news and views

Akt2 relaxes podocytes in chronic kidney disease

Jochen Reiser

npg

2013 Nature America, Inc. All rights reserved.

A signaling cascade is activated in podocytes to induce survival and cope with stress during advanced glomerular
disease, a new study shows. The findings may also explain why the immunosuppressor sirolimus, an inhibitor of this
pathway, can cause proteinuria in a subset of patients with chronic kidney disease (pages 12881296).
The loss of proteins into the urine, or proteinuria, often occurs at early stages of chronic
kidney disease (CKD), a condition that affects
about 500 million people worldwide, and this
loss is a driver of both morbidity and mortality. Kidney podocytes are the gatekeepers in
renal ultrafiltration, ensuring that proteins
larger than albumin are essentially kept in
the circulation and solutes and other aqueous products are being routed for excretion
in the urine. Proteinuria occurs upon damage to podocytes that results in simplification
of their foot processes, a term called effacement, which, if not reversed, can lead to loss
of podocytes through detachment, necrosis
and apoptosis1. After loss of a critical number of podocytes, progression of renal disease
ensues with an increase in serum creatinine
and loss of functional nephrons, which poses
an additional overload in the remaining
kidney cells, causing metabolic and mechanical stress and finally leading to their death. To
date, effective therapies that completely halt
or reverse the pathological changes resulting from advanced proteinuria and podocyte
injury are still lacking.
In this issue of Nature Medicine, Canaud et al.2
found a crucial role for mammalian target of
rapamycin (mTOR) and the downstream target
Akt2 in the maintenance of podocytes during
advanced glomerular diseases. The authors
identify a counterbalancing pathway in podocytes that becomes operational as kidney cell
mass is progressively lost (Fig. 1). In particular, activation of the kinase Akt2 by mTORC2
is essential for podocytes to cope with stress
and survive in patients with severe nephron
reduction. Mechanistically, Akt2 reduces the
activity of the small GTPase Rac-1, whose
overactivation is associated with the onset of
podocyte foot process effacement3,4. As prolonged treatment with the immunosuppressor sirolimus (an mTOR inhibitor) seems to
inhibit both mTOR complexes (mTORC1 and
mTORC2)5,6, the findings have clinical implications for human CKD, as sirolimus can cause
podocyte injury and proteinuria in individuals
Jochen Reiser is at the Department of Medicine,
Rush University, Chicago, Illinois, USA.
e-mail: jochen_reiser@rush.edu

1212

with reduced nephron mass, but not in patients

with preserved renal function.
Podocytes are key elements of the filtration
apparatus, and their function depends on prosurvival signals that include phosphoinositide 3-kinasedependent Akt signaling7; the
molecular pathways that counteract the stress
imposed upon injury of the failing kidney filter,
however, are largely unknown. In an analysis
of human kidney biopsies from patients with
different types of CKD, the authors found
that Akt2 was mainly expressed in podocytes,
whereas Akt1 was predominant in tubules2.
By combining experimental mouse models of nephron reduction with genetic deletion of Akt1, Akt2 and Rictor (as a surrogate
of mTORC2 deletion), they showed that Akt2,
but not Akt1, has a pivotal role in podocyte
adaptation under increased workload caused
by nephron reduction2. Inactivation of Akt-2
mediated signaling resulted in podocyte apoptosis and foot process effacement after both
experimental and aging-induced nephron
reduction, leading to severe proteinuria and
glomerulosclerosis in these mice. Podocytes
of mice lacking Akt2 displayed cytoskeleton
changes owing to increased signaling by Rac1
(ref. 2), whose activity can be in part regulated
by Akt2 (ref. 8). Although mice with podocytespecific inactivation of Rictor also showed
reduced levels of Akt2 phosphorylation and
podocyte foot process effacement, they had
only mild proteinuria, which suggests a compensatory effect, possibly through Raptor.
Overall, these findings indicate that phosphorylation of Akt2 at Ser473 confers protection
during nephron loss by promoting podocyte
survival and cytoskeleton integrity, which are
necessary for their function.
Canaud et al.2 found that disruption of this
adaptive pathway via sirolimus caused glomerular lesions and albuminuria only in kidneytransplanted patients with severe nephron
reduction, possibly explaining the often heavy
proteinuria found in these patients treated with
this agent9. Therefore, mTOR inhibitors, such
as sirolimus, should be used with caution in
patients with nephron reduction, to preserve
the activity of the mTORC2-Akt2 axis and
prevent podocyte apoptosis. Staining of Akt2
can be used to differentiate inactive and active

