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PubMed1998

Variability of the canonical loop conformations in serine proteinases inhibitors and other proteins.

Canonical loops of protein inhibitors of serine proteinases occur in proteins having completely different folds. In this article, conformations of the loops have been analyzed for inhibitors belonging to 10 structurally different families. Using deviation in Calpha-Calpha distances as a criterion for loop similarity, we found that the P3-P3' segment defines most properly the length of the loop. When conformational differences among loops of individual inhibitors were compared using root mean square deviation (rmsd) in atomic coordinates for all main chain atoms (deltar method) and rmsd operating in main chain torsion angles (deltat method), differences of up to 2.1 A and 72.3 degrees, respectively, were observed. Such large values indicate significant conformational differences among individual loops. Nevertheless, the overall geometry of the inhibitor-proteinase interaction is very well preserved, as judged from the similarity of Calpha-Calpha distances between Calpha of catalytic Ser and Calpha of P3-P3' residues in various enzyme-inhibitor complexes. The mode of interaction is very well preserved both in the chymotrypsin and subtilisin families, as distances calculated for subtilisin-inhibitor complexes are almost always within the range of those for chymotrypsin-inhibitor complexes. Complex formation leads to conformational changes of up to 160 degrees for chi1 angle. Side chains of residue P1 and P2' adopt in different complexes a similar orientation (chi1 angle = -60 degrees and -180 degrees, respectively). To check whether the canonical conformation can be found among non-proteinase-inhibitor Brookhaven Protein Data Bank structures, two selection criteria--the allowed main chain dihedral angles and Calpha-Calpha distances for the P3-P3' segment--were applied to all these structures. This procedure detected 132 unique hexapeptide segments in 121 structurally and functionally unrelated proteins. Partial preferences for certain amino acids occurring at particular positions in these hexapeptides could be noted. Further restriction of this set to hexapeptides with a highly exposed P1 residue side chain resulted in 40 segments. The possibility of complexes formation between these segments and serine proteinases was ruled out in molecular modeling due to steric clashes. Several structural features that determine the canonical conformation of the loop both in inhibitors and in other proteins can be distinguished. They include main chain hydrogen bonds both within the P3-P3' segment and with the scaffold region, P3-P4 and P3'-P4' hydrophobic interactions, and finally either hydrophobic or polar interactions involving the P1' residue.

Animals↗

PubMed1997

Helix-loop-helix motif in GnRH associated peptide is critical for negative regulation of prolactin secretion.

The GnRH associated prolactin inhibiting factor (GAP) reveals the signature sequence associated with the helix-loop-helix structural motif. A number of different peptide fragments of GAP were designed, synthesized and analysed by circular dichroism and by an in vivo assay for prolactin secretion inhibiting activity. Peptides corresponding to the two individual alpha-helices and a 44-residue peptide comprising the entire helix-loop-helix motif show significant helical propensity in circular dichroism spectra. However, a peptide corresponding to the loop sequence shows no helical propensity. Albeit, the peptide corresponding to helix-loop-helix motif was found to inhibit prolactin secretion and augment circulating levels of gonadotropins in the in vivo assay; other shorter peptides did not show such activity. The activity profile of the 44-residue peptide was biphasic and very similar to that of the recombinant GAP. Thus, the prolactin inhibiting activity of this factor is defined by its helix-loop-helix motif as in the case of the transcription factors of developmental genes. The structural features of a homology-based model of GAP in complex with E47, a ubiquitous HLH-type developmental gene regulator, are consistent with the structural requirements of the negative regulation of transcription by helix-loop-helix proteins.

Amino Acid Sequence↗

PubMed1975

The ultrastructure of the thin loop limbs of the mouse kidney.

The thin limbs of the loops of Henle in the mouse kidney have been investigated by conventional electron microscopy. Resulting from light microscopic investigations, a distinction in the epithelia of short and long loops can be demonstrated. Ultrastructurally, the thin limbs (descending) of short loops are composed of a uniformly thin and simple epithelium. In contrast, long loops (thin descending and ascending) are composed of three different epithelial types which are representative of a distinctly more complex epithelial system. Two epithelial types were observed in the thin descending limbs of long loops and the third type was observed in the ascending thin limbs. Based upon these findings it is suggested that the thin descending limbs of short and long loops of Henle in the mouse kidney cannot perform the same functions in the renal concentrating mechanism.

Animals↗

PubMed1988

Effect of inhibitors of prostaglandin synthesis on the furosemide action in the loop Henle of rat kidney.

