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W Kriz

Publications and source records attributed to W Kriz.

At least 37 records · Page 2Linked to original sources
PubMed1999

Ganglioside GM2-activator protein and vesicular transport in collecting duct intercalated cells.

This study describes the molecular characterization of an antigen defined by an autoantibody from a woman with habitual abortion as GM2-activator protein. The patient showed no disorder of renal function. Accidentally with routine serum screening for autoantibodies, an immunoreactivity was found in kidney collecting duct intercalated cells. Three distinct patterns of immunostaining of intercalated cells were observed: staining of the apical pole, basolateral pole, and diffuse cytoplasmic labeling. Ultrastructurally, the immunoreactivity was associated with "studs," which represent the cytoplasmic domain of the vacuolar proton pump in intercalated cells. This pump is subjected to a shuttling mechanism from cytoplasmic stores to the cell membrane, which exclusively occurs in intercalated cells. Peptide sequences of a 23-kD protein purified from rat kidney cortex showed complete identity with corresponding sequences of GM2-activator protein. In the brain, GM2-activator protein is required for hexosaminidase A to split a sugar from ganglioside GM2. Because neither ganglioside GM2 nor GM1 (its precursor) is present in significant amounts in the kidney, the previous finding that this tissue contains the highest level of activator protein in the body was confusing. In this study, a novel role for GM2-activator protein in intercalated cells is proposed, and possible roles in the shuttling mechanism are discussed.

Abortion, Habitual↗
PubMed1998

Nonuniform microtubular polarity established by CHO1/MKLP1 motor protein is necessary for process formation of podocytes.

Podocytes are unique cells that are decisively involved in glomerular filtration. They are equipped with a complex process system consisting of major processes and foot processes whose function is insufficiently understood (Mundel, P., and W. Kriz. 1995. Anat. Embryol. 192:385-397). The major processes of podocytes contain a microtubular cytoskeleton. Taking advantage of a recently established cell culture system for podocytes with preserved ability to form processes (Mundel, P., J. Reiser, A. Zúñiga Mejía Borja, H. Pavenstädt, G.R. Davidson, W. Kriz, and R. Zeller. 1997b. Exp. Cell Res. 36:248-258), we studied the functional significance of the microtubular system in major processes. The following data were obtained: (a) Microtubules (MTs) in podocytes show a nonuniform polarity as revealed by hook-decoration. (b) CHO1/ MKLP1, a kinesin-like motor protein, is associated with MTs in podocytes. (c) Treatment of differentiating podocytes with CHO1/MKLP1 antisense oligonucleotides abolished the formation of processes and the nonuniform polarity of MTs. (d) During the recovery from taxol treatment, taxol-stabilized (nocodazole- resistant) MT fragments were distributed in the cell periphery along newly assembled nocodazole-sensitive MTs. A similar distribution pattern of CHO1/MKLP1 was found under these circumstances, indicating its association with MTs. (e) In the recovery phase after complete depolymerization, MTs reassembled exclusively at centrosomes. Taken together, these findings lead to the conclusion that the nonuniform MT polarity in podocytes established by CHO1/MKLP1 is necessary for process formation.

Animals↗
PubMed1998

Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism.

Mineralocorticoid receptor (MR)-deficient mice were generated by gene targeting. These animals had a normal prenatal development. During the first week of life, MR-deficient (-/-) mice developed symptoms of pseudohypoaldosteronism. They finally lost weight and eventually died at around day 10 after birth from dehydration by renal sodium and water loss. At day 8, -/- mice showed hyperkalemia, hyponatremia, and a strong increase in renin, angiotensin II, and aldosterone plasma concentrations. Methods were established to measure renal clearance and colonic transepithelial Na+ reabsorption in 8-day-old mice in vivo. The fractional renal Na+ excretion was elevated >8-fold. The glomerular filtration rate in -/- mice was not different from controls. The effect of amiloride on renal Na+ excretion and colonic transepithelial voltage reflects the function of amiloide-sensitive epithelial Na+ channels (ENaC). In -/- mice, it was reduced to 24% in the kidney and to 16% in the colon. There was, however, still significant residual ENaC-mediated Na+ reabsorption in both epithelia. RNase protection analysis of the subunits of ENaC and (Na++ K+)-ATPase did not reveal a decrease in -/- mice. The present data indicate that MR-deficient neonates die because they are not able to compensate renal Na+ loss. Regulation of Na+ reabsorption via MR is not achieved by transcriptional control of ENaC and (Na+ + K+)-ATPase in RNA abundance but by transcriptional control of other as yet unidentified genes. MR knockout mice will be a suitable tool for the search of these genes.

