Am J Physiol Regul Integr Comp Physiol 299: R723–R727, 2010.
First published July 21, 2010; doi:10.1152/ajpregu.00364.2010.
Perspectives
Structural antioxidant defense mechanisms in the mammalian
and nonmammalian kidney: different solutions to the same problem?
Paul M. O’Connor1 and Roger G. Evans2
1
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; and 2Department of Physiology, Monash
University, Melbourne, Australia
Submitted 4 June 2010; accepted in final form 16 July 2010
O’Connor PM, Evans RG. Structural antioxidant defense
mechanisms in the mammalian and nonmammalian kidney: different solutions to the same problem? Am J Physiol Regul Integr
Comp Physiol 299: R723–R727, 2010. First published July 21,
2010; doi:10.1152/ajpregu.00364.2010.—Tissue oxygen levels are
tightly regulated in all organs. This poses a challenge for the kidney,
as its function requires blood flow, and thus, oxygen delivery to
greatly exceed its metabolic requirements. Because superoxide production in the kidney is dependent on oxygen availability, tissue
hyperoxia could drive oxidative stress. In the mammalian renal cortex,
this problem may have been solved, in part, through a structural
antioxidant defense mechanism. That is, arteries and veins are closely
associated in a countercurrent arrangement, facilitating diffusional
arterial-to-venous (AV) oxygen shunting. Because of this mechanism, a
proportion of the oxygen delivered in the renal artery never reaches
kidney tissue but instead diffuses to the closely associated renal veins,
thus limiting oxygen transport to tissue. In the nonmammalian kidney,
arteries and veins are not arranged in an intimate countercurrent
fashion as in mammals; thus AV oxygen shunting is likely less
important in regulation of kidney oxygenation in these species. Instead, the kidney’s blood supply is predominately of venous origin.
This likely has a similar impact on tissue oxygenation as AV oxygen
shunting, of limiting delivery of oxygen to renal tissue. Thus, we
hypothesize the evolution of structural antioxidant mechanisms that
are anatomically divergent but functionally homologous in the mammalian and nonmammalian kidney.
hyperoxia; hypoxia; kidney circulation; oxidative stress; portal system
life. Too little oxygen (hypoxia) reduces
the ability of tissues to function and initiates a cascade of
events loosely called hypoxic injury. In clinical medicine, we
are familiar with the contributions of acute and/or chronic
tissue hypoxia in the pathogenesis of myocardial infarction (4),
chronic heart failure (12), stroke (38), and peripheral vascular
disease (21). There is also now very strong evidence that
kidney tissue hypoxia is a major player in the pathogenesis of
acute kidney injury (37) and chronic renal disease (29) and
likely also contributes to development of kidney damage in
hypertension (44) and diabetes (35). But oxygen is the source
of reactive oxygen species (ROS), which are highly toxic to
living tissue (18). Thus, the level of oxygen in living tissues
must be tightly regulated.
It is a functional requirement for the lungs of air-breathing
animals to be exposed to a relatively high partial pressure of
oxygen (⬃110 mmHg) (11) to allow uptake of oxygen into the
circulation. This results in the production of ROS, but the lungs
have a range of highly developed chemical antioxidant defense
OXYGEN IS THE STAFF OF
Address for reprint requests and other correspondence: R. Evans, Dept. of
Physiology, PO Box 13F, Monash Univ., Victoria 3800, Australia (e-mail:
[email protected]).
http://www.ajpregu.org
mechanisms that act to prevent oxidative stress. Thus, inhibition
of antioxidant enzymes, such as superoxide dismutase, catalase,
glutathione peroxidase, and glutathione reductase exacerbates
oxygen toxicity in the lungs (23). Nevertheless, the toxicity of
oxygen is graphically demonstrated by the consequences of placing experimental animals in an environment of 100% oxygen.
These animals rapidly perish as a consequence of ROS-induced
lung damage. Ironically, they die of hypoxia (6).
Most other tissues in the body are exposed to oxygen levels
considerably lower than those in the lungs (⬃30 mmHg). But
the function of the kidney poses a series of challenges for
maintenance of homeostasis of intrarenal oxygenation (16, 30).
