation of catechol-O-methyltransferase (COMT) in rats

Catechol-O-methyltransferase (COMT) activity depends on gender, age and physiological status suggesting that estrogen may regulate COMT activity. In fact, estrogens down-regulate the function of COMT promoters in cell cultures. On the other hand, COMT may play an important role in estrogen-induced cancers due to its ability to inactivate estrogen metabolites and thereby lowering the levels of these potential carcinogens. In this study, we explored the effect of estrogen on COMT activity in vivo in rats. Male and female Wistar rats received 14-day treatments with either estradiol (100 μg/kg/day; s.c.) or tamoxifen (500 μg/kg/day; s.c.), respectively; in addition ovariectomized rats were studied. COMT activity and COMT protein expression were measured from various brain- and peripheral tissues. Although we found a regulatory function of estrogen, its effects were sex and tissue dependent. Antagonizing the effects of estrogen via tamoxifen increased COMT protein expression in several central and peripheral tissues. However, amounts of COMT protein and COMT activities did not always match. Generally, COMT activities were quite resistant to the effects of tamoxifen and estradiol. Estradiol, unexpectedly, doubled the amount of COMT protein in the prostate but exhibited down-regulatory function in the prefrontal cortex and kidneys. Ovariectomy by itself, however, had only minor effects on COMT activity and expression. It is noteworthy that the estrogen down-regulation and tamoxifen up-regulation of COMT were best substantiated in the prefrontal cortex and kidneys where COMT is physiologically important for dopamine metabolism.     

Bacterial lipopolysaccharide (LPS) and interleukin 1 (IL-1) exert multiple physiological effects in the tilapia Oreochromis mossambicus (Teleostei)

To gain insight in immuno-endocrine communication in teleosts the physiological effects of interleukin 1 and bacterial lipopolysaccharide in teleosts were investigated. Tilapia (Oreochromis mossambicus) were treated with murine interleukin 1 and E. coli lipopolysaccharide in vivo, and lipopolysaccharide was administered to pituitary lobes and head kidneys in vitro. The integument of the fish appeared to be a sensitive target for the preparations tested, since proliferation of chloride cells and of epidermal mucous cells was observed as well as an increase in epidermal thickness. These effects may relate to an acute phase-like reaction caused by the treatments. Lipopolysaccharide administration furthermore resulted in an increase in plasma free fatty acids levels. Lipopolysaccharide, but not interleukin 1, stimulated the interrenal axis of the fish, as judged by the increase in cortisol production measured in superfusion of head kidneys. In addition to these in vivo effects, lipopolysaccharide also displayed several effects in vitro. Pituitary adrenocorticotropic hormone, as well as -melanocyte stimulating hormone, release was inhibited, and the head kidney responsiveness to adrenocorticotropic hormone was inhibited after pretreatment of the tissue with the E. coli product. This latter effect coincided with the release of an unidentified -melanocyte stimulating hormone immunoreactive fraction by the head kidneys which could be stimulated by lipopolysaccharide. The data strongly support the notion that the immune system is involved in adaptive regulations in teleosts, and that immuno-endocrine interactions are phylogenetically old mechanisms.Abbreviations ACTH adrenocorticotropic hormone - AUC area under the curve - FFA free fatty acids - HPLC high-performance liquid chromatography - IL-1 interleukin 1 - LPS lipopolysaccharide/endotoxin - -MSH alpha melanocyte stimulating hormone - NIL neurointermediate lobe - POMC proopiomelanocortin - RIA radioimmunoassay - RPD rostral pars distalis     

Cd, Cu, Zn, Se, and Metallothioneins in Two Amphibians, Necturus maculosus (Amphibia, Caudata) and Bufo bufo (Amphibia, Anura)