Amiloride↗
PubMed1998

The swelling-activated chloride channel ClC-2, the chloride channel ClC-3, and ClC-5, a chloride channel mutated in kidney stone disease, are expressed in distinct subpopulations of renal epithelial cells.

The mammalian genome encodes at least nine different members of the ClC family of chloride channels. So far only two of them could be localized on a cellular level in the kidney. We now report on the precise intrarenal localization of the mRNAs coding for the chloride channels ClC-2, ClC-3 and ClC-5. Expression of ClC-2 mRNA, encoding a swelling-activated chloride channel, could be demonstrated in the S3 segment of the proximal tubule. The chloride channel ClC-3 mRNA and ClC-5 mRNA, coding for a chloride channel mutated in kidney stone disease, were both expressed in intercalated cells of the connecting tubule and collecting duct. Whereas ClC-3 mRNA expression was most prominent in the cortex of rat kidneys, ClC-5 mRNA was expressed from the cortex through the upper portion of the inner medulla. A detailed analysis revealed that ClC-3 was expressed by type B intercalated cells, whereas ClC-5 was expressed by type A intercalated cells. These findings have important implications for the pathogenesis of hereditary kidney stone disease caused by mutations in the CLCN5 gene.

Animals↗
PubMed1998

The vascular pole of the renal glomerulus of rat.

In the present study we provide a detailed structural analysis of the vascular pole of superficial and midcortical glomeruli of the rat kidney. A description of the juxtaglomerular portions of the afferent and efferent arterioles, the extraglomerular mesangium and the glomerular stalk is included. The specific structural elaboration of the epithelial transition from the podocytes to the parietal epithelium is emphasized, with particular attention to the arrangement of the cytoskeleton and its connections to extracellular matrix elements. The branching patterns of the afferent and efferent arterioles are quite different. Immediately at the glomerular entrance, the afferent arteriole divides into its primary branches. In contrast, the efferent arteriole has a specific outflow segment (consisting of an intraglomerular portion and a portion associated with the extraglomerular mesangium) established by the confluence of capillary tributaries deep inside the glomerular tuft. Just at the transition from inside to outside, this segment includes a prominent narrow portion with conspicuous endothelial cells bulging into the vessel lumen. The extraglomerular mesangium has been found to represent a solid block of cells and matrix filling the space between the macula densa and both arterioles and extending into the entrance funnel. Peripherally located extraglomerular mesangial cells attach to the outer aspect of the parietal basement membrane. As a whole, the extraglomerular mesangium occludes the glomerular tuft. The results appear relevant with respect to four major aspects: (1) a support function counteracting the expansile forces resulting from the high intraglomerular pressures, (2) a direct functional influence of the afferent on the efferent arteriole, resulting from their narrow assemblage at the glomerular entrance, (3) a specific shear stress receptor function of the intraglomerular segment of the efferent arteriole, and (4) fluid leakage from the glomerular tuft through the stalk and the extraglomerular mesangium into the cortical interstitium. 1. The glomerulus is a high-pressure compartment; expansile forces continuously tend to expand glomerular capillaries, the glomerular stalk, and the glomerular entrance. Counteracting centripetal forces at the vascular pole appear to be developed as circular forces by the cytoskeleton of podocytes and parietal cells surrounding the glomerular entrance and as interconnecting forces between both arterioles and between opposing walls of the glomerular entrance, as well as of the glomerular stalk. These interconnecting forces are developed by the extraglomerular mesangium which--as a whole--forms a spiderlike closure device holding the glomerular entrance together. In addition, the extraglomerular mesangium develops occluding forces, allowing a gradual pressure drop between the glomerular stalk and the macula densa. 2. At the glomerular entrance, the outflow segment of the efferent arteriole is narrowly associated with the bifurcation of the afferent arteriole. Both are enclosed together in a common compartment surrounded by the glomerular basement membrane; there is no pressure barrier individually encompassing each vessel. Therefore, it may readily be suggested that the hydrostatic pressure of the afferent arteriole acts on the efferent arteriole. As a consequence, the luminal width of the efferent arteriole at this site, i.e., its resistance, may be directly modified by the pressure in the afferent arteriole. 3. The efferent arteriole at the transition of the intraglomerular segment to the segment that passes through the extraglomerular mesangium has a conspicuously narrow portion with endothelial cells protruding into the vessel lumen. In addition, this segment is prominent by the expression of the neuronal type of nitric oxide synthase. We therefore propose that this segment acts as a specific shear stress receptor. The possible relevance of a shear stress receptor at this site would be

Animals↗
PubMed1998

Whole-body hyperthermia combined with ifosfamide and carboplatin causes hypotension and nephrotoxicity.