In particular, a high level of blood flow, well in excess of
metabolic demand, is required to facilitate a high glomerular
filtration rate (16, 30). Superoxide production in renal tissue is
exquisitely sensitive to oxygen availability (5), thus renal
tissue hyperoxia would be expected to result in oxidative
stress. Indeed, NADPH-dependent superoxide production appears to be, if anything, greater in kidney tissue than in
vascular smooth muscle and cardiac tissue, at equivalent levels
of oxygen availability (5). As is the case in the lungs, enzymatic antioxidant defense mechanisms, such as superoxide
dismutase, catalase, glutathione reductase, and glutathione peroxidase are well developed in the kidney (19, 27, 34, 41). We
have previously argued that an additional solution to the
problem of oxygen-driven oxidative stress in the mammalian
kidney has been the evolution of a structural antioxidant
defense mechanism: AV oxygen shunting (31). Here, we
mount an argument that a very different solution has evolved in
the nonmammalian kidney.
The Mammalian Solution: Arterial-to-Venous Oxygen
Shunting?
The kidney of humans and other mammalian species filters
the entire plasma volume ⬃60 times each day (30). This is
achieved through a unique aspect of the glomerular capillary
bed: its high intracapillary hydrostatic pressure (30 –70 mmHg)
(13). Furthermore, to achieve a high glomerular filtration rate,
renal blood flow must greatly exceed that required for the
metabolic requirements of the kidney. Indeed, together the
kidneys receive ⬃25% of the cardiac output, yet weigh ⬍ 1%
of body weight. Consequently, the kidney extracts only ⬃10%
of the oxygen delivered to it via the renal artery (30). One
might expect this to result in a relatively high oxygen tension
in kidney tissue, particularly in the renal cortex. There is
considerable spatial heterogeneity in renal tissue PO2. PO2 in
microdomains within the renal cortex varies from ⬃85 mmHg
to ⬍ 10 mmHg, while medullary tissue PO2 can be as low as 5
mmHg (2, 24). Nevertheless, spatially averaged tissue PO2 in
0363-6119/10 Copyright © 2010 the American Physiological Society
R723
Perspectives
R724
COMPARATIVE PHYSIOLOGY OF KIDNEY OXYGENATION
the kidney is comparable to that in other tissues, such as
resting skeletal muscle, ranging from ⬃20 to 50 mmHg in
the cortex and 10 –30 mmHg in the medulla (30). The
normalization of tissue PO2 in the kidney is achieved largely
through the diffusional shunting of oxygen from arteries to
veins (31). This mechanism is facilitated by the intimate
relationship between arteries and veins in the mammalian
kidney (17, 28, 31). Not only are these vessels arranged in
a countercurrent fashion, but the veins appear to wrap
around much of the axial profile of the arteries, thus providing a direct pathway for oxygen diffusion (Fig. 1). The
marsupial kidney appears to have a vascular structure similar to that of the eutherian kidney (36). The critical evidence for the existence of arterial-to-venous (AV) oxygen
shunting in the kidney was the finding in rats that the PO2 of
renal venous blood is greater than that of blood in the
efferent arterioles of the outer cortex, the most welloxygenated part of the kidney (45). Thus, because of diffusional oxygen shunting, a proportion of the oxygen deliv-
ered to the kidney in the renal artery never reaches the renal
parenchyma.
We have argued that the adaptive advantage of AV oxygen
shunting in the mammalian kidney is that it prevents excess
oxygenation of kidney tissue, which would otherwise lead to
excessive production of ROS and kidney damage (31). The
corollary of this argument, of course, is that the price paid for
this structural antioxidant defense mechanism is that the kidney
is rendered susceptible to damage from hypoxia when oxygen
delivery is limited (e.g., anemia and ischemia) (15, 25, 43).
As we will see below, renal vascular architecture in many
nonmammalian species is strikingly different from that in
mammals. In particular, the intimate countercurrent arrangement of arteries and veins, which facilitates AV oxygen shunting in the mammalian kidney, is not present in the kidneys of
birds, amphibians, reptiles, and fishes. How, then, are they
protected from renal tissue hyperoxia and oxidative stress?
