The FASEB Journal article fj.201601087RR. Published online November 14, 2016.

THE

JOURNAL • REVIEW • www.fasebj.org

Role of post-transcriptional regulation of mRNA

stability in renal pathophysiology: focus on chronic
kidney disease
Eva Feigerlová*,†,‡,1 and Shyue-Fang Battaglia-Hsu§
*Service d’Endocrinologie, Centre Hospitalier Universitaire de Poitiers, Pôle DUNE, Poitiers, France; †Université de Poitiers, Unité de
Formation et de Recherche Médecine Pharmacie, Poitiers, France; ‡Clinical Investigation Centre 1402, Unité 1082, INSERM, Poitiers, France;
and §Nutrition Génétique et Exposition aux Risques Environnementaux, INSERM Unité 954, Université de Lorraine et Centre Hospitalier
Régional Universitaire de Nancy, Vandœuvre les Nancy, France

ABSTRACT: Chronic kidney disease (CKD) represents an important public health problem. Its progression to end-
stage renal disease is associated with increased morbidity and mortality. The determinants of renal function
decline are not fully understood. Recent progress in the understanding of post-transcriptional regulation of
mRNA stability has helped the identification of both the trans- and cis-acting elements of mRNA as potential
markers and therapeutic targets for difficult-to-diagnose and -treat diseases, including CKDs such as diabetic
nephropathy. Human antigen R (HuR), a trans-acting element of mRNA, is an RNA binding factor (RBF) best
known for its ability to stabilize AU-rich-element-containing mRNAs. Deregulated HuR subcellular localization
or expression occurs in a wide range of renal diseases, such as metabolic acidosis, ischemia, and fibrosis. Besides
RBFs, recent evidence revealed that noncoding RNA, such as microRNA and long noncoding RNA, participates
in regulating mRNA stability and that aberrant noncoding RNA expression accounts for many pathologic re-
nal conditions. The goal of this review is to provide an overview of our current understanding of the post-
transcriptional regulation of mRNA stability in renal pathophysiology and to offer perspectives for this class of
diseases. We use examples of diverse renal diseases to illustrate different mRNA stability pathways in specific
cellular compartments and discuss the roles and impacts of both the cis- and trans-activating factors on the
regulation of mRNA stability in these diseases.—Feigerlová, E., Battaglia-Hsu, S.-F. Role of post-transcriptional
regulation of mRNA stability in renal pathophysiology: focus on chronic kidney disease. FASEB J. 31, 000–000 (2017).
www.fasebj.org
KEY WORDS: RNA binding factor • noncoding RNA • P-body • stress granule • RNA-exosome

The progression of chronic kidney disease (CKD) to
end-stage renal disease results in increased morbidity
and mortality. Diabetes and hypertension are major
causes of CKD in Western countries. The determinants
of renal function decline are not fully understood.
Tubulointerstitial fibrosis is the hallmark of disease
progression caused by an accumulation of extracellular
matrix (ECM). The TGF-b is a master regulator of ECM
and one of the major mediators of fibrotic events (1).
Abnormalities in several signaling pathways have been
demonstrated—among them, the renin–angiotensin
system, reactive oxygen species, endoplasmic reticu-
lum stress, and proinflammatory cytokines (2). The
pathophysiological mechanisms leading to these changes

ABBREVIATIONS: z-cryst, z-crystallin/NADPH:quinone reductase; AngII, angiotensin II; ARE, AU-rich element; AUF1, ARE/poly(U)-binding/degradation
factor 1; BicC, bicaudal C protein; CCD, cortical collecting duct; CKD, chronic kidney disease; Col1a2, collagen type I a2; COX, cyclooxygenase; DN,
diabetic nephropathy, Dvl, dishevelled; ECM, extracellular matrix; GA, glutaminase; HNF, hepatocyte nuclear factor; hnRNP K, heterogeneous ribo-
nucleoprotein K; HuR, human antigen R; KSRP, K-homology splicing regulator protein; lncRNA, long noncoding RNA; miRNA, microRNA; MMP,
metalloproteinase; MR, mineralocorticoid receptor; NMD, nonsense-mediated mRNA decay; NOD, nucleotide-binding oligomerization domain-containing
protein; NOX, hydrogen peroxide-producing NADPH oxidase; NSD, nonstop mRNA decay; PAI, plasminogen activator inhibitor; P-body, processing
body; PEPCK, phosphoenolpyruvate carboxykinase; PGE2, prostaglandin E2; pHRE, pH response element; Pin, peptidyl-prolyl cis-trans isomerase; PKD,
polycystic kidney disease; PTC, premature termination codon; PTH, parathyroid hormone; RISC, RNA-induced silencing complex; RBF, RNA binding
factor; SG, stress granule; SNAT3, System N and A transporter 3; TIAR, T-cell–restricted intracellular antigen-1-related protein; Tis, tetradecanoyl phorbol
acetate–inducible sequence; tonEBP, tonicity-responsive enhancer-binding protein; Tsc, TGF-b-stimulated clone; TTP, tristetraprolin; V-ATPase, vacuolar
H+-translocating ATPase; Ybx, Y-box binding protein
1
Correspondence: Centre Hospitalier Universitaire de Poitiers, Service d’Endocrinologie, Pôle DUNE, Poitiers, France. E-mail: eva.feigerlova@
fulbrightmail.org
doi: 10.1096/fj.201601087RR