It was previously postulated on the basis of clinical data that the cardiovascular sequelae of extracorporeal whole-body hyperthermia (e-WBH), i.e., hypotension (which requires catecholamine support) results in unique nephrotoxicity in combination with select chemotherapeutic agents. In an attempt to explain this phenomenon, we mimicked e-WBH physiological conditions in a rat model. Animals were treated with and without ifosfamide (IFO) and/or carboplatin (CBDCA) at 37 degrees C or 41.5-41.8 degrees C, with blood pressure monitoring and catecholamine support comparable to the clinical setting. Ex vivo post-treatment data (24 h) from artificially perfused kidneys (i.e., histology, urine volume, perfusion rate, glomerular filtration rate, and the reabsorption of sodium, glucose, and water) demonstrated unique toxicity including proximal tubular necrosis for the combination of WBH and IFO, for WBH and CBDCA and for WBH and IFO plus CBDCA, but not for IFO and CBDCA without WBH. These data, considered together with results derived from a subsequent clinical trial and the laboratory work of others were consistent with the hypothesis.

Animals↗
PubMed1998

Progression of glomerular diseases: is the podocyte the culprit?

The stereotyped development of the glomerular lesions in many animal models and human forms of progressive renal disease suggests that there are common mechanisms of disease progression. We propose the outline of such a mechanism based on following aspects: (1) The glomerulus is a complex structure, the stability of which depends on the cooperative function of the basement membrane, mesangial cells and podocytes, counteracting the distending forces originating from the high glomerular hydrostatic pressures. Failure of this system leads to quite uniform architectural lesions. (2) There is strong evidence that the podocyte is incapable of regenerative replication post-natally; when podocytes are lost for any reason they cannot be replaced by new cells. Loss of podocytes may therefore lead to areas of "bare" GBM. which represent potential starting points for irreversible glomerular injury. (3) Attachment of parietal epithelial cells to bare GBM invariably occurs when bare GBM coexists with architectural lesions, leading to the formation of a tuft adhesion to Bowman's capsule, the first "committed" lesion progressing to segmental sclerosis. (4) Within an adhesion the tuft merges with the interstitium, allowing filtration from perfused capillaries inside the adhesion towards the interstitium. The relevance of such filtration is as yet unclear but may play a considerable role in progression to global sclerosis and interstitial fibrosis.

Humans↗
PubMed1998

Oligonephronia, not exuberant apoptosis, accounts for the development of glomerulosclerosis in the bcl-2 knockout mouse.

BACKGROUND: A main function attributed to B cell leukaemia/lymphoma 2 gene (bcL-2) is its ability to confer resistance against apoptosis. In bcl-2 deficient mice, extensive apoptosis occurs during abnormal nephrogenesis, and renal failure is found very quickly after birth. However, the underlying mechanisms remain poorly understood. The aim of the present study was to clarify whether the degenerative process in the kidneys seen after birth is based either on increased apoptosis of glomerular cells or on mechanisms independent from the genetic defect. MATERIALS AND METHODS: Kidneys from 7-56-day-old bcl-2 knockout mice and wild-type litter mates were studied. Glomerular number, glomerular tuft volume, cell counts in 'non-sclerotic' glomeruli as well as the glomerular damage score were determined by histomorphometrical studies. Apoptosis was evaluated by morphological criteria and the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL)-technique. RESULTS: The number of nephrons at birth was severely decreased in bcl-2 knockout mice compared to controls (<20%; P < 0.001). These nephrons undergo dramatic hypertrophy with an approximately 4-fold increase in volume (P < 0.001). In hypertrophic, but 'non-sclerotic' glomeruli, the number density of glomerular cells progressively declined with time (P<0.001). Starting with day 20, enlarged glomeruli developed sclerosis beginning with a segmental distribution, but quickly progressing to global sclerosis. Apoptosis was neither detected in non-sclerotic glomeruli nor in stages prior to fully established sclerosis. As shown by the glomerular damage score, post-natal degeneration of kidneys from bcl-2 knockout animals proceeded rapidly. CONCLUSIONS: Bcl-2 knockout mice exhibit deficient nephrogenesis resulting in severe oligonephronia at birth. Post-partum development of glomerulosclerosis does not seem to be due to augmented apoptosis. The degenerative process appears to be based on a glomerular overload with increased mechanical stress to the filtration barrier, leading via glomerular hypertrophy, podocyte damage and formation of tuft adhesions to glomerulosclerosis.