Before considering this question, we will first remind readers
Fig. 1. Arrangement of arteries and veins in the mammalian
kidney. A: artist’s impression of the parallel arrangement of
arteries (red) and veins (blue) in the renal cortex, based on
the structural analysis of the renal circulation performed by
Nordsletten et al. (28). B: diagrammatic representation of
the pathways for oxygen diffusion from arteries and veins in
the renal cortex relative to skeletal muscle. In the kidney,
arteries and veins are intimately associated, allowing a
direct pathway for arterial-to-venous (AV) oxygen shunting. The left side of the diagram depicts the typical arrangement of arcuate and interlobular vessels and is based on a
photomicrograph of arcuate vessels from O’Connor et al.
(31). Arteries (A) and veins (V) in skeletal muscle are also
arranged in a countercurrent fashion but are usually separated by tissue, which would be expected to retard AV
oxygen shunting, as demonstrated by Honig et al. (22). The
right side of the diagram depicts the typical arrangement of
arteries and veins within canine and rat gracilis muscle
reported by Honig et al. (22). Note differences in scale.
AJP-Regul Integr Comp Physiol • VOL
299 • SEPTEMBER 2010 •
www.ajpregu.org
Perspectives
R725
COMPARATIVE PHYSIOLOGY OF KIDNEY OXYGENATION
of some critical issues in the developmental biology of the
kidney.
and many other vertebrates, they are structurally and functionally very different (8).
Ontogeny and Phylogeny of the Vertebrate Kidney
The Nonmammalian Solution: Perfusion of the Kidney with
Venous Blood?
All vertebrates have distinct embryonic and adult kidneys.
When the adult kidney develops, the embryonic kidney either
degenerates, becomes part of the male reproductive system, or
switches to a new role as a lymphoid organ (42). Three
different pairs of renal organs develop progressively during the
embryological and fetal phases of development in mammals:
the pronephros, the mesonephros, and the metanephros (26).
The pronephros is essentially a single large nephron. It is
nonfunctional in developing mammals, but does act as the
embryonic kidney in amphibians and fish. It plays a particularly important role in organisms with aquatic larvae, allowing
them to excrete dilute urine to maintain water balance (42).
The mesonephros is more complex than the pronephros and is
the permanent kidney in fish and amphibians (8). It regresses
during development in animals that develop a metanephric
kidney, which includes reptiles, birds, and mammals. Yet,
despite the similar embryonic origin of the kidney in mammals
There are considerable morphological and functional differences between the kidneys of mammals compared with those
of birds, reptiles, and amphibians (10). Nevertheless, the requirement for perfusion, well in excess of metabolic demand,
to facilitate a high glomerular filtration rate, appears to be
conserved, at least across homeothermic vertebrate species
(10). For example, basal renal blood flow in the domestic
chicken [⬃6 ml·min⫺1·g wet kidney weight⫺1 (20)] is not less
than that in the rat or rabbit (32). In contradistinction to
mammals, the kidneys of amphibians, reptiles, birds, and some
seawater fishes have a portal vascular system (7) (Fig. 2). That
is, while the blood supply to glomeruli is chiefly arterial, the
blood supply to most peritubular capillaries is venous. For
example, in the domestic chicken the renal portal vein arises
from the external iliac vein and supplies one-half to two-thirds
of total renal blood flow (20, 39). Blood flow in this portal
Fig. 2. Renal portal system in the domestic
fowl. Glomerular capillaries are perfused
with arterial blood, but peritubular capillaries are perfused with a mixture of postglomerular blood from efferent arterioles and
venous blood from the renal portal system.
Regulation of blood flow within the renal
portal system has been relatively little studied, but can be achieved through control of
the renal portal valve and vascular tone in the
various vascular beds that comprise the complete system. (Figure redrawn from Ref. 1.)
AJP-Regul Integr Comp Physiol • VOL
299 • SEPTEMBER 2010 •
www.ajpregu.org
Perspectives
R726
COMPARATIVE PHYSIOLOGY OF KIDNEY OXYGENATION
system can be regulated by the portal valve, which controls the
balance of blood flow to the kidney and common iliac vein.