Inhibitors of prostaglandin synthesis such as indomethacin and meclofenamate may attenuate the diuretic response to furosemide. The purpose of the present study was to clarify whether an inhibition of furosemide's action in the loop of Henle is involved in this interaction. In a first set of experiments, the effect of indomethacin and meclofenamate on the diuretic response to furosemide was re-evaluated in anaesthetized rats. Single loops of Henle of rat kidneys were perfused in vivo in a second group of rats. Furosemide was added to the perfusion fluid and the effect of indomethacin (5 mg/kg i.v.) and meclofenamate (5 mg/kg i.v.) on furosemide's action in the loops was tested. In the absence of furosemide, indomethacin and meclofenamate did not significantly affect urine flow and sodium chloride excretion, or the loop's sodium and chloride reabsorption. Both prostaglandin inhibitors, however, significantly attenuated the diuretic effect of furosemide (1 mg/kg i.v.) and the inhibitory action of the diuretic, at a concentration of 10(-4) M, on the loop's sodium and chloride transport. The results identify the loop of Henle as a tubular site of interaction between furosemide and prostaglandin inhibitors. The interaction may be related to a furosemide-induced stimulation of renal prostaglandins.

Animals↗

PubMed1979

Protein digestion and absorption in the blind loop syndrome.

Protein digestion and absorption was studied in rats with 6-week-old surgically constructed self-filling intestinal blind loops and steatorrhea, ie, blind-loop animals and controls were fed a 14C-labeled protein meal containing a nonabsorbable marker, 51CrCl3, and sacrificed 1 or 2 hr later. Intestinal contents were analyzed for 14C, 51Cr, protein, trypsin, and the products of digestion. At 1 hr, 14C absorption was greater in controls, but at 2 hr there was no difference in absorption between the two groups. Marker studies showed that blind-loop filling resulted in a delay of the progression of intestinal contents distally. Intraluminal trypsin and porteolysis were similar in the two groups. Endogenous protein was greater in the blind-loop animals. The early stages of the blind-loop syndrome may be characterized by delayed protein absorption secondary to blind-loop filling, which is compensated for by the distal gut resulting in an absence of overall protein malabsorption.

Animals↗

PubMed1984

Altered motility and duration of bacterial overgrowth in experimental blind loop syndrome.

To better understand the pathogenesis of the increased motility previously described in the blind loop rat, we studied the relationship between duration of bacterial overgrowth and both myoelectric activity and bacterial flora in this model. Myoelectric studies and quantitative bacterial cultures were performed on self-filling and self-emptying (control) blind loop rats one, two, and three weeks postoperatively. All self-filling blind loop rats had greater random action potential activity and higher frequencies of migrating action potential complexes than controls (P less than 0.05). One-week self-filling blind loop rats had a higher frequency of migrating action potential complexes (P less than 0.05) and a higher ratio of counts of Escherichia coli to Bacteroides species (P less than 0.05) than the two- or three-week self-filling blind loop groups. Thus, qualitative changes in myoelectric activity occur during the development of bacterial overgrowth in the blind loop rat which may reflect evolving alterations in the bacterial flora.

Action Potentials↗

PubMed1998

The clinical pharmacology of loop diuretics in the pediatric patient.

The loop diuretics furosemide and bumetanide are frequently employed in the pediatric population for the management of fluid overload in both acute and chronic disease states. They act mainly by inhibiting sodium reabsorption in the nephron at the thick ascending limb of Henle's loop. Important pharmacokinetic differences between adults and infants include a reduced clearance and prolonged half-life, that may cause accumulation of these agents to potentially toxic levels if dosing intervals are not adjusted. Unfortunately, little is known about the time required for maturation of loop diuretic elimination in older infants, children, and adolescents. Similar to adults, limited pharmacodynamic evidence in neonates suggests that a maximally efficient diuretic dose exists. Increasing the diuretic dose beyond this maximum does not offer further benefit, but may increase the risk of toxicity. Common problems encountered in the pediatric patient as well as in adults are loop diuretic tolerance and resistance. Loop diuretic dosing strategies aimed at overcoming these phenomena include administration by continuous infusion, coadministration with albumin, and coadministration with metolazone or thiazides. This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of furosemide and bumetanide in pediatric patients. A better understanding of the clinical pharmacology of the loop diuretics should aid clinicians in the development of dosing regimens aimed at producing adequate diuresis without promoting excessive diuretic tolerance.