Animals↗
PubMed1998

From segmental glomerulosclerosis to total nephron degeneration and interstitial fibrosis: a histopathological study in rat models and human glomerulopathies.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is consistently associated with tubular degeneration and interstitial fibrosis, altogether, accounting for the progressive decline in renal function. The mechanisms which link glomerular injury to tubulo-interstitial fibrosis are controversial. The present study describes the step-by-step sequence of histopathological events, i.e. the evolution of the injury from the initial lesion in the glomerulus to total nephron destruction. METHODS: The investigation was performed in male hypertensive Fawn-hooded rats (6-, 9-, and 12-month-old) and 14-month-old Milan normotensive rats. The kidneys were fixed by in vivo perfusion and processed for structural investigation. Autopsy materials from human cases of focal segmental glomerulosclerosis and diabetic nephropathy were also examined. RESULTS: FSGS as seen in rat models consists of collapsed and hyalinized capillaries and mesangial portions which are included within a synechia between the glomerular tuft and Bowman's capsule. In addition, a synechia generally contains glomerular capillaries which are perfused and continue to filter with the filtrate being delivered into the interstitium rather than into Bowman's capsular space. Such filtration creates a paraglomerular space on the outer aspect of the parietal epithelium. This space becomes separated from the interstitium by a dense layer of sheet-like fibroblast processes. Associated with the progression to global sclerosis, this space spreads around the entire circumference of a glomerulus; all 'sclerotic' tuft portions are eventually contained in this space. Starting from the urinary pole this process also involves the proximal tubule, initially by expanding the tubular basement membrane (TBM) and later, by separating the TBM from its epithelium, thus creating a peritubular space by misdirected filtrate spreading. Similar to the situation observed at the glomerulus this space becomes separated from the interstitium by a layer of fibroblast processes. The final degeneration of the nephron occurs via two pathways. Pathway I whereby development to global sclerosis is dominant or develops concurrently with tubular degeneration, eventually terminating in global and cylindrical remnants of extracellular matrix surrounded by abundant fibrous tissue. Pathway II where the degeneration of the tubule is ahead of damage progression in the glomerulus leading to atubular glomerular cysts. CONCLUSION: The present study suggests that severely injured glomeruli may continue to filter with the filtrate spreading along interstitial routes. Fluid added locally to the interstitium from such 'extraterritorial' glomerular capillaries probably is quite different in quantity and composition compared to that from interstitial capillaries. We propose that this kind of abnormal addition of fluid to the interstitium is the essential mechanism accounting for interstitial progression of the disease. Similar histopathological phenomena in human kidneys with focal segmental glomerulosclerosis suggest that the pathogenetic pathways defined in the rat models operate in human disease as well.

Animals↗
PubMed1998

Kid-1 expression is high in differentiated renal proximal tubule cells and suppressed in cyst epithelia.

The cDNA coding for the transcriptional repressor protein Kid-1 was cloned in a screen for zinc finger proteins, which are regulated during renal development and after renal ischemia. Kid-1 mRNA levels increase in the course of postnatal renal development and decrease after acute renal injury caused by ischemia or administration of folic acid. We have raised a monoclonal anti-Kid-1 antibody and demonstrate that the Kid-1 protein is strongly expressed in the proximal tubule of the adult rat kidney. During nephron development, the Kid-1 protein appears after the S-shaped body stage concomitantly with the brush-border enzyme alkaline phosphatase. In two animal models of polycystic kidney disease, the expression of Kid-1 is downregulated. The loss of expression of Kid-1 in cyst wall cells correlates with the loss of alkaline phosphatase histochemical staining. Kid-1 mRNA levels are also reduced in rodent renal cell carcinomas, another condition characterized by epithelial cell dedifferentiation and increased proliferation. We propose that Kid-1 plays an important role during the differentiation of the proximal tubule.