0892-6638/17/0031-0001 © FASEB 1
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have not been clearly established. Similarly, specific
biomarkers are not currently known. Recently, post-
transcriptional regulation of mRNA stability has emerged
as a major mechanism modulating gene expression, and its
involvement in renal diseases has been evidenced.
POST-TRANSCRIPTIONAL REGULATION OF
mRNA TURNOVER
The major mRNA surveillance pathways in mammalian
cells include nonsense-mediated mRNA decay (NMD) and
nonstop mRNA decay (NSD) (3). NMD is mediated by
either the RNA exosome in the 39–59 direction (4) or by
processing bodies (P-bodies) in the 59–39 direction after an
initial removal of poly(A) tail by deadenylases (5). NMD
regulates the degradation of both normal mRNAs, like
those with alternatively spliced exons in 39-UTR, and ab-
normal mRNAs, like those with premature termination
codon (PTC) (6). It is estimated that about one-third of hu-
man diseases are caused by PTC (7). One such example of
renal disease is Liddle syndrome, elicited by a PTC in the
SCNN1B gene (8). Unlike NMD, NSD is activated only in
the presence of mRNA transcripts missing a stop codon. In
mammalian cells, eRF3-like factor Ski7 appears to detect the
presence of stalled RNA-ribosome complex at the 39 end of
RNA transcripts that lack a stop codon, targeting them to
the RNA exosome for elimination. This pathway, however,
is not well characterized in humans.
Role of cis-elements and trans-regulatory
factors in mRNA stability
The stability of mRNA depends on its interactions with both
cis- and trans-regulatory factors. Cis-regulatory elements
reside within mRNA transcript, including not only the
untranslated regions but also the coding region (9).
Adenylate-uridylate-rich elements (AREs) are the best-
studied cis-elements localized to the 39-UTR of many
mRNAs. In silico analyses predicted their occurrence in
5–8% of human mRNAs encoding functionally important
proteins (10). The presence of unique ARE sequences im-
plies complex regulatory mechanisms involving interac-
tions, even between different RNA binding factors (RBFs)
for competitive binding to mRNAs (3). RBFs and non-
coding RNAs are examples of trans-regulatory elements.
The interactions of RBF, with its target transcripts can often
be modulated by both the subcellular localization and the
post-translational modification of the RBF itself. The RBF
interacts mainly with 39-UTR of the target transcript (11).
HuR, a member of the embryonic lethal abnormal vision-
like family of RNA-binding proteins (12), is among the RBFs
most studied in renal pathophysiology. Depending on
the type of cell, the pathophysiological condition, and the
presence of interacting RBFs, HuR can either promote the
stability or the decay of its mRNA target (13, 14). Non-
coding RNAs such as microRNA (miRNA) and long non-
coding RNA (lncRNA), have recently been implicated in
diverse human diseases; the particular involvement of
miRNA in renal pathology has been the subject of recent
reviews (15–18).
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Role of lncRNA, P-body, and stress granule in
the regulation of mRNA stability
Experimental evidence has suggested that both miRNA
and lncRNA participate in the regulation of mRNA sta-
bility. miRNAs the short single-stranded RNAs bearing
fully or partially complimentary sequences to target genes,
can be incorporated into RNA-induced silencing complex
(RISC) for interaction with their target mRNA, mainly at
its 39-UTR. A typical miRNA-mediated mRNA decay re-
quires Argonaute proteins, GW182 from P-body, CCR4:
NOT deadenylase, and DCP1:DCP2 decapping complexes
(19, 20). The incorporation of GW182 appears to mark the
transcript for degradation by deadenylation and decapp-
ing (21, 22). For the degradation of ARE-mRNAs mediated
through RISC, current evidence suggests that miRNA
within RISC recognizes the ARE sequences through the
help of ARE binding proteins (AUBPs) such as triste-
traprolin (TTP) (23). In fact, AUBPs act as linkers between
ARE-mRNA and degradation machinery, and the binding
of AUBPs to mRNA target activates deadenylation as well
as decapping, triggering its decay via both RNA exosome
and Xrn1-containing decapping complex [see Carpenter
et al. (24)]. Several AUBPs have actually been identified;
these include K homology splicing regulatory protein
(KSRP), TTP, and butyrate response factor-1, all capable of
interacting with poly(A) ribonuclease and RNA exosome
complex (25–27). The relevance of AUBPs in kidney func-
tion can be appreciated in an experimental model of CKD
associated with hyperparathyroidism, where an increased
parathyroid hormone (PTH) mRNA level can be attributed
to a decreased interaction between the 39-UTR of PTH
mRNA and KSRP and causes decreased mRNA decay via
the RNA exosome (28, 29) (Table 1). The relevance of
lncRNA in mRNA stability has been discussed only very
recently. For example, Sirt1 antisense lncRNA is found to
stabilize Sirt1 transcripts via a direct interaction with Sirt1
39-UTR, thus rescuing the suppression mediated by
miRNA-34a (30). Similar base-pairing interaction be-
tween various lncRNAs and cognate mRNA has also
been found to affect the stability of target transcripts
with developmental function (31, 32). Its contribution to
renal diseases, however, is not yet clear.
P-bodies and stress granules (SGs) are cytoplasmic
structures containing a network of proteins necessary for
mRNA regulation and silencing (33, 34). In renal epithelial
cells, sequestration of mRNA-protein complex in SGs was
evidenced during osmotic stress (35). P-bodies have been
shown to participate in the formation of planar cell polarity
via an RBF-dependent uncoupling of dishevelled (Dvl)
signaling from the canonical Wnt pathway (36) and are
also implicated in TGF-b-driven fibrosis in mouse kidney
cells (37) (Table 1).
POST-TRANSCRIPTIONAL REGULATION OF mRNA
STABILITY IN CKD
CKD and progressive renal fibrosis remain a therapeutic
challenge. Fibrotic kidney has a limited ability to recover
from such injuries as ischemia–reperfusion and is associated
FEIGERLOVÁ AND BATTAGLIA-HSU
TABLE 1. Post-transcriptional regulation of mRNA in renal pathophysiology and disease