Bumetanide↗

PubMed1989

The deconjugation ability of bacteria isolated from the jejunal fluids in the blind loop syndrome with high 14CO2 excretion--using the breath analysis technique and thin-layer chromatography.

Five patients with blind loop syndrome (Billroth II) were examined by measuring 14CO2 specific activity of expired breath samples taken at intervals after a meal containing glycine-1-14C cholate. The 5 patients tested showed a marked increase of 14CO2 specific activity. Furthermore, the ability of deconjugation of bacteria isolated from the jejunal fluids in the efferent loop of these patients was tested by thin layer chromatography. The bacterial species identified from the samples were as follows: enterococcus, Lactobacillus (L) buchneri, L. bifidus, L. brevis, Eubacterium (E) lentum, Bacteroides (B) vulgaricus, B. filamentosum, Corynebacterium (C) granulosum, Escherichia (E) coli, Staphylococcus (S) epidermidis, and Aerobacter (A) aerogenes. These species of bacteria, except E. coli and A. aerogenes, showed the deconjugation ability by which conjugated bile acids in ox gall was hydrolyzed. Administration of chloramphenicol (1g per day for 14 days orally divided doses) to the 5 patients reduced 14CO2 specific activity significantly. On the other hand, 9 healthy men (control subjects) who were tested showed a flat curve, and 8 of the 9 had no growth of bacteria isolated from the jejunal fluids. The remaining healthy man showed an overgrowth of E. coli and Pseudomonas (P) aeruginosa, but the species did not have the ability of deconjugation. Thus, we concluded that the patients with blind loop syndrome(Billroth II) had the bacterial overgrowth in the efferent loop that contained species with deconjugation ability, and, as a result the bacterial overgrowth contributed to causing abnormalities (increased deconjugation) in the metabolism of bile acids in the small intestine. When the concentration of conjugated bile acids in the small intestine was reduced to levels below the critical micellar concentration by several factors, fat malabsorption and subsequent steatorrhea were induced (1,-4). Furthermore, H. Fromm and A. F. Hofmann presented in vivo that the patients with blind loop syndrome had fat malabsorption and the patients who had a high 14CO2 output after oral administration of glycine-1-14C cholate showed a low 14CO2 output after oral administration of antibiotic drug (5,6). However, there has been no report on the deconjugation ability of bile acids of bacteria isolated from the jejunal fluids in the efferent loop of patients with Billroth II who had positive breath tests.(ABSTRACT TRUNCATED AT 400 WORDS)

Bacteria↗

PubMed1989

The vulnerability of the thin descending limbs of Henle's loop in the isolated perfused rat kidney.

In the isolated rat kidney perfused without erythrocytes, the medullary thick ascending limb shows extensive injury. Damage to the thin limbs of Henle's loop has been mentioned only briefly. Thin limbs were examined in the isolated perfused kidney under a variety of conditions that alter oxygenation and active transport in the medulla and are known to affect injury to the medullary thick ascending limb. The thin descending limbs of short loops were preserved in all experimental groups, but those of the long loop showed necrosis that was restricted to the proximal portion, where the epithelium is more complex. In oxygenated kidneys, necrosis involved 41% +/- 5% (mean +/- SE) of the medullary thick ascending limbs and 10% +/- 3% of the proximal portion of long loops of thin descending limbs. Under hypoxic conditions, necrosis involved 90% +/- 3% of the medullary thick ascending limbs and 70% +/- 5% of the proximal portion of long loops of thin descending limbs (P less than 0.0001 compared with oxygenated kidneys). Ouabain and absence of filtration completely prevented necrosis of both nephron segments. Thus, the proximal portions of long loops of thin descending limbs, in resemblance to medullary thick ascending limbs, are especially susceptible to transport-dependent hypoxic injury.

Animals↗

PubMed1999

Crystal structure of mouse acetylcholinesterase. A peripheral site-occluding loop in a tetrameric assembly.

The crystal structure of mouse acetylcholinesterase at 2.9-A resolution reveals a tetrameric assembly of subunits with an antiparallel alignment of two canonical homodimers assembled through four-helix bundles. In the tetramer, a short Omega loop, composed of a cluster of hydrophobic residues conserved in mammalian acetylcholinesterases along with flanking alpha-helices, associates with the peripheral anionic site of the facing subunit and sterically occludes the entrance of the gorge leading to the active center. The inverse loop-peripheral site interaction occurs within the second pair of subunits, but the peripheral sites on the two loop-donor subunits remain freely accessible to the solvent. The position and complementarity of the peripheral site-occluding loop mimic the characteristics of the central loop of the peptidic inhibitor fasciculin bound to mouse acetylcholinesterase. Tetrameric forms of cholinesterases are widely distributed in nature and predominate in mammalian brain. This structure reveals a likely mode of subunit arrangement and suggests that the peripheral site, located near the rim of the gorge, is a site for association of neighboring subunits or heterologous proteins with interactive surface loops.

