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WIREs Syst Biol Med
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Kidney modeling and systems physiology

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Abstract We present an overview of currently available resources in renal systems physiology and indicate directions for development toward the renal physiome. After a brief resumé of objectives, we summarize legacy‐modeling studies that can serve as the foundation for a more complete toolset. These include detailed models of practically all renal cell types and nephron segments and a variety of models of nephro‐vascular exchanges in the medulla, of renal hemodynamics, and studies of tubuloglomerular feedback and autoregulation. Recent detailed anatomical reconstructions have brought surprising new results to bear on classic unsolved problems. In parallel with the modeling environment, progress has been made toward the quantitative database and model repository resources that must accompany the modeling environment in order to attain the goal of an open‐ended, flexible, and collaborative infrastructure for renal systems biology, with an indication of prospects for integration with initiatives in the larger IUPS Physiome Project. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Models of Systems Properties and Processes > Cellular Models Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Translational, Genomic, and Systems Medicine > Translational Medicine

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Schematic representations of epithelia in medullary tubules emphasize differentiation of luminal and basolateral cell membranes. (a) locations of epithelia in (b–e). (b) Proximal tubule cells are only sparsely interdigitated and contain few mitochondria. (c) Thin limb. Epithelia of short and of lower part of long descending thin limbs are remarkably undifferentiated. In ascending thin limb, epithelium the paracellular pathways are strikingly ‘leaky’ in appearance. (d) Medullary thick ascending limb. Basolateral interdigitated cell membranes narrowly associate with large plate‐like mitochondria. In cortical part, epithelium is generally less high, less interdigitated and stuffed with less mitochondria than in medullary part. (e) Two cell types of collecting ducts; both are of simple polygonal shape and do not interdigitate. Principal cell has an electron‐lucent cytoplasm and smooth apical surface. Intercalated cells frequently have an electron‐dense cytoplasm, filled with many vesicles and mitochondria. Apical cell surface may be stuffed with prominent microplicae or microvilli. (Reprinted with permission from Ref 25. Copyright 1981 The American Physiological Society).

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Basic anatomy of uni‐lobed mammalian kidneys. The tip of the conical IM is called the papilla. On the right, a short‐looped and a long‐looped nephron, together with the collecting duct system (not to scale). Within the cortex, a medullary ray is indicated with a dashed line. G, glomerulus; PCT, proximal convoluted tubule; LDL, long descending thin limb of Henle; LAL, long‐ascending thin limb of Henle (inner medulla only); MTAL, medullary thick limb of Henle (outer medulla only); DCT, distal convoluted tubule; CNT, connecting tubule; CCD, cortical collecting duct; OMCD, outer medullary collecting duct; IMCD, inner medullary collecting duct. The microvascular system (not shown), including the vasa recta of the medulla, surrounds this nephron system. (Adapted with permission from Ref 6. Copyright 1991 Springer‐Verlag, and Ref 7. Copyright 1986 Elsevier).

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A Grid‐based eResearch Architecture for Integration of Distributed Kidney Models. (Reprinted with permission from Ref 145. Copyright 2008 Wiley Periodicals, Inc.).

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Kidneyome Portal, with QKDB Query Pane. The three‐dimensional (3D) kidney was constructed from CT‐scans of a rat kidney. It can be rotated, zoomed, and disassembled using the computer mouse, to focus on a region or component of interest. One can then call up relevant models from the repository or launch a QKDB query.

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Side view of rat renal vasculature with vessel thickness proportional to a quarter the true radial value. Color of the arterial tree indicates vessel order stability. The venous tree exhibits the same information on a fading blue scale. (Reprinted with permission from Ref 127. Copyright 2006 The American Physiological Society).

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All short and long nephrons and collecting ducts traced within one mouse kidney. The red lines represent the renal capsule and the papilla. The white dots represent glomeruli (not actual size). Tubule segments are represented in different colors: PT, blue; thin limbs (TL), green; TAL, red; DCT, purple; connecting tubules (CNT), orange; and CD, brown. Scale = 50 µm. (Reprinted with permission from Ref 108. Copyright 2006 American Society of Nephrology).

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Three‐dimensional reconstruction of all papillary CDs (AQP2, blue), ATLs (ClC‐K1, green), and DTLs (α B‐crystallin, yellow) from a single kidney. Papillary surface epithelium is shown in gray. (a) Lateral view. (b) Axial view from papilla tip. Scale bars = 100 µm. (Reprinted with permission from Ref 126. Copyright 2007 The American Physiological Society).

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Mutations and polymorphisms altering blood pressure levels in humans. They have been identified in rare Mendelian forms of hypertension or hypotension or have been linked to essential hypertension. Most are present in genes involved directly or indirectly in renal sodium handling, i.e., genes coding for tubular sodium transport systems or for proteins belonging to regulatory pathways. (Reprinted with permission from Ref 56. Copyright 2000 The American Physiological Society).

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Schematic representations of published models of nephron segments. (a) Transport model for macula densa (MD) cells. (with permission from Ref. 28) (b) Schematic of distal convoluted tubule (DCT) cell showing coupled transport pathways and ion channels within luminal and peritubular membranes. The cell solute concentrations (mM) and solute fluxes (pmol/min/mm) correspond to a midtubule cell (0.5 mm from the tubule inlet). PD, potential difference. (with permission from Ref. 29) (c) Cellular transport pathways of late DT, CCD, OMCD, and IMCD, with luminal membranes facing left. (Reprinted with permission from Ref 30. Copyright 2002 The American Physiological Society).

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Translational, Genomic, and Systems Medicine > Translational Medicine
Physiology > Mammalian Physiology in Health and Disease
Models of Systems Properties and Processes > Cellular Models
Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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