SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Nephron

194

Abatacept (cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin fusion protein [CTLA-4-Ig]) is a costimulatory inhibitor that targets B7-1 (CD80). The present report describes five patients who had focal segmental glomerulosclerosis (FSGS) (four with recurrent FSGS after transplantation and one with primary FSGS) and proteinuria with B7-1 immunostaining of podocytes in kidney-biopsy specimens. Abatacept induced partial or complete remissions of proteinuria in these patients, suggesting that B7-1 may be a useful biomarker for the treatment of some glomerulopathies. Our data indicate that abatacept may stabilize β1-integrin activation in podocytes and reduce proteinuria in patients with B7-1-positive glomerular disease.

Concepts: Nephron, Glomerulus, Protein, Proteinuria, CTLA-4, Glomerulosclerosis, Nephrotic syndrome, Focal segmental glomerulosclerosis

167

Juxtaglomerular neurons represent one of the largest cellular populations in the mammalian olfactory bulb yet their role for signal processing remains unclear. We used two-photon imaging and electrophysiological recordings to clarify the properties of these cells and their functional organization in the juxtaglomerular space. Juxtaglomerular neurons coded for many perceptual characteristics of the olfactory stimulus such as (1) identity of the odorant, (2) odorant concentration, (3) odorant onset, and (4) offset. The odor-responsive neurons clustered within a narrow area surrounding the glomerulus with the same odorant specificity, with ~80% of responding cells located ≤20 μm from the glomerular border. This stereotypic spatial pattern of activated cells persisted at different odorant concentrations and was found for neurons both activated and inhibited by the odorant. Our data identify a principal glomerulus with a narrow shell of juxtaglomerular neurons as a basic odor coding unit in the glomerular layer and underline the important role of intraglomerular circuitry.

Concepts: Olfactory receptor neuron, Potassium, Nephron, Action potential, Odor, Olfaction, Olfactory system, Olfactory bulb

164

Renal proximal tubular epithelial cells play a central role in renal physiology and are among the cell types most sensitive to ischemia and xenobiotic nephrotoxicity. In order to investigate the molecular and cellular mechanisms underlying the pathophysiology of kidney injuries, a stable and well-characterized primary culture model of proximal tubular cells is required. An existing model of proximal tubular cells is hampered by the cellular heterogeneity of kidney; a method based on cell sorting for specific markers must therefore be developed. In this study, we present a primary culture model based on the mechanical and enzymatic dissociation of healthy tissue obtained from nephrectomy specimens. Renal epithelial cells were sorted using co-labeling for CD10 and CD13, two renal proximal tubular epithelial markers, by flow cytometry. Their purity, phenotypic stability and functional properties were evaluated over several passages. Our results demonstrate that CD10/CD13 double-positive cells constitute a pure, functional and stable proximal tubular epithelial cell population that displays proximal tubule markers and epithelial characteristics over the long term, whereas cells positive for either CD10 or CD13 alone appear to be heterogeneous. In conclusion, this study describes a method for establishing a robust renal proximal tubular epithelial cell model suitable for further experimentation.

Concepts: Renal cortex, Renal pelvis, Skin, Nephron, Flow cytometry, Epithelium, Cell biology, Kidney

39

Three-dimensional models of kidney tissue that recapitulate human responses are needed for drug screening, disease modeling, and, ultimately, kidney organ engineering. Here, we report a bioprinting method for creating 3D human renal proximal tubules in vitro that are fully embedded within an extracellular matrix and housed in perfusable tissue chips, allowing them to be maintained for greater than two months. Their convoluted tubular architecture is circumscribed by proximal tubule epithelial cells and actively perfused through the open lumen. These engineered 3D proximal tubules on chip exhibit significantly enhanced epithelial morphology and functional properties relative to the same cells grown on 2D controls with or without perfusion. Upon introducing the nephrotoxin, Cyclosporine A, the epithelial barrier is disrupted in a dose-dependent manner. Our bioprinting method provides a new route for programmably fabricating advanced human kidney tissue models on demand.

Concepts: Basement membrane, Renal pelvis, Nephrotoxicity, Organ, Skin, Nephron, Extracellular matrix, Kidney

36

Lithium is a widely used and highly effective treatment for mood disorders, but causes poorly characterised adverse effects in kidney and endocrine systems. We aimed to analyse laboratory information system data to determine the incidence of renal, thyroid, and parathyroid dysfunction associated with lithium use.

Concepts: Retrospective, Systems theory, Parathyroid gland, Renin-angiotensin system, Nephron, Kidney, Thyroid, Endocrine system

28

Vasopressin modulates sodium reabsorption in the collecting duct through adenylyl cyclase-stimulated cyclic AMP, which exists as multiple isoforms; the specific isoform involved in vasopressin-stimulated sodium transport is unknown. To assess this, we studied mice deficient in adenylyl cyclase type VI specifically in the principal cells of the collecting duct. Knockout mice had increased urine volume and reduced urine sodium concentration, but regardless of the level of sodium intake, they did not exhibit significant alterations in urinary sodium excretion, arterial pressure, or pulse rate. Plasma renin concentration was elevated in knockout mice, however, suggesting a compensatory response. Valsartan significantly reduced arterial pressure in knockout mice but not in controls. Knockout mice had decreased renal cortical mRNA content of all three epithelial sodium channel (ENaC) isoforms, and total cell sodium channel isoforms α and γ were reduced in these animals. Patch-clamp analysis of split-open cortical collecting ducts revealed no difference in baseline activity of sodium channels, but knockout mice had abolished vasopressin-stimulated ENaC open probability and apical membrane channel number. In summary, these data suggest that adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity in the kidney.