RNA binding factor Target Effect site Model Mechanism Reference

Metabolic acidosis
z-cryst, AUF-1 GA 3UTR Rat renal cortex pH-responsive stabilization of 14
HuR (proximal GA mRNA through binding
convoluted of z-cryst, AUF1, and HuR to
tubule) pHRE
Not indicated SNAT3 3UTR LLC-PK1-F+-cells pH-responsive stabilization of 47
SNAT3 mRNA via binding
to pHRE
AUF-1 PEPCK 3UTR LLC-PK1-F+-9C cells pH- responsive stabilization of 43, 48
HuR PEPCK mRNA via HuR and
AUF1
Osmotic stress
TIA-1 Osmolytes SG NRK 52E Sequestration of mRNA-protein 35
complex in SGs
Tis11b MR 3UTR CCD cell line Tis11b favors degradation of Mr 52
B6D2 mice mRNA under hypertonic
conditions
ATP depletion and
ischemia/reperfusion
injury
HuR V-ATPase 3UTR Porcine proximal HuR maintains stability of V-ATPase 55
tubule, LLC-PK1 mRNAs during ATP depletion
cells
HuR Bcl-2, Hsp70 3UTR Rat kidneys HuR protects proximal tubule cells 56
LLC-PK1 cells during and after I/R through
modulation of Bcl-2 and Hsp70
expression
Inflammation and
fibrosis
HuR COX-2 3UTR Human MC AngII via activation of HuR 61
shuttling causes an increase in
COX-2 mRNA stability with
a rise in PGE2
HuR COX-2 3UTR Sprague-Dawley AngII via HuR shuttling stabilizes 62
rats kidney Pai1 and Cox2 mRNAs
PAI-1 Rat MC
HuR cyclin D1 3UTR Human MC AngII stabilizes cyclin D1 mRNA 65
via HuR
HuR MMP-9 3UTR Rat MC HuR-mediated Mmp9 mRNA 67
stabilization
TIAR MMP-13 3UTR Human MC Inhibition of MMP-13 translation 69
by TIAR bound to MMP-13 mRNA
Diabetic nephropathy
HuR NOD2 3UTR Human kidney HuR mediates hyperglycemia 70
STZ-diabetic enhanced NOD2 expression
rat kidney and mRNA stability
NRK-52E
Rat MC
Ybx1 Tsc-22 P-bodies Mouse MC TGF-b induced increase in miR-216a 37
inhibits Ybx1 leading to a release
of Tsc-22 mRNA from the P-body
with an increase in Tsc-22
translation
Ybx1 TGF-b 5UTR Human proximal TGF-b1 translation requires Ybx1
tubular binding to a high-affinity site
epithelial within the 59-UTR TGF-b-mRNA
cell line HK-2
hnRNPK VEGF 3UTR Murine proximal PKC-d positively regulates Vegf 75, 76
tubular epithelial mRNA translation through
cells activation of hnRNPK
Diabetic db/db
mice
(continued on next page)

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TABLE 1. (continued)