The accumulation of cadmium, its affinity for metallothioneins (MTs), and its relation to copper, zinc, and selenium were investigated in the experimental mudpuppy Necturus maculosus and the common toad Bufo bufo captured in nature. Specimens of N. maculosus were exposed to waterborne Cd (85???g/L) for up to 40?days. Exposure resulted in tissue-dependent accumulation of Cd in the order kidney, gills > intestine, liver, brain > pancreas, skin, spleen, and gonads. During the 40-day exposure, concentrations increased close to 1???g/g in kidneys and gills (0.64?C0.95 and 0.52?C0.76; n?=?4), whereas the levels stayed below 0.5 in liver (0.14?C0.29; n?=?4) and other organs. Cd exposure was accompanied by an increase of Zn and Cu in kidneys and Zn in skin, while a decrease of Cu was observed in muscles and skin. Cytosol metallothioneins (MTs) were detected as Cu,Zn?Cthioneins in liver and Zn,Cu?Cthioneins in gills and kidney, with the presence of Se in all cases. After exposure, Cd binding to MTs was clearly observed in cytosol of gills as Zn,Cu,Cd?Cthionein and in pellet extract of kidneys as Zn,Cu,Cd?Cthioneins. The results indicate low Cd storage in liver with almost undetectable Cd in liver MT fractions. In field trapped Bufo bufo (spring and autumn animals), Cd levels were followed in four organs and found to be in the order kidney > liver (0.56?C5.0???g/g >0.03?C0.72???g/g; n?=?11, spring and autumn animals), with no detectable Cd in muscle and skin. At the tissue level, high positive correlations between Cd, Cu, and Se were found in liver (all r?>?0.80; ???=?0.05, n?=?5), and between Cd and Se in kidney (r?=?0.76; n?=?5) of autumn animals, possibly connected with the storage of excess elements in biologically inert forms. In the liver of spring animals, having higher tissue level of Cd than autumn ones, part of the Cd was identified as Cu,Zn,Cd?Cthioneins with traces of Se. As both species are special in having liver Cu levels higher than Zn, the observed highly preferential Cd load in kidney seems reasonable. The relatively low Cd found in liver can be attributed to its excretion through bile and its inability to displace Cu from MTs. The associations of selenium observed with Cd and/or Cu (on the tissue and cell level) point to selenium involvement in the detoxification of excessive cadmium and copper through immobilization.     

Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13)

The orphan transporter hORCTL3 (human organic cation transporter like 3; SLC22A13) is highly expressed in kidneys and to a weaker extent in brain, heart, and intestine. hORCTL3-expressing Xenopus laevis oocytes showed uptake of [(3)H]nicotinate, [(3)H]p-aminohippurate, and [(14)C]urate. Hence, hORCTL3 is an organic anion transporter, and we renamed it hOAT10. [(3)H]Nicotinate transport by hOAT10 into X. laevis oocytes and into Caco-2 cells was saturable with Michaelis constants (K(m)) of 22 and 44 microm, respectively, suggesting that hOAT10 may be the molecular equivalent of the postulated high affinity nicotinate transporter in kidneys and intestine. The pH dependence of hOAT10 suggests p-aminohippurate(-)/OH(-), urate(-)/OH(-), and nicotinate(-)/OH(-) exchange as possible transport modes. Urate inhibited [(3)H]nicotinate transport by hOAT10 with an IC(50) value of 759 microm, assuming that hOAT10 represents a low affinity urate transporter. hOAT10-mediated [(14)C]urate uptake was elevated by an exchange with l -lactate, pyrazinoate, and nicotinate. Surprisingly, we have detected urate(-)/glutathione exchange by hOAT10, consistent with an involvement of hOAT10 in the renal glutathione cycle. Uricosurics, diuretics, and cyclosporine A showed substantial interactions with hOAT10, of which cyclosporine A enhanced [(14)C]urate uptake, providing the first molecular evidence for cyclosporine A-induced hyperuricemia.     

