Ascending Vasa Recta Are Angiopoietin/Tie2-Dependent Lymphatic-Like Vessels

Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism. Medullary hyperosmolarity is protected from washout by countercurrent exchange and efficient removal of interstitial fluid resorbed from the loop of Henle and collecting ducts. In most tissues, lymphatic vessels drain excess interstitial fluid back to the venous circulation. However, the renal medulla is devoid of classic lymphatics. Studies have suggested that the fenestrated ascending vasa recta (AVRs) drain the interstitial fluid in this location, but this function has not been conclusively shown. We report that late gestational deletion of the angiopoietin receptor endothelial tyrosine kinase 2 (Tie2) or both angiopoietin-1 and angiopoietin-2 prevents AVR formation in mice. The absence of AVR associated with rapid accumulation of fluid and cysts in the medullary interstitium, loss of medullary vascular bundles, and decreased urine concentrating ability. In transgenic reporter mice with normal angiopoietin-Tie2 signaling, medullary AVR exhibited an unusual hybrid endothelial phenotype, expressing lymphatic markers (prospero homeobox protein 1 and vascular endothelial growth factor receptor 3) as well as blood endothelial markers (CD34, endomucin, platelet endothelial cell adhesion molecule 1, and plasmalemmal vesicle–associated protein). Taken together, our data redefine the AVRs as Tie2 signaling–dependent specialized hybrid vessels and provide genetic evidence of the critical role of AVR in the countercurrent exchange mechanism and the structural integrity of the renal medulla.

Physiologic hypoxia and oxygen homeostasis in the healthy intestine. A Review in the Theme: Cellular Responses to Hypoxia

In recent years, the intestinal mucosa has proven to be an intriguing organ to study tissue oxygenation. The highly vascularized lamina propria juxtaposed to an anaerobic lumen containing trillions of metabolically active microbes results in one of the most austere tissue microenvironments in the body. Studies to date have determined that a healthy mucosa contains a steep oxygen gradient along the length of the intestine and from the lumen to the serosa. Advances in technology have allowed multiple independent measures and indicate that, in the healthy mucosa of the small and large intestine, the lumen-apposed epithelia experience Po2 conditions of <10 mmHg, so-called physiologic hypoxia. This unique physiology results from a combination of factors, including countercurrent exchange blood flow, fluctuating oxygen demands, epithelial metabolism, and oxygen diffusion into the lumen. Such conditions result in the activation of a number of hypoxia-related signaling processes, including stabilization of the transcription factor hypoxia-inducible factor. Here, we review the principles of mucosal oxygen delivery, metabolism, and end-point functional responses that result from this unique oxygenation profile.

Targeted delivery of solutes and oxygen in the renal medulla: role of microvessel architecture

Renal medullary function is characterized by corticopapillary concentration gradients of various molecules. One example is the generally decreasing axial gradient in oxygen tension (Po2). Another example, found in animals in the antidiuretic state, is a generally increasing axial solute gradient, consisting mostly of NaCl and urea. This osmolality gradient, which plays a principal role in the urine concentrating mechanism, is generally considered to involve countercurrent multiplication and countercurrent exchange, although the underlying mechanism is not fully understood. Radial oxygen and solute gradients in the transverse dimension of the medullary parenchyma have been hypothesized to occur, although strong experimental evidence in support of these gradients remains lacking. This review considers anatomic features of the renal medulla that may impact the formation and maintenance of oxygen and solute gradients. A better understanding of medullary architecture is essential for more clearly defining the compartment-to-compartment flows taken by fluid and molecules that are important in producing axial and radial gradients. Preferential interactions between nephron and vascular segments provide clues as to how tubular and interstitial oxygen flows contribute to safeguarding active transport pathways in renal function in health and disease.

A laboratory exercise using a physical model for demonstrating countercurrent heat exchange

A physical model was used in a laboratory exercise to teach students about countercurrent exchange mechanisms. Countercurrent exchange is the transport of heat or chemicals between fluids moving in opposite directions separated by a permeable barrier (such as blood within adjacent blood vessels flowing in opposite directions). Greater exchange of heat or chemicals between the fluids occurs when the flows are in opposite directions (countercurrent) than in the same direction (concurrent). When a vessel loops back on itself, countercurrent exchange can occur between the two arms of the loop, minimizing loss or uptake at the bend of the loop. Comprehension of the physical principles underlying countercurrent exchange helps students to understand how kidneys work and how modifications of a circulatory system can influence the movement of heat or chemicals to promote or minimize exchange and reinforces the concept that heat and chemicals move down their temperature or concentration gradients, respectively. One example of a well-documented countercurrent exchanger is the close arrangement of veins and arteries inside bird legs; therefore, the setup was arranged to mimic blood vessels inside a bird leg, using water flowing inside tubing as a physical proxy for blood flow within blood vessels.