Vascular tone in other segments of the portal system, such as
the hepatic portal circulation, likely also contribute to regulation of renal perfusion (33). This arrangement has been considered to be adaptive for water conservation by allowing
maintenance of relatively stable renal blood flow but allowing
glomerular filtration to be labile (47). There are also a few
examples of nonmammalian kidneys that do not have a portal
circulation, such as the lamprey kidney, which has a system of
venous sinuses intimately associated with tubular elements but
not intrarenal arteries (47). Thus, arteries and veins are not
arranged in a countercurrent fashion in the nonmammalian
kidney (20) and there is little opportunity for AV oxygen
shunting (31). Instead, the kidney is perfused with blood
predominantly of venous origin. Potentially, renal portal systems could also facilitate physiological regulation of kidney
oxygenation by adjusting the proportions of oxygenated and
deoxygenated blood delivered to the kidney through fine control of portal blood flow. Importantly, regulation of blood flow
in this system can be achieved not just through control of the
renal portal valve, but also through adjustments to vascular
tone in other parts of the venous network, including the
associated hepatic portal system (33). There is evidence that
the renal portal system operates as a partial shunt rather than in
an all-or-none fashion and that the blood supply to the two
kidneys is under independent control (1, 33). The portal system
also seems to allow independent control of blood flow to the
different lobes of the avian kidney (1), contributes to autoregulation of total renal blood flow (20, 46), and is known to be
under autonomic control (3).
Conclusions
Many of the seminal studies in renal physiology were carried
out in nonmammalian species. For example, the studies of
William Bowman (9, 14), which formed the initial basis of our
understanding of glomerular filtration, relied heavily on a
comparative approach through the study of both mammalian
and nonmammalian species. A large proportion of Homer
Smith’s work focused on the function of the fish kidney (40).
Furthermore, the art of renal micropuncture arose out of studies
of the kidneys of amphibians (14). The study of comparative
renal physiology can shed light on the evolution of physiological processes and also allows investigation of specific mechanisms that might be exaggerated or diminished or absent in
specific species.
The central message of this article is the hypothesis that
structural antioxidant defense mechanisms have evolved to
partially deoxygenate blood delivered to the renal microcirculation, and thus reduce the potential for tissue hyperoxia to
drive oxidative stress. We propose that these structural antioxidant defense mechanisms are very different in the mammalian
and avian kidney. The mammalian solution may be AV oxygen
shunting, while the avian solution may be perfusion of the
kidney with a mixture of venous and arterial blood. This
structural antioxidant defense mechanism could potentially
also operate within the kidneys of poikilotherm vertebrates
such as reptiles, amphibians, and fish whose kidneys are also
perfused with a mixture of venous and arterial blood. However,
glomerular filtration rate (and thus presumably renal blood
AJP-Regul Integr Comp Physiol • VOL
flow) tends to be lower in these species than in mammals and
birds (9, 10). Thus, a structural antioxidant defense mechanism
may not be an adaptive imperative for these species. Unfortunately, we are aware of no experimental studies of intrarenal
oxygenation in nonmammals. Such studies may provide new
insights into the physiological and pathophysiological significance of kidney oxygen regulation.
ACKNOWLEDGMENTS
The authors thank Jake Pomeranz for preparation of the artwork in the
figures.
GRANTS
The author’s work has been supported by National Health and Medical
Research Council of Australia Grants 143603, 143785, 384101, and 606601.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
REFERENCES
1. Akester AR. Renal portal shunts in the kidney of the domestic fowl. J
Anat 101: 569 –594, 1967.
2. Baumgartl H, Leichtweiss HP, Lubbers DW, Weiss C, Huland H. The
oxygen supply of the dog kidney: measurements of intrarenal PO2. Microvasc Res 4: 247–257, 1972.
3. Bennett T, Malmfors T. Autonomic control of renal portal blood flow in
the domestic fowl. Experientia 31: 1177–1178, 1975.
4. Burke AP, Virmani R. Pathophysiology of acute myocardial infarction.
Med Clin North Am 91: 553–572; ix, 2007.
5. Chen Y, Gill PS, Welch WJ. Oxygen availability limits renal NADPHdependent superoxide production. Am J Physiol Renal Physiol 289:
F749 –F753, 2005.
6. Crapo JD, Sjostrom K, Drew RT. Tolerance and cross-tolerance using
NO2 and O2. I. Toxicology and biochemistry. J Appl Physiol 44: 364 –369,
1978.
7. Dantzler WH. Comparative aspects of renal function. In: The Kidney:
Physiology and Pathophysiology, edited by Seldin DW and Giebisch G.
