Pericyte-mediated constriction of renal capillaries evokes no-reflow and kidney injury following ischemia

Acute kidney injury is common, with ~13 million cases and 1.7 million deaths/year worldwide. A major cause is renal ischemia, typically following cardiac surgery, renal transplant or severe hemorrhage. We examined the cause of the sustained reduction in renal blood flow (no-reflow), which exacerbates kidney injury even after an initial cause of compromised blood supply is removed. After 60 min kidney ischemia and 30-60 min reperfusion, renal blood flow remained reduced, especially in the medulla, and kidney tubule damage was detected as Kim-1 expression. Constriction of the medullary descending vasa recta and cortical peritubular capillaries occurred near pericyte somata, and led to capillary blockages, yet glomerular arterioles and perfusion were unaffected, implying that the long-lasting decrease of renal blood flow contributing to kidney damage was generated by pericytes. Blocking Rho kinase to decrease pericyte contractility from the start of reperfusion increased the post-ischemic diameter of the descending vasa recta capillaries at pericytes, reduced the percentage of capillaries that remained blocked, increased medullary blood flow and reduced kidney injury. Thus, post-ischemic renal no-reflow, contributing to acute kidney injury, reflects pericytes constricting the descending vasa recta and peritubular capillaries. Pericytes are therefore an important therapeutic target for treating acute kidney injury.

The vasoconstrictor endothelin system involvement in chronic kidney diseases pathogenesis is now the most often employed treatment method

Over 30,000 publications have been published about the vasoconstrictor endothelin-1, which was identified by Yanagisawa and co-workers in 1988. While the evidence is quite compelling, scientists can only speculate on how the endothelin (ET) system affects blood pressure and renal function at this time. ET system involvement in chronic kidney diseases (CKD) pathogenesis is now the most often employed treatment method. ET1, ET2, and ET3 are all members of the endothelin family. Endothelium, renal, and smooth muscle cells all generate ET-1, a significant isoform found in both cardiovascular and renal systems.Kidney cells act on, and contain, ET-1. The ETA receptor is found in the brain and medulla, but not in the vasa recta or glomeruli. Epithelial and endothelial cells contain the ETB receptor, which is most prominent in collecting duct cells. 3 In several experiments, ET-1 has been established to be largely a preglomerular vasoconstrictor. Mesangial proliferation, contraction, and collagen production are regulated by ET-1 and ETB receptors in podocytes. The epithelium in the collecting duct cells in the medulla is important in controlling Na excretion and BP. Without the ET-1 gene, the mice have hypertension and reduced natriuresis in response to salt loading. Et-1, ETB receptor, and hypertension are shown in mice that have lost the ETB receptor gene. There is no correlation between blood pressure regulation and natriuresis.Combined disruption of the ETA and ETB receptors has greater effects on blood pressure and Na reabsorption than when ETB receptor activity is missing. It appears that the ETB receptor doesn't work until ETB is present. Collecting duct-derived ET receptors reduces the transport of sodium. Src kinase and MAPK1/2 decrease epidermal Na channel (ENaC) function, decreasing water and salt reabsorption. Moreover, inner medullary collecting duct cells and vasa recta-bearing cells will release NO, which decreases sodium transport.

Ultraselective transcatheter arterial embolization with small-sized microcoils for acute lower gastrointestinal bleeding

Purpose To evaluate the clinical outcome of ultraselective transcatheter arterial embolization (TAE) with small-sized microcoils for acute lower gastrointestinal bleeding (LGIB). Materials and methods The subjects were 17 consecutive patients (mean age, 69 years) with LGIB who were treated with ultraselective TAE using small-sized microcoils between December 2013 and December 2019. Ultraselective TAE was defined as embolization of one or both of the long or short branches of the vasa recta. The etiologies of bleeding were colonic diverticulosis in 16 patients (94%) and malignancy in one patient (6%). The bleeding foci were in the ascending colon in 11 patients (65%), transverse colon in 2 patients (12%), and sigmoid colon in 4 patients (23%). A total of 18 branches (diameter: range 0.5–1.5 mm, mean 1.1 mm) of the vasa recta in 17 patients were embolized with small-sized microcoils (size range 1–3 mm, mean combined lengths of all microcoils 7.6 cm). The mean follow-up period was 19 months (range 1–80 months). The technical and clinical success rate, recurrent bleeding rate, major complications and long-term clinical outcomes were retrospectively evaluated. Results Technical and clinical success was achieved in all patients (17/17). The rates of early recurrent bleeding (within 30 days of TAE) and major complications were 0% (0/17). Recurrent bleeding occurred in one patient at 2 months after TAE, but was stopped with conservative treatment. There were no other bleeding episodes or complications in the follow-up period. Conclusion Ultraselective TAE with small-sized microcoils is a highly effective and safe treatment modality for LGIB.