Acetylcholinesterase↗

PubMed1986

Chloride transport inhibition by various types of loop diuretics in fish opercular epithelium.

Isolated opercular epithelia of killifish (Fundulus heteroclitus), mounted in an Ussing chamber, were used to study the effects of various diuretics on chloride transport, measured as short-circuit current (SCC). The acidic 'loop' diuretics, ethacrynic acid and azosemide, and the basic 'loop' diuretics, muzolimine and MK 447, reduced SCC and exhibited similar dose-effect curves, with EC50s for SCC of 64, 17, greater than 500 and 224 microM, respectively. The alkaline diuretic tizolemide (HOE 740) and the p-COOH-analogue of sulphanilamide were inactive, suggesting that the chloruretic effects of these agents are of a thiazide type. The method can thus discriminate between the effects of loop and thiazide types of diuretics, but not between those of structurally highly different 'loop' diuretics of an acidic and basic nature. Monomethylation of the SO2NH2 group of bumetanide had no effect on the activity of this agent whereas dimethylation reduced it fourfold. The (-)enantiomers of the 'loop' diuretics indacrinone and ozolinone were four and greater than 100 times more active, respectively, than the (+)forms. These results are in accordance with those obtained for the same drugs in the mammalian kidney, and point to the presence of a highly specific binding site for these diuretics. Attempts were also made to explore the prerequisites for binding of the loop diuretic to the active site. Pretreatment of the opercular epithelium with an alpha-L-fucose-binding lectin did not prevent the inhibitory actions of furosemide and indacrinone. Probenecid and (+)ozolinone, both of which block organic anion transport, did not prevent the effects of bumetanide and (-)ozolinone.

Animals↗

PubMed1987

Adaptation of the jejunal mucosa in the experimental blind loop syndrome: changes in paracellular conductance and tight junction structure.

Self-filling blind loops of rat jejunum exhibit hyperregenerative transformation of the mucosa. We used this experimental model to characterise mechanisms, which may occur under similar conditions in man (stagnant loop syndrome). Epithelial and subepithelial resistance were measured in the Ussing-chamber by voltage divider ratio measurements after positioning a microelectrode between epithelium and subepithelial tissue layers. In the blind loop, epithelial resistance increased from 8 +/- 1 to 23 +/- 1 omega cm2 and subepithelial resistance from 39 +/- 4 to 86 +/- 8 omega cm2 as compared with control jejunum. The increase in the subepithelial resistance was paralleled anatomically by an increase in the thickness of the subepithelial tissue layers from 63 +/- 4 microns to 177 +/- 19 microns. Ultrastructural analysis of the tight junction area by freeze fracture electron microscopy revealed an increase in the total junctional 'depth' in the crypts from 243 +/- 9 nm in control jejunum to 396 +/- 17 nm in the blind loop, while the number of horizontally oriented 'strands' remained unchanged. Villus tight junctions did not differ between blind loop and control. We interpret the alterations in the self-filling blind loop as an adaptive response of the epithelium which reduces backleakage of already absorbed electrolytes across the tight junction into the intestinal lumen. This mechanism is suitable to support the intestine in maintaining body electrolyte and water contents during cellular electrolyte malabsorption.

Adaptation, Physiological↗

PubMed1977

Maturation of diluting capacity in loop of Henle of rat superficial nephrons.

The postnatal development of renal diluting capacity was studied by free-flow micropuncture and by microdissection of single superficial loops of Henle in rats kept on a high salt diet. Total renal filtration rate, sodium absorption, total solute excretion, and systemic arterial pressure were monitored during single nephron evaluation at two maturational stages (12-15 days and 27-35 days postnatal). Nephron filtration rates were identical when measured in early distal and late proximal segments of the same nephron. Absolute fluid absorption between these sites increased by a factor of 2.5, whereas loop fractional absorption of the volume load changed from 38.1 +/- 6.9 to 49.8 +/- 4.8% (SD), while proximal volume delivery to the loop increased from 4.33 +/- 1.12 to 7.14 +/- 0.65 nl/min. Simultaneously, the osmolarity of early distal fluid (8.8% of distal length) decreased significantly from 284 + 19.8 to 180.9 +/- 18.2 mosmol/liter during maturation. This study suggests that the ability of the loop of Henle to generate hypotonic fluid is attained only gradually during ontogeny. Volume absorption in the loop of Henle increases disproportionately to the loop volume load.