RNA binding factor Target Effect site Model Mechanism Reference

Polycystic kidney
disease
BicC Dvl P-bodies MDCK cell line Uncoupling of Dvl2 36
BicC1 2/2 mouse signaling from the
canonical Wnt
pathway leads to
accumulation of
BicC and Dvl2 in
P-bodies
miR-17–92 PKD1, PKD2 3UTR mIMCD3 cells Pkd2 mRNA and 86
Pkd1 mRNA
repression by
binding of miR-17
miR-17– 92 HNF-1b 3UTR mIMCD3 cells Hnf1b mRNA 86
repression by
binding
of miR-92a
miR-200 PKD1 3UTR mIMCD3 cells Repression of 87
Pkd1 mRNA by
binding of miR-200
Hyperparathyroidism
KSRP PTH 3UTR RNA HEK293 cells, Decrease in PTH 28, 29
exosome rat parathyroid mRNA levels
glands involves PTH
mRNA 39-UTR
ARE, KSRP and
the RNA exosome
Pin 1 PTH 3UTR HEK293 cells, Pin1 activation 78
rat parathyroid increases
glands KSRP–PTH
mRNA interactions,
decreasing PTH
mRNA levels

MC, mesangial cell; mIMCD3, mouse inner medullary collecting duct cells; NRK-52E, rat renal proximal tubular cells; ns, not specified; R,
reperfusion; STZ, streptozotocin

with a progressive renal function decline that ultimately
leads to end-stage renal failure. The recent discoveries point
to the important role of mRNA stability during the patho-
logical process. In this section, we first summarize our actual
knowledge of the role of post-transcriptional regulation of
mRNA turnover in the kidney in pathophysiological states,
such as chronic metabolic acidosis, osmotic stress, and
ischemia–reperfusion injury. Further, we detail its role
in diabetic nephropathy, chronic kidney fibrosis, and
inflammation. Finally, we discuss how mRNA stability
affects the physiology and pathology of the kidney in
the context of planar cell polarity and hyperparathy-
roidism to illustrate the emerging role of miRNA on
mRNA decay through exosome and P-bodies.
Chronic metabolic acidosis
During chronic metabolic acidosis, enzymes and ion
transporters involved in the synthesis and production
of ammonium and bicarbonates are up-regulated (38).
Glutamine is the precursor needed for the formation
of ammonium. Metabolic acidosis thus activates the
transport of excess plasma glutamine across the baso-
lateral membrane of the epithelium via glutamine Sys-
tem N and A transporter 3 (SNAT3) in the renal proximal
tubule (Fig. 1) (39). In the mitochondria of renal tubular
cells, glutamine is first deaminated by glutaminase
(GA), then oxidized by glutamate dehydrogenase (40)
to produce ammonium ion and a-ketoglutarate (41).
The latter either produces HCO32 and H+ ions or is
oxidized by cytosolic phosphoenolpyruvate carbox-
ykinase (PEPCK) to generate phosphoenolpyruvate
(42). The combined reactions also lead to the production
of HCO32 and H+ ions, which are used for the conver-
sion of phosphoenolpyruvate to glucose or for its oxi-
dation to CO2.
Several RBFs mediate the stabilization or the degrada-
tion of certain mRNAs involved in the chronic adaptive
metabolic response, including GA, PEPCK and SNAT3
(43, 44). RBFs such as z-cryst (45), AU-factor 1 (AUF1) (13),
and HuR (12) can all interact with the cis pH-response
element (pHRE) (direct repeat or a single copy of an 8 nt
AU-sequence: UUAAAAUA) of the GA mRNA (46) and
modify its stability—for example, binding to z-crystallin/
NADPH:quinone reductase (z-cryst) accelerates its decay,
and binding to HuR increases its stability. It is thought
that, in response to metabolic acidosis, z-cryst is recruited
to the cytoplasmic SGs, and HuR is translocated into cy-
toplasm as the result of endoplasmic reticulum stress.
Because cytoplasmic HuR helps to stabilize GA mRNA,

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Figure 1. Role of RNA-stabilizing factors in renal response to chronic metabolic acidosis. Selective stabilization of GA mRNA and
PEPCK mRNA in maintaining adaptive metabolic response. A pHRE containing a direct repeat of 8-nt AU sequences
(UUAAAUUAUUU), within the GA mRNA binds RNA-binding proteins, including z-cryst and HuR. In response to metabolic
acidosis, stabilization of the GA mRNA by z-cryst and HuR produces an increase in GA mRNA. The concurrent binding of AUF1
and HuR to the AU-rich sequences within the 39-UTR of the PEPCK mRNA mediates pH-responsive stabilization of PEPCK mRNA
(adapted from refs. 43–45, 47).

