Nephrol Dial Transplant (2010) 25: 32–34
doi: 10.1093/ndt/gfp464
Advance Access publication 15 September 2009
Translational Nephrology
Kidney calling lung and call back: how organs talk to each other∗
Jürgen Floege1 and Stefan Uhlig2
1
Division of Nephrology and Immunology and 2 Institute of Pharmacology and Toxicology, Medical Faculty, RWTH University of
Aachen, Aachen, Germany
Correspondence and offprint requests to: Jürgen Floege; E-mail: [email protected]
∗
Based on Hobo A, Yuzawa Y, Kosugi T et al. The growth factor midkine regulates the renin–angiotensin system in mice.
J Clin Invest 2009; 119: 1616–1625
Summary of key findings
kidneys (see below), liver [3], intestines [4], hind limbs [5]
and pancreas [6].
Midkine (MK) is a retinoic acid-inducible heparin-binding
growth factor involved in developmental and regeneration
processes (e.g. vasculogenesis, proliferation, neurite outgrowth), but apparently also in inflammation (e.g. fibrinolysis, chemokine production, leucocyte migration) [1].
In [2] Hobo et al. show that hypertension and kidney injury that follow 5/6 nephrectomy are mediated by midkine through the activation of the renin–angiotensin system
(RAS). Intriguingly, the only organ in which 5/6 nephrectomy caused upregulation of angiotensin-converting enzyme (ACE) gene and protein expression as well as enzyme
activity was the lung. Midkine-deficient mice showed no
upregulation of pulmonary ACE and were largely protected
from hypertension and severe renal damage. Chronic administration of recombinant midkine to the MK−/− mice
restored hypertension and the increased pulmonary ACE
expression seen after 5/6 nephrectomy. The authors provide evidence for a chain of events: the kidney communicates with the lungs via midkine; expression of ACE
in lung microvascular endothelial cells is enhanced; this
in turn promotes angiotensin-II-mediated hypertension and
renal damage independent of the hypertension (Figure 1).
These data identify midkine as a novel regulator of the RAS
(at least in mice) and provide evidence for an interorgan
crosstalk in the pathogenesis of angiotensin-II-mediated
renal damage.
(1) Lung kidney interactions. Ventilator-induced lung
injury [7–9] offers the most studied example of lung–
kidney interaction. In patients with acute kidney injury
(AKI), mortality rates are 81% versus 29%, depending
upon whether or not mechanical ventilation is required
[10]. On the molecular level, mechanical ventilation has
been shown to increase the renal expression of endothelial NO synthase [11], and to stimulate the production of
endothelin [12]. High tidal volume ventilation is associated with AKI in animals [11,13] and in patients with
acute lung injury [14]. Furthermore, intratracheal instillation of LPS has been reported to cause renal inflammation [15]. And also in 5/6 nephrectomy, renal damage
appears to be related to pulmonary ACE expression and
to lung-borne angiotensin II [2].
(2) Kidney lung interactions. Comprehensive studies
have shown how bilateral renal ischaemia and 5/6
nephrectomy [16,17] dramatically alter pulmonary gene
expression [18,19], as for example ACE [2]. Renal injury may increase pulmonary vascular permeability and
downregulate ion channels critical for fluid absorption
in the lungs [20] leading to pulmonary inflammation,
haemorrhage, septal oedema and apoptosis within the
first days [21–25], although in some studies the extent
of the lung injury was weak or even absent [2,18,26].
Review of the field
The lungs harbour the largest microcapillary network in the
body and receive the entire cardiac output. In this central
position, the lungs are designated to interact with other
organs, as illustrated by the conversion of angiotensin I to
angiotensin II in the lungs. This also implies that (i) agents
released from injured lungs may affect distant organs, and,
conversely, (ii) the lungs are prone to respond to agents
released from injured extrapulmonary organs such as the
Thus, there is ample evidence for the interaction between
lungs and kidneys. However, little is known about how the
information is actually transferred from one organ to the
other. So far, only for sFasL [13] and angiotensin II [2]
is there firm evidence of kidney damage by lung-borne
mediators; vice versa, the only renal mediators strongly implicated in signalling to the lungs are IL-6 [24] and midkine
[2]. These studies indicate a novel interaction between the
lungs and kidneys, unrelated to blood gases, alterations in
the acid–base balance, activation of the sympathetic nervous system, or regulation of blood pressure. While there is
convincing evidence that the above mediators cause distant
organ injury, direct evidence of their source is still lacking.