Absorption↗

PubMed1990

Amino acid transport: microinfusion and micropuncture of Henle's loops and vasa recta.

Amino acids appear to be reabsorbed distal to the tips of loops of Henle and may be recycled between loops and vasa recta in rat papilla. These possibilities were examined further by microinfusion and micropuncture of loops of Henle and vasa recta. To obtain information on the specificity of amino acid transport distal to the tips of the loops, ascending limbs were continuously microinfused with radioactively labeled L- and D-alanine, L-glutamate, taurine, and mannitol. About 30% of the L- and D-alanine and L-glutamate but none of the taurine or mannitol appeared to be reabsorbed. These results suggest that an acidic and a neutral amino acid are reabsorbed to a similar extent, that reabsorption is not stereospecific, but that it does not occur indiscriminately for all amino acids or for all molecules of similar size. Continuous microinfusion of ascending vasa recta with radioactively labeled L- and D-alanine suggests that amino acids may be able to move from vasa recta into tubules (apparently loops of Henle) without first entering the systemic circulation. However, micropuncture measurements of concentrations of endogenous amino acids in thin ascending limbs and adjacent descending vasa recta do not demonstrate a gradient for passive movement out of loops.

Alanine↗

PubMed1991

Specificity of amino acid transport in renal papilla: microinfusion of Henle's loops and vasa recta.

Amino acids can be reabsorbed distal to tips of Henle's loops and may be recycled between loops and vasa recta in rat papilla. Transport specificity was examined during continuous microinfusions of ascending Henle's loops and vasa recta with radiolabeled amino acids. Percent of recovered radiolabel as intact amino acid was also determined. Previous data indicated that, relative to simultaneously microinfused inulin, 30-40% of radiolabeled L- and D-Ala, L-Glu, L-Glu(NH2), and Gly, but no taurine (Tau) or mannitol, microinfused into Henle's loops was reabsorbed. In the present study, reabsorption was shown to involve intact L- and D-Ala, D-Glu, and L-Ser. L-Phe (50 mM) in infusate had no effect on reabsorption of L-Ala (2.5 mM) or L-Glu(NH2) (42.6 microM), and D-Asp (50 mM) had no effect on reabsorption of L-Glu (1.5 mM). Thus reabsorption from Henle's loops is not stereospecific, not different for neutral and acidic amino acids, and not inhibited by competitive inhibitors of proximal tubule amino acid transport, but it was not completely nonspecific and not a simple leak. Previous vasa recta microinfusions suggested that Ala could move directly from vasa recta to tubules. These studies were extended with simultaneous collections from ipsilateral and contralateral kidneys. Relative to simultaneously microinfused inulin, 40-50% of radiolabeled L- and D-Ala, L-Glu, and L-Glu(NH2) and 30% of L-Ser microinfused into ascending vasa recta appeared intact in urine from ipsilateral kidney, whereas only 1-3% appeared in urine from contralateral kidney. Fifty percent of infused D-Glu was excreted intact by each kidney; 70% of infused Tau was excreted intact by ipsilateral kidney, and 22% was excreted by contralateral kidney. L-Phe (50 mM) in infusate inhibited appearance of L-Ala (2.5 mM) and D-Ala (10 mM) but not L-Glu(NH2) (42.6 microM) in ipsilateral urine. D-Asp (50 mM) inhibited appearance of L-Glu (1.5 mM), and beta-Ala (50 mM) inhibited appearance of Tau (78 microM) in ipsilateral urine. Thus some amino acids can move directly from vasa recta into tubules (probably descending thin limbs of Henle's loops) by a process showing significant specificity.

Alanine↗

PubMed1984

Effect of loop of Henle flow rate on glomerular capillary pressure.