New York: Raven, 1992, p. 885–942.
8. Dantzler WH. Comparative Physiology of the Vertebrate Kidney. Heidelberg, Germany: Springer-Verlag, 1989.
9. Dantzler WH. Significance of comparative studies for renal physiology.
Am J Physiol Renal Fluid Electrolyte Physiol 238: F437–F444, 1980.
10. Dantzler WH, Braun EJ. Comparative nephron function in reptiles,
birds, and mammals. Am J Physiol Regul Integr Comp Physiol 239:
R197–R213, 1980.
11. Davies KJ. Oxidative stress, antioxidant defenses, and damage removal,
repair, and replacement systems. IUBMB Life 50: 279 –289, 2000.
12. De Boer RA, Pinto YM, Van Veldhuisen DJ. The imbalance between
oxygen demand and supply as a potential mechanism in the pathophysiology of heart failure: the role of microvascular growth and abnormalities.
Microcirculation 10: 113–126, 2003.
13. Denton KM, Anderson WP. Glomerular ultrafiltration in rabbits with
superficial glomeruli. Pflügers Arch 419: 235–242, 1991.
14. Ditrich H. Renal Structure and Function in Vertebrates. Enfield, NH:
Science, 2005.
15. Evans RG, Eppel GA, Michaels S, Burke SL, Nematbakhsh M, Head
GA, Carroll JF, O’Connor PM. Multiple mechanisms act to maintain
kidney oxygenation during renal ischemia in anesthetized rabbits. Am J
Physiol Renal Physiol 298: F1235–F1243, 2010.
16. Evans RG, Gardiner BS, Smith DW, O’Connor PM. Intrarenal oxygenation: unique challenges and the biophysical basis of homeostasis. Am
J Physiol Renal Physiol 295: F1259 –F1270, 2008.
17. Frank M, Kriz W. The luminal aspect of intrarenal arteries and veins in
the rat as revealed by scanning electron microscopy. Anat Embryol (Berl)
177: 371–376, 1988.
18. Freeman BA, Crapo JD. Hyperoxia increases oxygen radical production
in rat lungs and lung mitochondria. J Biol Chem 256: 10986 –10992, 1981.
19. Fujii T, Endo T, Fujii J, Taniguchi N. Differential expression of
glutathione reductase and cytosolic glutathione peroxidase, GPX1, in
developing rat lungs and kidneys. Free Radic Res 36: 1041–1049, 2002.
299 • SEPTEMBER 2010 •
www.ajpregu.org
Perspectives
COMPARATIVE PHYSIOLOGY OF KIDNEY OXYGENATION
20. Glahn RP, Bottje WG, Maynard P, Wideman RF Jr. Response of the
avian kidney to acute changes in arterial perfusion pressure and portal
blood supply. Am J Physiol Regul Integr Comp Physiol 264: R428 –R434,
1993.
21. Ho TK, Abraham DJ, Black CM, Baker DM. Hypoxia-inducible factor
1 in lower limb ischemia. Vascular 14: 321–327, 2006.
22. Honig CR, Gayeski TE, Clark A Jr, Clark PA. Arteriovenous oxygen
diffusion shunt is negligible in resting and working gracilis muscles. Am
J Physiol Heart Circ Physiol 261: H2031–H2043, 1991.
23. Jamieson D. Oxygen toxicity and reactive oxygen metabolites in mammals. Free Radic Biol Med 7: 87–108, 1989.
24. Johannes T, Mik EG, Ince C. Dual-wavelength phosphorimetry for
determination of cortical and subcortical microvascular oxygenation in rat
kidney. J Appl Physiol 100: 1301–1310, 2006.
25. Johannes T, Mik EG, Nohe B, Unertl KE, Ince C. Acute decrease in
renal microvascular PO2 during acute normovolemic hemodilution. Am J
Physiol Renal Physiol 292: F796 –F803, 2007.
26. Moritz KM, Wintour EM. Functional development of the meso- and
metanephros. Pediatr Nephrol 13: 171–178, 1999.
27. Nakao C, Ookawara T, Sato Y, Kizaki T, Imazeki N, Matsubara O,
Haga S, Suzuki K, Taniguchi N, Ohno H. Extracellular superoxide
dismutase in tissues from obese (ob/ob) mice. Free Radic Res 33: 229 –
241, 2000.