Aging↗
PubMed1998

Development of vascular pole-associated glomerulosclerosis in the Fawn-hooded rat.

Fawn-hooded hypertensive (FHH) rats constitute a spontaneous model of chronic renal failure with early systemic and glomerular hypertension, proteinuria, and development of focal and segmental glomerulosclerosis. The goal of the present study was to elucidate a step-by-step sequence of histopathologic events leading from an initial glomerular injury to segmental sclerosis. Segmental sclerosis in the FHH rat is consistently associated with the glomerular vascular pole. The initial injury involves the expansion of primary branches of the afferent arteriole. Apposition of those capillaries to Bowman's capsule, together with the degeneration and detachment of corresponding podocytes, allows parietal cells to attach to the naked glomerular basement membrane of this capillary, i.e., allows the formation of a tuft adhesion to Bowman's capsule. The adhesion enlarges to a broad synechia by encroaching to neighboring capillaries, apparently based on progressive podocyte degeneration at the flanks of the adhesion. Capillaries inside the adhesion--before undergoing collapse or hyalinization--appear to stay perfused for some time and to maintain some kind of filtration misdirected toward the cortical interstitium. Thereby, a prominent paraglomerular space comes into existence, enlarging in parallel with the adhesion. Toward the cortical interstitium this space is delimited by a layer of sheetlike fibroblast processes, which has obviously been assembled in response to the formation of this space. Toward the urinary space, the paraglomerular space is demarcated by the parietal epithelium and by the interface between the adhesion and the "intact" tuft remnant. Thus, the sclerotic tuft portions all become enclosed within the paraglomerular space.

Animals↗
PubMed1997

The Krüppel-associated box (KRAB)-zinc finger protein Kid-1 and the Wilms' tumor protein WT1, two transcriptional repressor proteins, bind to heteroduplex DNA.

Zinc finger proteins of the Cys2His2 class represent a large group of DNA-binding proteins. A major subfamily of those proteins, the Krüppel-associated box (KRAB) domain-containing Cys2His2-zinc finger proteins, have been described as potent transcriptional repressors. So far, however, no DNA-binding sites for KRAB domain-containing zinc finger proteins have been isolated. Using a polymerase chain reaction-based selection strategy with double- and single-stranded DNA, we failed to reveal a binding site for Kid-1, one member of KRAB-zinc finger proteins. Binding of Kid-1 both to single- and homoduplex double-stranded DNA was negligible. We now present evidence that Kid-1 binds to heteroduplex DNA. Similar to Kid-1, the non-KRAB-zinc finger protein WT1 also bound avidly to heteroduplex DNA (both the -KTS and +KTS splice variant of WT1), whereas the POU domain protein Oct-6, the ets domain protein Ets-1 and the RING finger of BRCA-1 did not bind to heteroduplex DNA. Binding of WT1 to heteroduplex DNA was markedly reduced in naturally occurring mutants. The recognition of certain DNA structures by transcriptional repressor proteins may therefore represent a more common phenomenon than previously thought.

DNA↗
PubMed1997

Rearrangements of the cytoskeleton and cell contacts induce process formation during differentiation of conditionally immortalized mouse podocyte cell lines.

Mature podocytes are among the most complex differentiated cells and possess a highly branched array of foot processes that are essential to glomerular filtration in the kidney. Such differentiated podocytes are unable to replicate and culturing of primary podocytes results in rapid growth arrest. Therefore, conditionally immortalized mouse podocyte clones (MPC) were established, which are highly proliferative when cultured under permissive conditions. Nonpermissive conditions render the majority of MPC cells growth arrested within 6 days and induce many characteristics of differentiated podocytes. Both proliferating and differentiating MPC cells express the WT-1 protein and an ordered array of actin fibers and microtubules extends into the forming cellular processes during differentiation, reminiscent of podocyte processes in vivo. These cytoskeletal rearrangements and process formation are accompanied by the onset of synaptopodin synthesis, an actin-associated protein marking specifically differentiated podocytes. In addition, focal contacts are rearranged into an ordered pattern in differentiating MPC cells. Most importantly, electrophysiological studies demonstrate that differentiated MPC cells respond to the vasoactive peptide bradykinin by changes in intracellular calcium concentration. These results suggest a regulatory role of podocytes in glomerular filtration. Taken together, these studies establish that conditionally immortalized MPC cells retain a differentiation potential similar to podocytes in vivo. Therefore, the determinative steps of podocyte differentiation and process formation are studied for the first time using an inducible in vitro model.