higher GA protein expression alleviates acidosis (14). On
the contrary, under physiologic pH, binding of z-cryst to
pHRE of GA mRNA promotes the degradation of GA
mRNA, leading to lower but normal GA protein expres-
sion (14). Similarly, a pHRE-dependent stabilization by
RBFs of the SNAT3 and PEPCK transcripts also helps to
up-regulate the cognate protein products to eventually
eliminate H+ (43, 47). The function of specific RBFs, such
as AUF1, in mRNA metabolism seems to change under
some still ill-defined conditions, in that its knockdown
appears to increase the basal PEPCK mRNA level and
hence the protein product (48).
Osmotic stress
In response to chronic hypertonic stress, the tonicity-
responsive enhancer-binding protein (TonEBP), known
as nuclear factor of activated T cells 5 (NFAT5), activates
certain enzymes and membrane proteins to synthesize
and transport osmolytes needed to restore cell volume
and to maintain intracellular ionic strength (49–51). The
broader roles played by NFAT5 in kidney pathophysiol-
ogy can be illustrated by the renal atrophy in Nfat5
knockout mice (50). In rat kidney epithelial NRK-52E cells,
acute hypertonic stress (.200 mOsmol/kg) caused
heightened SG formation (35), suggesting that the
shutdown of global protein synthesis (via mRNA se-
questration in SGs) favors the eventual production and
transport of the osmolytes. Another example is the post-
transcriptional regulation of mineralocorticoid recep-
tor (MR) by a RNA binding and destabilizing protein,
tetradecanoyl phorbol acetate-inducible-sequence 11b
(Tis11b). Indeed, when cortical collecting duct (CCD)
cells are exposed to hypertonic milieu, Tis11b expression
is increased, leading to greater Mr mRNA degradation
(52). Because MR is known to regulate aldosterone-
stimulated Na+ reabsorption in the renal cortex, the post-
transcriptional regulation of MR by Tis11b can contribute to
the pathophysiology of hypertension or renal insufficiency.
It is notable that besides hosting the binding sites for sev-
eral RBFs, the 39-UTR of TonEBP mRNA contains several
miRNA recognition sites based on in silico analyses; the
presence of such sites is a likely explanation for why the
overexpression of miR-200b and miR-717 significantly di-
minishes the level of TonEBP mRNA and its protein (53).
ATP depletion and ischemia/reperfusion injury
Vacuolar H+-translocating (V)-ATPases are transporters
responsible for the acidification of membrane-bound

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Figure 2. HuR-mediated mRNA stability in renal fibrosis and inflammation. Overview of AngII and cytokine-induced stabiliza-
tion of target mRNAs. Treatments with AngII or IL-1b induce PKCd-dependent phosphorylation of HuR, triggering the
nucleocytoplasmic shuttling of HuR to facilitate HuR binding to its AU-rich target mRNAs in the cytoplasm. This results in the
stabilization of COX-2 mRNA, PAI-1 mRNA, CCND1 mRNA, and MMP-9 mRNA and the consequent higher protein syntheses that
eventually lead to more inflammation and ECM accumulation (adapted from refs. 61, 62, 67).

intracellular compartments (54). As ATP depletion acti-
vates the nucleocytoplasmic shuttling of HuR and in-
creases HuR mRNA translatability, ATP depletion can
increase V-ATPase expression through HuR-mediated
mRNA stabilization (55). In energy-depleted LLC-PK1
cells, HuR suppression via RNA interference leads to
reduced expression of antiapoptotic proteins Bcl-2 and
Hsp70, and a higher rate of cellular apoptosis, indicat-
ing that the cellular stress caused by ATP insufficiency
in kidney cells can be eased by the presence of HuR. The
protective function of HuR was also observed in rat
proximal tubular cells exposed to ischemia–reperfusion
events, given that these cellular insults lead to both
higher HuR expression and HuR export into the cyto-
plasm to stabilize the mRNAs of antistress genes (56).
These pieces of evidence support the role of HuR in
protecting renal epithelia from injury.
Diabetic nephropathy, inflammation,
and fibrosis
Early events involved in renal fibrosis are related to
proliferation of mesangial cells and ECM accumulation.
Vasodilatory prostaglandins participate in regulation of
renal blood flow, glomerular filtration rate (57), and so-
dium reabsorption at the thick ascending limb of the loop
of Henley (58) and are essential to maintain proper kidney
function. Cyclooxygenase (COX)- 2 is a prerequisite for the
conversion of arachidonic acid to prostaglandins; its ac-
tivity is needed for renal protection against vasoactive
Angiotensin (Ang)II (59). The expression of COX-2 mostly
occurs through transcriptional activation induced by
proinflammatory cytokines and tumor promoters (60). In
renal mesangial cells, PKC responds to vasoactive factors,
and its activation has been shown to control HuR export
(Fig. 2). Doller et al. (61) demonstrated that in human
mesangial cells, AngII can trigger an intracellular prosta-
glandin E2 (PGE2) increase via HuR-mediated COX2
mRNA stabilization and that the enhanced HuR binding
to COX-2 ARE was the result of an increased nucleocyto-
plasmic HuR shuttling consequent to PKC-d mediated
phosphorylation. Moreover, in AngII-treated rats, greater
nucleocytoplasmic HuR shuttling as well as stronger HuR
binding to Pai-1 mRNA and Cox2 mRNA were observed in
the cytoplasmic fractions of renal homogenate, confirming
the participation in vivo of HuR in the AngII-induced