28. Nordsletten DA, Blackett S, Bentley MD, Ritman EL, Smith NP.
Structural morphology of renal vasculature. Am J Physiol Heart Circ
Physiol 291: H296 –H309, 2006.
29. Norman JT, Fine LG. Intrarenal oxygenation in chronic renal failure.
Clin Exp Pharmacol Physiol 33: 989 –996, 2006.
30. O’Connor PM. Renal oxygen delivery: matching delivery to metabolic
demand. Clin Exp Pharmacol Physiol 33: 961–967, 2006.
31. O’Connor PM, Anderson WP, Kett MM, Evans RG. Renal preglomerular arterial-venous O2 shunting is a structural anti-oxidant defence
mechanism of the renal cortex. Clin Exp Pharmacol Physiol 33: 637–641,
2006.
32. O’Connor PM, Kett MM, Anderson WP, Evans RG. Renal medullary
tissue oxygenation is dependent on both cortical and medullary blood
flow. Am J Physiol Renal Physiol 290: F688 –F694, 2006.
33. Odlind B. Blood flow distribution in the renal portal system of the intact
hen. A study of venous system using microspheres. Acta Physiol Scand
102: 342–356, 1978.
AJP-Regul Integr Comp Physiol • VOL
R727
34. Ookawara T, Imazeki N, Matsubara O, Kizaki T, Oh-Ishi S, Nakao C,
Sato Y, Ohno H. Tissue distribution of immunoreactive mouse extracellular superoxide dismutase. Am J Physiol Cell Physiol 275: C840 –C847,
1998.
35. Palm F. Intrarenal oxygen in diabetes and a possible link to diabetic
nephropathy. Clin Exp Pharmacol Physiol 33: 997–1001, 2006.
36. Reid IA, McDonald IR. Renal function in the marsupial Trichosurus
vulpecula. Comp Biochem Physiol 25: 1071–1079, 1968.
37. Rosenberger C, Rosen S, Heyman SN. Renal parenchymal oxygenation
and hypoxia adaptation in acute kidney injury. Clin Exp Pharmacol
Physiol 33: 980 –988, 2006.
38. Saeed SA, Shad KF, Saleem T, Javed F, Khan MU. Some new
prospects in the understanding of the molecular basis of the pathogenesis
of stroke. Exp Brain Res 182: 1–10, 2007.
39. Siller WG, Hindle RM. The arterial blood supply to the kidney of the
fowl. J Anat 104: 117–135, 1969.
40. Smith HW. From Fish to Philosopher. Boston: Little, Brown, 1953.
41. Sun JS, Lu FJ, Huang WC, Hou SM, Tsuang YH, Hang YS. Antioxidant status following acute ischemic limb injury: a rabbit model. Free
Radic Res 31: 9 –21, 1999.
42. Vize PD. Introduction: embryonic kidneys and other nephrogenic models.
In: The Kidney, edited by Vize PD, Woolf AS, and Bard JBL. Amsterdam:
Academic, 2003.
43. Warner L, Gomez SI, Bolterman R, Haas JA, Bentley MD, Lerman
LO, Romero JC. Regional decreases in renal oxygenation during graded
acute renal arterial stenosis: a case for renal ischemia. Am J Physiol Regul
Integr Comp Physiol 296: R67–R71, 2009.
44. Welch WJ. Intrarenal oxygen and hypertension. Clin Exp Pharmacol
Physiol 33: 1002–1005, 2006.
45. Welch WJ, Baumgartl H, Lubbers D, Wilcox CS. Nephron PO2 and
renal oxygen usage in the hypertensive rat kidney. Kidney Int 59: 230 –
237, 2001.
46. Wideman RF Jr, Glahn RP, Bottje WG, Holmes KR. Use of a thermal
pulse decay system to assess avian renal blood flow during reduced renal
arterial perfusion pressure. Am J Physiol Regul Integr Comp Physiol 262:
R90 –R98, 1992.
47. Youson JH, McMillan DB. Intertubular circulation in the opisthonephric
kidneys of adult and larval sea lamprey, Petromyzon marinus L. Anat Rec
170: 401–411, 1971.
299 • SEPTEMBER 2010 •
www.ajpregu.org