Animals↗
PubMed1997

Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes.

Synaptopodin is an actin-associated protein of differentiated podocytes that also occurs as part of the actin cytoskeleton of postsynaptic densities (PSD) and associated dendritic spines in a subpopulation of exclusively telencephalic synapses. Amino acid sequences determined in purified rat kidney and forebrain synaptopodin and derived from human and mouse brain cDNA clones show no significant homology to any known protein. In particular, synaptopodin does not contain functional domains found in receptor-clustering PSD proteins. The open reading frame of synaptopodin encodes a polypeptide with a calculated Mr of 73.7 kD (human)/74.0 kD (mouse) and an isoelectric point of 9.38 (human)/9. 27 (mouse). Synaptopodin contains a high amount of proline ( approximately 20%) equally distributed along the protein, thus virtually excluding the formation of any globular domain. Sequence comparison between human and mouse synaptopodin revealed 84% identity at the protein level. In both brain and kidney, in vivo and in vitro, synaptopodin gene expression is differentiation dependent. During postnatal maturation of rat brain, synaptopodin is first detected by Western blot analysis at day 15 and reaches maximum expression in the adult animal. The exclusive synaptopodin synthesis in the telencephalon has been confirmed by in situ hybridization, where synaptopodin mRNA is only found in perikarya of the olfactory bulb, cerebral cortex, striatum, and hippocampus, i.e., the expression is restricted to areas of high synaptic plasticity. From these results and experiments with cultured cells we conclude that synaptopodin represents a novel kind of proline-rich, actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and podocyte foot processes.

Actins↗
PubMed1997

Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: a podocyte disease.

In Milan normotensive (MNS) rats glomerulosclerosis and interstitial fibrosis develop spontaneously in the absence of hypertension. Renal changes were sequentially assessed in these rats between 2 and 10 months of age. At 10 months, rats were characterized by heavy proteinuria, increased serum creatinine, focal or global glomerulosclerosis in 51 +/- 12% of the glomeruli as well as tubulointerstitial injury involving > 25% of the section area. Cell injury in podocytes (evidenced as increased expression of desmin and by electron microscopy) and interstitial fibroblasts (increased expression of alpha-smooth muscle actin) and mild glomerular hypertrophy were witnessed as early as three to four months of age and preceded glomerulosclerosis and interstitial fibrosis. Only minor evidence of mesangial cell activation (as assessed by glomerular (de novo alpha-smooth muscle actin or type I collagen expression or increased cell proliferation) was noted throughout the observation period. Later stages of the disease were characterized by glomerular and/or tubulointerstitial macrophage influx and osteopontin expression (a chemoattractant), mild accumulation of lymphocytes, platelets, fibrinogen, as well as by a progressive accumulation of various matrix proteins. Progressive renal disease in MNS rats is thus noteworthy for the relative lack of mesangial cell activation. Rather, early podocyte damage, induced by yet unknown mechanisms, may underlie the development of glomerulosclerosis and subsequent interstitial fibrosis.

Actins↗
PubMed1997

Renal osmotic stress-induced cotransporter: expression in the newborn, adult and post-ischemic rat kidney.

The renal osmotic stress-induced cotransporter (ROSIT), a new putative member of a family of organic solute transporters, is highly expressed in the kidney. Our in situ hybridization data now reveal that large amounts of ROSIT mRNA can be found in the S3 segment of the proximal tubule. In the developing kidney, ROSIT mRNA is expressed after the S-shaped body stage. Because the S3 segment is the major site of damage in the post-ischemic kidney, we evaluated alterations in ROSIT mRNA expression after ischemic acute tubular necrosis. Renal osmotic stress-induced cotransporter mRNA levels were already decreased eight hours post-ischemia. At seven days post-ischemia, ROSIT mRNA reappeared in a mosaic pattern in the regenerating S3 segment, being fully expressed three weeks after the insult except for focal areas. The exact localization of this putative osmolyte transporter in the kidney, together with that of other known osmolyte transporter will contribute to a better understanding of the mechanism of medullary osmolyte accumulation and its vectorial transport.

Age Factors↗