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Figure 3. Renal damage and fibrosis in diabetic conditions. In rat glomerular mesangial cells, hyperglycemic conditions can
enhance the production of ROS via the NOX4 signaling pathway and help to stabilize the NOD2 mRNA via HuR binding to its
39-UTR. In another model, treatment with TGF-b under diabetic conditions leads to increased miR-216a level, which, in turn,
inhibits its target, Ybx1, an RNA binding protein. In parallel, miR-216a enhances the expressions of Tsc-22 and Col1a2. Ybx1
colocalizes with P-body and forms a ribonucleoprotein complex with Tsc-22 mRNA (adapted from refs. 37, 70, 101).

expression of the proinflammatory and profibrotic serine
protease inhibitor renal plasminogen activator inhibitor-1
(PAI-1) and COX-2 (62). In addition, AngII was shown to
promote a fibrotic process (63) through the overexpression
of the cell cycle regulator cyclinD1, which is known to
shorten the progression of the G1 phase (64). CCND1
mRNA contains specific AREs within its 39-UTR. The in-
creased cyclin D1 expression in mesangial cells after AngII
treatment observed by Che et al. (65) is thus the likely
result of increased HuR binding to the cytoplasmic
CCND1 mRNA; such an increase can lead to abnormal
proliferation of the mesangial cells.
Further insights into the post-transcriptional regulation
of ECM have been provided by studies of the matrix
metalloproteinases (MMPs). MMP-9 has been implicated
in both the remodeling of ECM and the progression of
chronic inflammatory renal diseases (66). In response to
inflammatory cytokines such as IL-1b, mesangial cells
treated with ATP displayed increased HuR nucleocyto-
plasmic shuttling and MMP-9 expression resulting from
HuR-mediated mRNA stabilization (67). In contrary,
neutralization of HuR after treatment with NO reduced
the stability of MMP-9 mRNA (68). Moreover, an alter-
natively spliced form of T-cell–restricted intracellular
antigen-1-related protein (TIAR), an RBF, has been shown
to inhibit the translation of human MMP-13 mRNA
through its binding to the 39-UTR of MMP-13 mRNA (69).
Human MMP-13 is also known for its involvement in in-
flammation and angiogenesis.
Our understanding of the role of post-transcriptional
RNA regulation in DN was recently advanced by several
studies. For example, Shang and collaborators (70) found
that an abnormally high HuR expression was present in
the kidney biopsies of patients with DN, and it appeared
to correlate with the level of nucleotide-binding oligo-
merization domain-containing protein (NOD)-2. Because
hyperglycemic conditions have been associated with
enhanced production of ROS via hydrogen peroxide-
producing NADPH oxidase (NOX4) signaling in rat
glomerular mesangial cells, it has been proposed that
higher NOD2 mRNA stability is mediated by higher
HuR-dependent NOD2 mRNA stabilization as a result
of the increased presence of cytoplasmic HuR conse-
quent to ROS-mediated cell signaling (Fig. 3). The in-
vestigators also evidenced that the expression and the
translocation of HuR, and the stability of NOD2 mRNA
were related to NADPH oxidase-mediated redox sig-
naling. In parallel, an amelioration of renal injury and a
reduction of NOD2 expression were observed after
HuR gene silencing in diabetic rats. Kato et al. (37)
suggested that post-transcriptional regulation partici-
pates in TGF-b-induced renal fibrosis in DN. They
showed that TGF-b treatment leads to miR-216a in-
crease in mouse mesangial cells and that this increase in