Klossiella (Apicomplexa, Klossiellidae) in petaurid and macropodid marsupials in Australia

Six new species of Klossiella are described in the kidneys of Australian marsupials: Klossiella rufogrisei in Bennett's Wallaby, Macropus rufogriseus; Klossiella rufi in the Red Kangaroo, Macropus rufus; Klossiella thylogale in the Red-Bellied or Tasmanian Pademelon, Thylogale billardierii; Klossiella beveridgei in the Spectacled Hare-Wallaby, Lagorchestes conspicillatus; Klossiella bettongiae in the Tasmanian Bettong, Bettongia gaimardi; and Klossiella schoinobatis in the petaurid Greater Glider, Petauroides volans. It is concluded that the genus Klossiella has radiated widely among Australian marsupials, and that since it is present in American marsupials, it may have an ancient association with the subclass.     

New nephron development in goldfish (Carassius auratus) kidneys following repeated gentamicin-induced nephrotoxicosis

Renal development in mammalian kidneys can only be studied in embryonic animals. Hence, research in this area is hampered by the need to maintain pregnant animals and by the small size of the embryonic kidney. Here, we describe a goldfish (Carassius auratus) model for studying renal repair and nephron development in an adult animal. Previous studies have indicated that chemically induced nephrotoxicosis in goldfish is followed by new nephron development. We tested the hypothesis that new nephron development is not a one-time only event and, thus, will occur after repeated nephrotoxic events. We used repeated injections of gentamicin (50 mg/kg of body weight), a nephrotoxic antibiotic, which has been used as a model nephrotoxicant to study renal repair. Fish were allowed either a recovery period of 9 or 24 weeks between injections. In both experiments, new nephrons developed after each injection of gentamicin, supporting our hypothesis. Nephron development occurring after a 9-week recovery period was similar to development observed after a 24-week recovery period; therefore, the shorter experimental paradigm appears sufficient and can save time and money. Future research using this fish nephrogenesis model may identify the genes responsible for nephron neogenesis. Such information is a prerequisite for developing alternative renal replacement therapies based on the induction of de novo nephrogenesis in diseased kidneys.     

Renal toxicity studies of protein-bound platinum(cis)

Incubation of dialyzed rat serum with cisplatin at a concentration of 908 ppm results in binding of platinum to the proteins and electrophoretic evidence of protein alterations.Intravenous administration of protein-bound platinum(cis), containing the same platinum content as an 8.5-mg/kg dose of cisplatin, fails to produce elevated serum BUN and creatinine levels as do equivalent doses of ‘free’ cisplatin in 0.9% saline.Light microscopy of the right side kidneys of rats receiving protein-bound platinum(cis) revealed no obvious pathology while the kidneys of rats receiving ‘free’ cisplatin showed consistent pathological alterations including hydropic degeneration and pyknotic nuclei.These observations suggest that a protein-bound form of platinum will be unlikely to contribute to the renal toxicity observed during cisplatin chemotherapy.     

Mechanism of garlic (Allium sativum) induced reduction of hypertension in 2K-1C rats: a possible mediation of Na/H exchanger isoform-1

Garlic causes reduction in blood pressure (BP), however the role of Na/H exchanger (NHE) which mediates hypertension and related tissue-damage is poorly understood. In this study the effect of an established dose of raw garlic extract was investigated on the expression of NHE-1 and -3 and sodium pump activity in a 2K-1C model of hypertension in rats. 2K-1C animals showed high BP, increased serum concentration of PGE2 and TxB2, hypertrophy of the unclipped kidneys, but not in the clipped kidneys In addition, NHE-1 and NHE-3 isoforms were increased in both the 2K-1C kidneys, whereas alpha-actin was increased in the clipped but not in unclipped kidneys. Sodium pump activity was decreased in the clipped kidneys, but remained unchanged in the unclipped kidneys. Garlic treatment reduced the induction of NHE-1 only in the unclipped 2K-1C kidneys, whereas garlic treatment increased the sodium pump activity in both the 2K-1C kidneys. These findings demonstrate that the antihypertensive action of garlic is associated with a reversal of NHE-1 induction in the unclipped kidneys. Induction of NHE isoforms together with a reduced sodium pump activity might cause necrosis in the 2K-1C clipped kidneys due to cellular retention of Na+. On the other hand, activation of sodium pump by garlic extract in the kidneys should reduce intracellular Na+ concentration and normalize BP. These findings signify the use of garlic in the treatment of hypertension.