C The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved.
For Permissions, please e-mail: [email protected]
Kidney calling lung and call back: how organs talk to each other
33
deficient mice showed reduced chemokine gene expression, leucocyte infiltration and lesser organ injury. MK
also enhances the production of chemokines from tubular epithelial cells in culture [31,32] and, interestingly, is
upregulated in hypoxaemic chronic obstructive pulmonary
disease (COPD) patients [33], possibly because midkine
is regulated by redox-sensitive genes such as HIF1 [34].
However, midkine has beneficial effects as well. In animal
models, it was demonstrated that the growth-promoting angiogenic and anti-apoptic properties of MK may protect
neuronal cells from ischaemia [1], contribute to liver regeneration [35] and attenuate ventricular remodelling and
mortality in myocardial infarction [36]. Thus, interference
with midkine may be a double-edged sword.
Take-home message
Fig. 1. Proposed chain of events following 5/6 nephrectomy in mice based
on the data of Hobo et al. [2]. Grey boxes on the right show interventions
that decreased renal injury. Ang, angiotensin.
At least three possibilities need to be considered: (i) mediators could indeed be released from specific organs. Proof
of this might be obtained by measuring differences in arteriovenous concentration, examining isolated organs or by
organ-specific gene manipulation. Without such evidence,
the source—for example, of circulating midkine following
5/6 nephrectomy—remains unknown. Moreover, in the case
of 5/6 nephrectomy, it remains to be established whether the
circulating midkine or midkine from the lungs themselves
induces pulmonary ACE [2]. (ii) Mediator levels might increase if one of their clearance organs is injured. This is
obvious for kidneys, e.g. for IL-6 [23], but also the lungs
have important clearance functions, e.g. for prostaglandins,
serotonin, bradykinin or endothelin [27,28]. (iii) Injured organs might stimulate leucocytes which then act in distant
organs [19], which may not necessarily be detrimental. In
fact, it has been shown that acute renal injury may even protect against ventilator-induced lung injury, because uraemia
attenuates pulmonary neutrophil recruitment [29].
Potential clinical implications
Communication between organs is an important factor to
be considered when trying to understand the pathomechanisms of organ failure. This is a relatively understudied field
and it calls for closer subspecialty interaction to achieve
progress in this area. Another, relatively unresolved issue is
the question whether organ interaction is purposeful, as in
the case of hormones, or whether it is simply an overflow
of inflammation throughout the body.
One kidney–lung communication factor may be midkine, which could represent an attractive pharmacological
target. MK has been implicated in the pathogenesis of several inflammatory diseases including ischaemic nephritis,
streptozotocin-induced diabetic nephropathy and neointima
formation during restenosis [30–32]. In these models, MK-
The clinical lesson for nephrologists is to be aware of distal
organ injury when amending kidney injury, while recognizing that other organs can also be the cause of kidney
ailments, as seems to be the case in ventilator-associated
lung injury [8,9] or COPD [37]. Specific treatment strategies concentrating on interorgan crosstalk need to be developed. Importantly, as is already known, the attenuation
of neutrophil recruitment in uraemia may not only mitigate ventilator-induced lung injury [29], but also increase
the risk of infection, in addition to having adverse effects
on several distal organs [38]. In contrast, factors such as
midkine may serve a more specific purpose. Just as the discovery of hormones led to novel therapies, one day, we may
profit from the clinical benefits of interorgan crosstalk.
Conflict of interest statement. None declared.
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Received for publication: 13.8.09; Accepted in revised form: 14.8.09
Nephrol Dial Transplant (2010) 25: 34–36
doi: 10.1093/ndt/gfp590
Advance Access publication 23 November 2009
Wnt signaling and rejuvenation of the adult kidney∗
Gerd Walz and Emily Kim
Renal Division, University Hospital Freiburg, Hugstetter Strasse 55, 79105 Freiburg, Germany
Correspondence and offprint requests to: Gerd Walz; E-mail: [email protected]
∗
Comment on Lancaster MA, Louie CM, Silhavy JL et al. Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and
leads to cystic kidney ciliopathy. Nat Med 2009; 15: 1046–1054
Defects in Wnt signaling appear to underlie some forms
of inherited cystic kidney disease. Knockout experiments
involving the Jouberin protein now examine how Wnt ac-
tivity helps repair injured renal tubules in adult mice—and
show that its absence leads to the formation of cysts in the
mature kidney.
C The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved.
For Permissions, please e-mail: [email protected]