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miR-216a, on the one hand, inhibits the RNA target
binding of a RBF called Y-box binding protein 1 (Ybx1)
(37, 71, 72), and, on the other hand, enhanced the ex-
pression of TGF-b-stimulated clone 22 (Tsc-22) and of
collagen type I a-2 (Col1a2). Mechanistically, it turned
out that Ybx1 colocalizes with P-body and forms a ri-
bonucleoprotein complex with Tsc-22 mRNA in the
mouse mesangial cells. The TGF-b-induced increase in
miR216 thus causes the release of Tsc-22 mRNA from
the P-body and promotes its translation by inhibiting
the binding of Ybx1 to Tsc-22 mRNA. Last, in a series of
studies, the role of VEGF and its regulation in diabetes
was examined. It was found that VEGF induces hy-
pertrophy in murine proximal tubular epithelial cells
and that its expression increases in the renal cortex of
diabetic mice (73). In addition, the application of AngII
in the proximal tubular epithelial cells leads to enhanced
Vegf synthesis via heterogeneous ribonucleoprotein
(hnRNP K)-mediated mRNA stabilization (74, 75).
Mechanistically, the activation of tyrosine/protein ki-
nase c/src by AngII plays a crucial role in the activation
of hnRNP K binding to Vegf mRNA, mediated through
a PKC-d-dependent hnRNP K Ser302 phosphorylation
(75, 76). Likewise, VEGF expression was found to be
increased in db/db diabetic mice as a result of a greater
Vegf mRNA stability made possible by hnRNP K binding
to Vegf mRNA (76).
Hyperparathyroidism in CKD
In CKD, low calcium and high phosphate levels lead to
hyperparathyroidism characterized by increased PTH
gene expression (77). Nechama et al. (28, 29) demonstrated
that PTH mRNA is more stable in parathyroid glands from
CKD or calcium-depleted animals comparing to para-
thyroid glands from control and phosphorus-depleted
rats. Low serum phosphate was shown to facilitate the
interaction between PTH mRNA and KSRP at 39-UTR of
the PTH mRNA. The binding of KSRP appeared to pro-
mote the binding of RNA exosome to PTH mRNA in
parathyroid extracts, leading to a decrease in PTH mRNA
stability and thus to reduced PTH protein level. In the
same animal model, in parathyroid glands from calcium-
depleted or CKD rats, AUF1 and N-ras appeared to
TABLE 2. Pharmaceutical agents modulating mRNA stability
Pharmaceutical
agent/molecule Mechanism of action
DHTS Inhibition of HuR–mRNA
interaction
Indoline Inhibition of nuclear–cytoplasmic
sulfonamide HuR shuttling
MPT0B098a
Latrunculin Ab Inhibition of nuclear–cytoplasmic
Blebbistatinc HuR shuttling
Model represents clinical indication. DHTS, 15,16-dihydrotanshinone-I; HIF-1a, hypoxia-inducible factor-1a. aInhibitor of microtubule
polymerization. bActin inhibitor. c Myosin II inhibitor.
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replace the binding of KSRP to PTH mRNA ARE, leading
to increased PTH mRNA stability and hence high PTH
protein levels. Furthermore, the peptidyl-prolyl cis-trans
isomerase (Pin)-1 was demonstrated to decrease PTH
mRNA by enhancing KSRP–PTH mRNA interactions (78).
On the contrary, when Pin-1 was not active, KSRP was
phosphorylated, which led to its inactivation and facilitated
the binding of AUF1 to the 39-UTR of PTH mRNA, resulting
in increased PTH mRNA stability.
Polycystic kidney disease and planar
cell polarity
The primary cilia of the renal epithelial cells are the me-
chanical sensors, transducing the urinary flow information
into biologic signal via the activation of Ca2+ channels (79).
Kidney cilia express regulators of planar cell polarity,
which are crucial for well-oriented renal cell divisions and
elongation of tubules (80, 81). The propagation of planar
cell polarity between cells depends on several principal
proteins, among them the Dvl-1 protein (Drosophila)/Dvl
(mammals) (82). The loss of planar cell polarity is associ-
ated with polycystic kidney disease (PKD) (80). Recently,
the observations of Maisonneuve et al. (36) have shed new
insights into the physiopathology of PKD, revealing that
bicaudal C (BicC), a conserved RNA-binding protein, can
uncouple Dvl2 signaling from the Wnt pathway. The Wnt
pathway controls the planar cell polarity and the activa-
tion of cell proliferation via b-catenin signaling. The tar-
geted inactivation of BicC produced abnormalities in the
planar alignment of motile cilia, with a consequent accu-
mulation of BicC in P-bodies. Evidence further suggested
that miRNAs are involved in PKD. For example, in
BicC12/2 mice, an increased Pkd2 gene expression (the
PC2 protein) was associated with the presence of bi-
lateral polycystic kidneys (83, 84). Additional experi-
mentation revealed that BicC1 specifically up-regulates
PC2 expression through blocking the mRNA destabili-
zation caused by the binding of miR-17 to the 39-UTR of
Pkd2 mRNA (85). Moreover, in renal epithelial cells,
miR-17 ;92 cluster and miR-200 have been shown to
down-regulate the expression of the key cystic genes
Pkd1, Pkd2, and Pkhd1 via the repression of HNF-1b (86,
87). In fact, Hnf-1b directly regulates the transcription of
Effect Model Reference
Down-regulation of TNFa Human breast cancer cells 98
expression
Destabilization of HIF-1a Human cancer cells and 99
mRNA normal endothelial cells
Decreased stability of HuR Human hepatocellular 100
targets COX-2, cyclin A, carcinoma cells