Super-Resolution Imaging with Ultrasound for Visualization of the Renal Microvasculature in Rats Before and After Renal Ischemia: A Pilot Study

In vivo monitoring of the microvasculature is relevant since diseases such as diabetes, ischemia, or cancer cause microvascular impairment. Super-resolution ultrasound imaging allows in vivo examination of the microvasculature by detecting and tracking sparsely distributed intravascular microbubbles over a minute-long period. The ability to create detailed images of the renal vasculature of Sprague-Dawley rats using a modified clinical ultrasound platform was investigated in this study. Additionally, we hypothesized that early ischemic damage to the renal microcirculation could be visualized. After a baseline scan of the exposed kidney, 10 rats underwent clamping of the renal vein (n = 5) or artery (n = 5) for 45 min. The kidneys were rescanned at the onset of clamp release and after 60 min of reperfusion. Using a processing pipeline for tissue motion compensation and microbubble tracking, super-resolution images with a very high level of detail were constructed. Image filtration allowed further characterization of the vasculature by isolating specific vessels such as the ascending vasa recta with a 15–20 μm diameter. Using the super-resolution images alone, it was only possible for six assessors to consistently distinguish the healthy renal microvasculature from the microvasculature at the onset of vein clamp release. Future studies will aim at attaining quantitative estimations of alterations in the renal microvascular blood flow using super-resolution ultrasound imaging.

Abstract P038: Renoprotective Effect Of SGLT1/2 Inhibitor In Rat Renal Congestion Model

Renal venous congestion by increased central venous pressure in congestive heart failure is responsible for renal dysfunction. We have created a novel rat renal congestion model presenting increased renal interstitial hydrostatic pressure and vasa recta expansion, which leads to renal congestion-mediated fibrosis. Current clinical trials suggest the renoprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in heart failure patients; however, the underlying mechanisms are still discussing. Thus, we investigated the effect of phlorizin, a commercially available SGLT1/2 inhibitor, in our renal congestion model. All animal procedures were performed in accordance with the policies and guidelines of the “Position of the American Heart Association on Research Animal Use” and were approved by the Tohoku Medical and Pharmaceutical University Animal Experiment Committee (registration number: A18019-a, A19039-cn and A20005-cn). The inferior vena cava between the renal veins was ligated, which induced congestion only in the left kidney. Phlorizin (400 mg/kg body weight) or saline were injected subcutaneously daily from 1 day before the operation. Both the right control kidney and left congested kidney were collected 3 days after the surgery. Increased kidney weight and renal fibrosis were observed in the congested kidneys. Phlorizin attenuated the increased kidney weight and suppressed renal fibrosis staining. Molecules related to kidney injury (Kim1) and fibrosis (Fn1 and αSma) were also suppressed by Phlorizin in the congested kidney. Low-vacuum electron microscopy revealed the vasa recta dilatation in the congested kidney. This morphological change was alleviated by Phlorizin. These results suggest that SGLT1/2 inhibitor could suppress renal congestion-mediated fibrosis. This mechanism could be a potential therapeutic target for renoprotection against heart failure.

A mathematical model of the rat kidney. II. Antidiuresis

Kidney water conservation requires a hypertonic medullary interstitium, NaCl in the outer medulla and NaCl and urea in the inner medulla, plus a vascular configuration that protects against washout. In this work, a multisolute model of the rat kidney is revisited to examine its capacity to simulate antidiuresis. The first step was to streamline model computation by parallelizing its Jacobian calculation, thus allowing finer medullary spatial resolution and more extensive examination of model parameters. It is found that outer medullary NaCl is modestly increased when transporter density in ascending Henle limbs from juxtamedullary nephrons is scaled to match the greater juxtamedullary solute flow. However, higher NaCl transport produces greater CO2 generation and, by virtue of countercurrent vascular flows, establishment of high medullary Pco2. This CO2 gradient can be mitigated by assuming that a fraction of medullary transport is powered anaerobically. Reducing vascular flows or increasing vessel permeabilities does little to further increase outer medullary solute gradients. In contrast to medullary models of others, vessels in this model have solute reflection coefficients close to zero; increasing these coefficients provides little enhancement of solute profiles but does generate high interstitial pressures, which distort tubule architecture. Increasing medullary urea delivery via entering vasa recta increases inner medullary urea, although not nearly to levels found in rats. In summary, 1) medullary Na+ and urea gradients are not captured by the model and 2) the countercurrent architecture that provides antidiuresis also produces exaggerated Pco2 profiles and is an unappreciated constraint on models of medullary function.

Urea Transporters Identified as Novel Diuretic Drug Targets

Background: Urea Transporters are a family of membrane channel proteins that facilitate the passive transport of urea across the plasma membrane. UTs are divided into two subgroups, UT-A and UT-B. UT-As are primarily located in renal tubule epithelia and UT-Bs are highly expressed in renal descending vasa recta and extrarenal multiple tissues. Various urea transporter knockout mice exhibit low urine concentrating ability, which suggests that UTs are novel diuretic targets. With highthroughput screening of small molecule drug-like compound libraries, various potent UT inhibitors with IC50 at nanomolar level were identified. Furthermore, selective UT inhibitors exhibit diuretic activity without disturbing electrolyte and metabolism balance, which confirms the potential of UTs as diuretic targets and UT inhibitors as novel diuretics that do not cause electrolyte imbalance. Objective: This review article summarizes the identification and validation of urea transporter as a potential diuretic target and the discovery of small molecule UT inhibitors as a novel type of diuretics. Conclusion: UTs are a potential diuretic target. UT inhibitors play significant diuresis and can be developed to diuretics without disturbing electrolyte balance.