Urine concentrating mechanism: impact of vascular and tubular architecture and a proposed descending limb urea-Na+ cotransporter

We extended a region-based mathematical model of the renal medulla of the rat kidney, previously developed by us, to represent new anatomic findings on the vascular architecture in the rat inner medulla (IM). In the outer medulla (OM), tubules and vessels are organized around tightly packed vascular bundles; in the IM, the organization is centered around collecting duct clusters. In particular, the model represents the separation of descending vasa recta from the descending limbs of loops of Henle, and the model represents a papillary segment of the descending thin limb that is water impermeable and highly urea permeable. Model results suggest that, despite the compartmentalization of IM blood flow, IM interstitial fluid composition is substantially more homogeneous compared with OM. We used the model to study medullary blood flow in antidiuresis and the effects of vascular countercurrent exchange. We also hypothesize that the terminal aquaporin-1 null segment of the long descending thin limbs may express a urea-Na+ or urea-Cl− cotransporter. As urea diffuses from the urea-rich papillary interstitium into the descending thin limb luminal fluid, NaCl is secreted via the cotransporter against its concentration gradient. That NaCl is then reabsorbed near the loop bend, raising the interstitial fluid osmolality and promoting water reabsorption from the IM collecting ducts. Indeed, the model predicts that the presence of the urea-Na+ or urea- Cl− cotransporter facilitates the cycling of NaCl within the IM and yields a loop-bend fluid composition consistent with experimental data.

Bird Brains and Bird Breath

To begin with, the bird lung is invested with a series of hollow air channels, not dead-end alveoli. These air channels are connected to a network of thoracic air sacs. When the air sacs contract and relax in coordination, they force inspired air through the air channels in an almost continuous, unidirectional flow. The air channels contact the pulmonary vessels in an architectural array that looks suspiciously like a countercurrent exchange device. Countercurrent exchange also is engineered into blood infusion devices to rapidly warm intravenous fluid or blood for patients with extensive hemorrhage. Countercurrent exchange takes advantage of the concept that 2 media will exchange properties between themselves more efficiently if they are very close to each other and flowing in opposite directions. There is also crosscurrent exchange. In a crosscurrent arrangement, one material divides into multiple parallel branches, and each of these branches crosses over the other material at multiple points. Although crosscurrent exchange looks similar, it is not quite as efficient as countercurrent exchange. There was controversy about whether the bird lung used crosscurrent or countercurrent gas exchange.

Architecture of inner medullary descending and ascending vasa recta: pathways for countercurrent exchange

Pathways and densities of descending vasa recta (DVR) and ascending vasa recta (AVR) in the outer zone of the inner medulla (IM) were evaluated to better understand medullary countercurrent exchange. Nearly all urea transporter B (UT-B)-positive DVR, those vessels exhibiting a continuous endothelium, descend with little or no branching exclusively through the intercluster region. All DVR have a terminal fenestrated (PV-1-positive) segment that partially overlaps with the UT-B-positive segment. This fenestrated segment descends a distance equal to ∼15% of the length of the connecting UT-B-positive segment before formation of the first branch. The onset of branching is indicative of vessel entry into the intracluster region. The number density of UT-B-positive DVR at 3,000 μm below the OM-IM boundary is ∼60% lower than the density at 400 μm below the OM-IM boundary, a result of DVR joining to fenestrated interconnecting vessels and an overall decline in UT-B expression. AVR that lie in the intercluster region (designated AVR2) lie distant from CDs and ascend to the OM-IM boundary with little or no branching. AVR2a represent a subcategory of AVR2 that abut DVR. The mean DVR length (combined UT-B- and PV-1-positive segments) nearly equals the mean AVR2a length, implying a degree of overall equivalence in fluid and solute countercurrent exchange may exist. The AVR2/DVR ratio is ∼2:1, and the AVR2a/DVR ratio is ∼1:1; however, the AVR/DVR ratio determined for the full complement of fenestrated vessels is ∼4:1. The excess fenestrated vessels include vessels of the intracluster region (designated AVR1). Countercurrent exchange between vasa recta occurs predominantly in the intercluster region. This architecture supports previous functional estimates of capillary fluid uptake in the renal IM.

Multiple mechanisms act to maintain kidney oxygenation during renal ischemia in anesthetized rabbits

We examined the mechanisms that maintain stable renal tissue Po2 during moderate renal ischemia, when changes in renal oxygen delivery (Ḋo2) and consumption (V̇o2) are mismatched. When renal artery pressure (RAP) was reduced progressively from 80 to 40 mmHg, V̇o2 (−38 ± 7%) was reduced more than Ḋo2 (−26 ± 4%). Electrical stimulation of the renal nerves (RNS) reduced Ḋo2 (−49 ± 4% at 2 Hz) more than V̇o2 (−30 ± 7% at 2 Hz). Renal arterial infusion of angiotensin II reduced Ḋo2 (−38 ± 3%) but not V̇o2 (+10 ± 10%). Despite mismatched changes in Ḋo2 and V̇o2, renal tissue Po2 remained remarkably stable at ≥40 mmHg RAP, during RNS at ≤2 Hz, and during angiotensin II infusion. The ratio of sodium reabsorption to V̇o2 was reduced by all three ischemic stimuli. None of the stimuli significantly altered the gradients in Pco2 or pH across the kidney. Fractional oxygen extraction increased and renal venous Po2 fell during 2-Hz RNS and angiotensin II infusion, but not when RAP was reduced to 40 mmHg. Thus reduced renal V̇o2 can help prevent tissue hypoxia during mild renal ischemia, but when renal V̇o2 is reduced less than Ḋo2, other mechanisms prevent a fall in renal Po2. These mechanisms do not include increased efficiency of renal oxygen utilization for sodium reabsorption or reduced washout of carbon dioxide from the kidney, leading to increased oxygen extraction. However, increased oxygen extraction could be driven by altered countercurrent exchange of carbon dioxide and/or oxygen between renal arteries and veins.