cyclin D mRNAs
FEIGERLOVÁ AND BATTAGLIA-HSU
Pkhd1, which plays a crucial role in the development of
autosomal recessive PKD (88).
CONCLUSIONS AND PERSPECTIVES
Recent data in the literature suggest that post-
transcriptional regulation of mRNA stability plays im-
portant roles in CKD. It underlies the capacity of renal
cells to form transient protein assemblies like stress
granules SGs and P-bodies, which functionally interact
with both translational and degradation machinery to
modulate the expression of genes contributing to disease
phenotypes. Given that the presently available thera-
peutic options are of rather limited efficacy, potential in-
terventions designed to modulate the metabolism of
relevant RNA species through influencing their decay
may offer new opportunities for the treatment of CKD.
Nonetheless, the current development for such ap-
proaches is still in its infancy, despite the many exciting
experimental results that are being reported. For example,
the RNA interference approach has been in the forefront
of such strategies and was successfully used for treating
small experimental animals with diseases such as in-
flammatory bowel disease (89). Small molecules have also
been found to modulate the function of RNA binding
proteins such as HuR (90) and RNA terminal uridylyl
transferase (91) for potential treatment of diseases ranging
from cancer to infectious disease. These findings represent
the broader research efforts devoted to identifying po-
tential targets for post-transcriptional modification of
mRNA stability. Such progress is particularly advanced
for cancer therapy (92). The application of chemical in-
hibitors to disrupt cytoskeleton dependent RBF-mRNA
transport (93) represents a potential new strategy for
controlling renal fibrosis, given that (1) the components of
cytoskeleton are implicated in ECM formation, and (2) the
actin/cytoskeleton-dependent HuR transport has been
shown to regulate hypertension-induced fibrosis and in-
flammation through stabilization of COX-2 mRNA (61).
Examples of recent advances in this field are summarized
in Table 2. It is our hope that the lessons learned from the
treatment strategies aimed at altering RNA stability in the
field of oncology can be applied in the near future to CKD,
given that similar mechanisms participate in modulating
the expression of renal disease–causing genes, such as the
TGF-b cytokine.
It is worth noting that the involvement of noncoding
RNA in the regulation of mRNA stability of the disease
genes remains to be explored in the field of renal disease.
For instance, in the experimental model of CKD associated
with hyperparathyroidism, the altered intracellular PTH
mRNA level was proposed to be caused by disrupted in-
teractions of the 39-UTR of PTH mRNA with both KSRP
and RNA exosome (28, 29). Are there any noncoding
RNAs that participate in the decay of PTH mRNA? If so,
what are the noncoding RNAs involved in regulating
the stability of the particular gene transcripts relevant to
individual kidney pathology? To fully appreciate the in-
volvement of specific noncoding RNAs in kidney dys-
function, one can begin with the identification of genes
REGULATION OF mRNA STABILITY IN RENAL DISEASE
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affected—in particular, renal diseases—and examine
their interacting noncoding RNAs by using either RNA
immunoprecipitation or microarray technology (94).
Equally, one may also search, at either the cellular or tissue
level, for the involvement of noncoding RNAs using
comparative profiling approaches. Take, for example, the
RNA-binding factor BicC, which has been shown to reg-
ulate the mRNA stability of Wnk1, V-ATPase B1 and
adenylate cyclase6 (95–97), it is not known whether non-
coding RNAs can alter the expression of BicC via modu-
lating its mRNA stability. If so, can these noncoding RNAs
be used as targets for treatment? Also, it is known that in
the 39-UTR of certain key pathogenic genes, such as PKD1
and TonEBP, there are conserved miRNA binding sites for
miR-200 (87) for PKD1, and miR-200b and miR-717 for
TonEBP (53); however, the involvement of these miRNAs
in the stability of the PKD1 and TonEBP mRNA remains
to be answered and their potential as therapeutic targets
investigated.
Altogether, deregulated mRNA stability appears to be a
significant mechanism controlling gene expression in renal
disease. It enables rapid and specialized local control of
gene expression in the special cellular compartments and
opens new diagnostic and therapeutic possibilities.
ACKNOWLEDGMENTS
The authors thank Dr. Battaglia (Laboratoire Interdisci-
plinaire des Environnements Continentaux, UMR 7360
CNRS/Université de Lorraine) for critical reading of the
manuscript.
AUTHOR CONTRIBUTIONS
E. Feigerlova wrote the manuscript, and S.-F Battaglia-Hsu
participated in writing in all sections.
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Received for publication September 26, 2016.
Accepted for publication November 7, 2016.
FEIGERLOVÁ AND BATTAGLIA-HSU
Role of post-transcriptional regulation of mRNA stability in renal
pathophysiology: focus on chronic kidney disease
Eva Feigerlová and Shyue-Fang Battaglia-Hsu

FASEB J published online November 14, 2016

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