Studies were performed in male Munich-Wistar rats weighing a mean of 100 g to evaluate further the hemodynamic effects of changing loop of Henle flow rate. When late proximal flow rate was varied by microperfusion from the late proximal tubule, single nephron glomerular filtration rate (SNGFR) measured in the early proximal tubule fell from 17.2 +/- 0.86 nl min-1 at a perfusion rate of zero to 11.8 +/- 0.88 nl min-1 at a perfusion rate of 14 nl min-1. Further increases in loop flow did not further depress SNGFR. Glomerular capillary pressure (Pgc) was measured directly in superficial glomeruli while loop of Henle flow was varied. Elevating loop flow was followed by a rapid decrease in Pgc, which was reversible when flow was reduced. The mean response to maximum stimulation was a decrease in Pgc of 6.6 +/- 0.7 mm Hg, and the response was close to maximum at a perfusion rate of 14 nl min-1. Parallel changes in stop-flow pressure were observed. These findings, together with previous observations that increasing loop of Henle flow results in decreased single nephron blood flow, permit the conclusion that the dominant vascular response to elevated loop of Henle flow is constriction of the afferent arteriole.

Animals↗

PubMed1977

Evidence for a concentration gradient favoring outward movement of sodium from the thin loop of Henle.

Recent models of the urinary concentrating mechanism have postulated that urea in the medullary interstitium creates a transtubular concentration gradient for sodium between fluid at the end of the descending limb of Henle's loop and the medullary interstitium, favoring the passive outward movement of sodium from Henle's thin ascending limb. These experiments were designed to determine whether such a gradient normally exists. Young nondiuretic Munich-Wistar rats were prepared for micropuncture of the exposed left renal papilla. Samples of loop of Henle fluid and vasa recta plasma (assumed to reflect the composition of interstitial fluid) were obtained from adjacent sites. Loop fluid values in 21 comparisons from 18 rats (mean +/- SE) were: sodium 344 +/- 12 meq/liter; potassium, 26 +/- 2 meq/liter; osmolality, 938 +/- 37 mosmol/kg H23. Vasa recta plasma values (in corresponding units of measurement) were: sodium, 284 +/- 11; potassium, 34 +/- 2; osmolality, 935 +/- 34. Mean values of paired differences (loop fluid minus vasa recta plasma) were: delta sodium, 60 +/- 11.1 (P less than 0.001); delta potassium, -8.0 +/- 2.1 (P less than 0.001); delta osmolality, 4 +/- 16 (NS). Corrected for plasma water, the loop fluid minus vasa recta differences (in milliequivalents per kilogram H2O) were: delta sodium, 40 +/- 11.4 (P less than 0.005); delta potassium, -9.7 +/- 1.9 (P less than 0.001). We interpret these findings to indicate that in the papilla of nondiuretic rats, a significant difference in sodium concentration exists across the thin loop of Henle favoring outward movement of sodium, which confirms a key requirement of the passive models. A concentration difference for potassium in the reverse direction was also observed.

Animals↗

PubMed2001

Cell proliferation in the loop of henle in the developing rat kidney.

In the developing rat kidney, there is no separation of the medulla into an outer and inner zone. At the time of birth, ascending limbs with immature distal tubule epithelium are present throughout the renal medulla, all loops of Henle resemble the short loop of adult animals, and there are no ascending thin limbs. It was demonstrated previously that immature thick ascending limbs in the renal papilla are transformed into ascending thin limbs by apoptotic deletion of cells and transformation of the remaining cells into a thin squamous epithelium. However, it is not known whether this is the only source of ascending thin limb cells or whether cell proliferation occurs in the segment undergoing transformation. This study was designed to address these questions and to identify sites of cell proliferation in the loop of Henle. Rat pups, 1, 3, 5, 7, and 14 d old, received a single injection of 5-bromo-2'-deoxyuridine (BrdU) 18 h before preservation of kidneys for immunohistochemistry. Thick ascending and descending limbs were identified by labeling with antibodies against the serotonin receptor, 5-HT(1A), and aquaporin-1, respectively. Proliferating cells were identified with an antibody against BrdU. BrdU-positive cells in descending and ascending limbs of the loop of Henle were counted and expressed as percentages of the total number of aquaporin-1-positive and 5-HT(1A)-positive cells in the different segments. In the developing kidney, numerous BrdU-positive nuclei were observed in the nephrogenic zone. Outside of this location, BrdU-positive tubule cells were most prevalent in medullary rays in the inner cortex and in the outer medulla. BrdU-labeled cells were rare in the papillary portion of the loop of Henle and were not observed in the lower half of the papilla after 3 d of age. BrdU-labeled nuclei were not observed in segments undergoing transformation or in newly formed ascending thin limb epithelium. It was concluded that the growth zone for the loop of Henle is located around the corticomedullary junction, and the ascending thin limb is mainly, if not exclusively, derived from cells of the thick ascending limb.

Aging↗