Concepts: Renin, Collecting duct system, Renal physiology, Nephron, Aldosterone, Blood pressure, Sodium, Kidney

28

Background: Tissue engineering of functional kidney tissue is an important goal for clinical restoration of renal function in patients damaged by infectious, toxicological, or genetic disease. One promising approach is the use of the self-organizing abilities of embryonic kidney cells to arrange themselves, from a simply reaggregated cell suspension, into engineered organs similar to fetal kidneys. The previous state-of-the-art method for this results in the formation of a branched collecting duct tree, immature nephrons (S-shaped bodies) beside and connected to it, and supportive stroma. It does not, though, result in the significant formation of morphologically detectable loops of Henle - anatomical features of the nephron that are critical to physiological function. Methods: We have combined the best existing technique for renal tissue engineering from cell suspensions with a low-volume culture technique that allows intact kidney rudiments to make loops of Henle to test whether engineered kidneys can produce these loops. Results: The result is the formation of loops of Henle in engineered cultured ‘fetal kidneys’, very similar in both morphology and in number to those formed by intact organ rudiments. Conclusion: This brings the engineering technique one important step closer to production of a fully realistic organ.

Concepts: Renal corpuscle, Electrolyte, Nephrology, Renal physiology, Loop of Henle, Organ, Nephron, Kidney

28

The mode of renin release from renal juxtaglomerular cells into circulation is still unsolved in several aspects. Here we studied the intracellular organization of renin-storage vesicles and their changes during controlled stimulation of renin release. This was accomplished using isolated perfused mouse kidneys with 3-dimensional electron microscopic analyses of renin-producing cells. Renin was found to be stored in a network of single granules and cavern-like structures, and dependent on the synthesis of glycosylated prorenin. Acute stimulation of renin release led to increased exocytosis in combination with intracellular fusion of vesicles to larger caverns and their subsequent emptying. Renin release from the kidneys of SCID-beige mice, which contain few but gigantic renin-storage vesicles, was no different from that of kidneys from wild-type mice. Thus, our findings suggest that renin is released by mechanisms similar to compound exocytosis.Kidney International advance online publication, 12 December 2012; doi:10.1038/ki.2012.392.

Concepts: Cell membrane, Glucose, Juxtaglomerular apparatus, Juxtaglomerular cell, Kidney, Gene, Nephron, Renin

28

Background/Aims: Owing to the precarious blood supply to the renal medulla and the high metabolic requirement of the medullary thick ascending limb of Henle’s loop, this nephron segment should be especially vulnerable when its supply of O(2) declines. Methods: Rats were exposed to 8 or 21% O(2) at different time points up to 5 h, and samples were collected for urine flow rate, urine (U(osm)) and renal papillary (RP(osm)) osmolality, urinary excretion of Na(+), Cl(-), K(+) and Mg(2+), blood gases, erythropoietin and vasopressinase activity in plasma. Other groups of rats were pretreated with desmopressin acetate (dDAVP) or underwent bilateral nephrectomy (BNX) 1 h prior to the exposure. Results: Hypoxic rats had water diuresis (WD) within 2.5 h, as evidenced by lower U(osm) (333 ± 42 mosm/l) and RP(osm) (869 ± 57 mosm/l), thus suggesting that hypoxia led to a failure to achieve osmotic equilibrium within the renal papilla. Circulating vasopressinase activity increased, which was partially renal in origin because it was lower after BNX. The renal concentrating ability during hypoxia was maintained with dDAVP pretreatment, suggesting that dDAVP may have improved O(2) delivery and the active reabsorption of Na(+) in the renal medullary region. Conclusions: WD or high vasopressinase activity may be valuable diagnostic tools to assess renal medullary hypoxia. Pretreatment with dDAVP may prevent these changes during hypoxia.

Concepts: Thin ascending limb of loop of Henle, Distal convoluted tubule, Friedrich Gustav Jakob Henle, Renal medulla, Kidney anatomy, Loop of Henle, Nephron, Kidney

28

In the late 1980s, urea permeability measurements produced values that could not be explained by paracellular transport or lipid phase diffusion. The existence of urea transport proteins were thus proposed and less than a decade later, the first urea transporter was cloned. The family of urea transporters has two major subgroups, designated SLC14A1 (or UT-B) and Slc14A2 (or UT-A). UT-B and UT-A gene products are glycoproteins located in various extra-renal tissues however, a majority of the resulting isoforms are found in the kidney. The UT-B (Slc14A1) urea transporter was originally isolated from erythrocytes and two isoforms have been reported. In kidney, UT-B is located primarily in the descending vasa recta. The UT-A (Slc14A2) urea transporter yields six distinct isoforms, of which three are found chiefly in the kidney medulla. UT-A1 and UT-A3 are found in the inner medullary collecting duct (IMCD), while UT-A2 is located in the thin descending limb. These transporters are crucial to the kidney’s ability to concentrate urine. The regulation of urea transporter activity in the IMCD involves acute modification through phosphorylation and subsequent movement to the plasma membrane. UT-A1 and UT-A3 accumulate in the plasma membrane in response to stimulation by vasopressin or hypertonicity. Long-term regulation of the urea transporters in the IMCD involves altering protein abundance in response to changes in hydration status, low protein diets, or adrenal steroids. Urea transporters have been studied using animal models of disease including diabetes mellitus, lithium intoxication, hypertension, and nephrotoxic drug responses. Exciting new genetically engineered mouse models are being developed to study these transporters.

Concepts: Protein, Diabetes mellitus, Cell membrane, Nephron, Vasa recta, Urine, Loop of Henle, Kidney