Critical Care Medicine  |   August 2018
Guanylyl Cyclase A in Both Renal Proximal Tubular and Vascular Endothelial Cells Protects the Kidney against Acute Injury in Rodent Experimental Endotoxemia Models
Author Notes
  • From the Department of Anesthesiology (H.K., Y.S., T.A., G.S.); Department of Pharmacology (D.N., A.N.), Kagawa University, Kagawa; Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto (J.N., H.Y., M.Y.); Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto (M.M.); and Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Osaka (T.T., K.K.), Japan.
  • Corresponding article on page 235.
    Corresponding article on page 235.×
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    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication August 31, 2017. Accepted for publication March 12, 2018.
    Submitted for publication August 31, 2017. Accepted for publication March 12, 2018.×
  • Address correspondence to Dr. Nakano: Department of Pharmacology, Kagawa University, 1750–1 Ikenobe, Miki, Kita, Kagawa 761–0793, Japan. dnakano@med.kagawa-u.ac.jp. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Critical Care / Infectious Disease / Renal and Urinary Systems / Electrolyte Balance
Critical Care Medicine   |   August 2018
Guanylyl Cyclase A in Both Renal Proximal Tubular and Vascular Endothelial Cells Protects the Kidney against Acute Injury in Rodent Experimental Endotoxemia Models
Anesthesiology 8 2018, Vol.129, 296-310. doi:10.1097/ALN.0000000000002214
Anesthesiology 8 2018, Vol.129, 296-310. doi:10.1097/ALN.0000000000002214
Abstract

What We Already Know about This Topic:

  • The physiologic role of natriuretic peptides is increasingly understood in critical illness, but how these peptides might impact sepsis-induced oliguria is not known

What This Article Tells Us That Is New:

  • In an in vivo study of experimental sepsis, fluid resuscitation restored glomerular filtration, but recombinant atrial natriuretic peptide restored renal tubular flow and glomerular filtration

Background: Natriuretic peptides are used, based on empirical observations, in intensive care units as antioliguric treatments. We hypothesized that natriuretic peptides prevent lipopolysaccharide-induced oliguria by activating guanylyl cyclase A, a receptor for natriuretic peptides, in proximal tubules and endothelial cells.

Methods: Normal Sprague-Dawley rats and mice lacking guanylyl cyclase A in either endothelial cells or proximal tubular cells were challenged with lipopolysaccharide and assessed for oliguria and intratubular flow rate by intravital imaging with multiphoton microscopy.

Results: Recombinant atrial natriuretic peptide efficiently improved urine volume without changing blood pressure after lipopolysaccharide challenge in rats (urine volume at 4 h, lipopolysaccharide: 0.6 ± 0.3 ml · kg−1 · h−1; lipopolysaccharide + fluid resuscitation: 4.6 ± 2.0 ml · kg−1 · h−1; lipopolysaccharide + fluid resuscitation + atrial natriuretic peptide: 9.0 ± 4.8 ml · kg−1 · h−1; mean ± SD; n = 5 per group). Lipopolysaccharide decreased glomerular filtration rate and slowed intraproximal tubular flow rate, as measured by in vivo imaging. Fluid resuscitation restored glomerular filtration rate but not tubular flow rate. Adding atrial natriuretic peptide to fluid resuscitation improved both glomerular filtration rate and tubular flow rate. Mice lacking guanylyl cyclase A in either proximal tubules or endothelium demonstrated less improvement of tubular flow rate when treated with atrial natriuretic peptide, compared with control mice. Deletion of endothelial, but not proximal tubular, guanylyl cyclase A augmented the reduction of glomerular filtration rate by lipopolysaccharide.

Conclusions: Both endogenous and exogenous natriuretic peptides prevent lipopolysaccharide-induced oliguria by activating guanylyl cyclase A in proximal tubules and endothelial cells.