forms on renal biopsies and can potentially be

developed as a prognostic marker, and Akt2
could be used as a therapeutic target to maintain glomerular functions during chronic renal
disease. The results of the study by Canaud
etal.2 are truly exciting and provide an intriguing hypothesis on the involvement of mTORC2
in sirolimus-induced proteinuria by identifying
a protective role for Akt2.
In addition to characterizing kidney biopsy
samples from patients who had received transplants, the authors investigated AKT2 status in
samples from patients with CKD and reduced
estimated glomerular filtration rates, in which
they also showed marked AKT phosphorylation
in podocytes. However, the data should be interpreted with caution, as the chronic pathological
changes that occur during CKD in nontransplanted kidneys are very different from those
observed in kidney transplant recipients, and
as such may not be the right model of nephron
loss. Furthermore, many variables, other than
immunosuppression, such as donor criteria,
ischemia times and hemodynamic aspects of
the kidney graft, could influence AKT2 signaling, directly or indirectly, even though the
authors tried to control for most of them. The
quantification of signaling pathways in kidney
biopsy samples can also be cumbersome, and an
involvement for mTORC1 in sirolimus-induced
proteinuria should not be ruled out, despite the
lack of downstream signals in the study2 and in
previous work, as it could also contribute to the
homeostasis of a damaged kidney by inducing
cell growth and proliferation.
Although Canaud et al.2 experimentally demonstrated the need for Akt2 and
mTORC2 in podocyte stress function, the lack
of mTORC1 in podocytes also causes severe
sclerosis even in otherwise normal mice, which
was aggravated when mTORC2 was concomitantly inactivated10. The study by Canaud
et al.2 suggests a linear connection between
sirolimus, the mTORC2-Akt2 axis in podocyte,
and disease and proteinuria; however, the data
from podocyte-specific mTORC2 deletion
seem to differ with respect to the onset, timing
and severity of histological lesions, as well as
with respect to proteinuria from the podocytespecific Akt2 deletion2. Until the role of
mTORC1 is clarified in this setting, we should

volume 19 | number 10 | OCTOBER 2013 nature medicine

news and views

Healthy kidney

Nephron reduction
(CKD)

Sirolimus treatment
during CKD

Podocyte

Overload

mTORC1

mTORC2

mTORC2

mTORC1

Marina Corral Spence

2013 Nature America, Inc. All rights reserved.

Akt2

npg

Sirolimus

Akt2 P

mTORC2
Akt2

Rac1

Rac-1

Rac-1

Podocyte survival
and function

Accelerated proteinuria
and podocyte stress
adaptation

Proteinuria

Normal renal
function

Retardation of CKD

Progression of
CKD and
renal failure

Figure 1 Podocyte function under conditions of nephron reduction. In healthy kidney, podocyte
numbers are stable and no proteinuria occurs (left). Under this condition, mTORC1 and mTORC2
activities are not upregulated, and Akt2 and podocyte Rac-1 activities remain low, which is typically
the case in healthy kidneys. Canaud et al.2 show that upon nephron reduction (middle), such as in
CKD, podocytes are adapting to the stress of cell loss and undergo mTORC2-mediated phosphorylation
of AKT2, which in turn downregulates Rac-1 activity, delaying kidney disease progression. However,
this adaptive response is abrogated by treatment with the immunosuppressor sirolimus, an mTOR
inhibitor that blocks mTORC1 and mTORC2 and that is widely used in transplantation (right). This
triggers a signaling blockade that aggravates proteinuria and nephron loss, which possibly explains
why patients with already established kidney disease treated with sirolimus can develop proteinuria
and renal failure.

keep in mind that mTORC2 activation may not

be the only player in podocyte protection, and
although the clinical effects of sirolimus on the
mTORC2-Akt2 axis are substantial, this drug is
mainly known as an inhibitor of mTORC1.

Despite these open questions, Canaud et al.2

not only shed light into the mechanism of a
drug widely used in transplantation but also
suggest that podocyte protection is possible by
directly targeting the podocytes function via

nature medicine volume 19 | number 10 | OCTOBER 2013

stabilization of Akt2 signaling, which limits

Rac1 activation, an early step in dysregulation of podocytes causing effacement and
proteinuria11. Because restoring the normal
podocyte structure and lowering proteinuria
increases podocyte survival12, it will be interesting to see whether early events damaging
podocytes in kidneys with normal renal mass
will also lead to the activation of Akt2 signals, or whether the oncoming Akt2 signal is
truly the last attempt for an otherwise dying
podocyte to counterbalance deleterious renal
effects. The US National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK)
has recently solicited applications to establish a large cohort of patients with primary
glomerular disease. The development of biomarkers such as Akt2 phosphorylation in renal
tissue is an example of going beyond renal
biopsy as the standard means of establishing
clinical diagnosis and prognosis toward the
development of new molecular diagnostic
tools for CKD.
COMPETING FINANCIAL INTERESTS
The author declares competing financial interests:
details are available in the online version of the paper
(doi:10.1038/nm.3357).
1. Reiser, J. & Sever, S. Annu. Rev. Med. 64, 357366
(2013).
2. Canaud, G. et al. Nat. Med. 19, 12881296 (2013).
3. Wei, C. et al. Nat. Med. 14, 5563 (2008).
4. Nagase, M. & Fujita, T. Nat. Rev. Nephrol. 9, 8698
(2013).
5. Sarbassov, D.D. et al. Mol. Cell 22, 159168
(2006).
6. Laplante, M. & Sabatini, D.M. Cell 149, 274293
(2012).
7. Huber, T.B. et al. Mol. Cell Biol. 23, 49174928
(2003).
8. Nozaki, S. et al. Cell Signal. 25, 13611371
(2013).
9. Diekmann, F. et al. Transplant. Rev. (Orlando) 26,
2729 (2012).
10. Gdel, M. et al. J. Clin. Invest. 121, 21972209
(2011).
11. Kistler, A.D. et al. Kidney Int. 81, 10531055
(2012).
12. Yaddanapudi, S. et al. J. Clin. Invest. 121, 39653980
(2011).

1213