mTOR
Signaling in Renal Disease and Therapy
Chunfa Huang, Carl
E. Freter
Chunfa
Huang, Carl E. Freter, Department
of Internal Medicine, School of Medicine, Saint Louis University, Saint Louis,
MO 63104, USA
Correspondence to: Chunfa
Huang, PhD, Associate Research Professor,
Department of Internal Medicine, School of Medicine, Saint Louis University,
Saint Louis, MO 63104, USA
Email:
chunfahuang@slu.edu
Telephone: +1-314-977-9860
Fax: +1-314-773-1167
Received: May 12, 2015
Revised: June 27, 2015
Accepted: June 30, 2015
Published online: October 2, 2015
ABSTRACT
The mTOR signaling plays a central role in the regulation
of cell growth, proliferation, survival, apoptosis, and metabolism in response
to mitogen, stress, energy, and nutrient signals as well as renal injury
factors such as glucose, hemodynamic force, immune factors, toxins, and cancer
causing agents. From cells to animal models, current data support that the
dysregulation of mTOR signaling in renal cells leads to renal disease
progression, including diabetic nephropathy, HIV-associated nephropathy, IgA
nephropathy, polycystic kidney diseases and renal cell carcinoma. Meanwhile,
the inhibitors that attenuate mTOR signaling at the levels of receptor, kinase,
phospholipase D or mTOR can slow or delay disease progression. In this review,
we update our current knowledge of mTOR signaling network in renal disease and
therapy.
© 2015 ACT. All rights reserved.
Key words: mTOR; Rapamycin;
Phosphatidic Acid; Signaling, Renal Disease; Therapy
Huang C, Freter CE. mTOR Signaling in Renal Disease
and Therapy. Journal of Nephrology Research 2015; 1(2): 40-48 Available from: URL: http://www.ghrnet.org/index.php/jnr/article/view/1188
Abbreviations
ACEI: angiotensin-converting enzyme inhibitor; AMPK:
AMP-activated protein kinase; ARB: angiotensin receptor blocker; EGF: epidermal
growth factor; EGFR: epidermal growth factor receptor; ESRD: end-stage renal
disease; 4E-BP: eukaryotic translation initiation factor-4E (eIF4E) binding
proteins; FRB: FKBP12-rapamycin-binding; GBM: glomerular basement membrane;
HIF: hypoxia-inducible factor; HIVAN: HIV-associated nephropathy; mTOR:
mammalian target of rapamycin; mTORC: mTOR complex; PKD: polycystic kidney disease;
PA: phosphatidic acid; PLD: phospholipase D; RCC: renal cell carcinoma; Rheb:
ras homolog enriched in brain; S6K: ribosomal S6 kinase; TSC: tuberous
sclerosis complex.
INTRODUCTION
Chronic kidney disease represents a significant and growing public health
problem and is recognized as a major global health burden[1,2].
During the past decades, the pathogenesis of chronic kidney disease has been
intensely investigated[3-6]. Experiments in cell and animal models
have accumulated a large amount of knowledge on the roles of glomeruli in
chronic kidney diseases[6,7]. The major causes of chronic kidney
diseases are sustained glomerular injury which is initiated by injury of
glomerular podocytes and induced by numerous factors including high glucose,
hemodynamics, infections and immunity, hereditary and metabolic diseases, and
toxicity[1-7]. Meanwhile, the damage of other renal cells such as
glomerular endothelial cells, mesangial cells and tubular epithelial cells also
plays an important role in the progression of chronic kidney disease. These
renal cells are regulated by different and multiple signaling pathways, and
play specific roles to maintain kidney function. Therefore, understanding the
alterations of signaling pathways that regulate renal cell functions in disease
progression and disease state could lead to discover novel potential targets
and to develop new therapeutic strategies. This brief review will focus on
recent progresses in our understanding of the role of mammalian target of
rapamycin (mTOR) signaling in renal disease and therapy.
Renal cell biology
The functioning unit of the kidney is the nephron including the
glomerulus and the tubule[8]. The glomerulus is a highly specialized
structure that is the site of plasma ultrafiltration. The glomerular
endothelium sits on a 250-300 nm thick glomerular membrane which is the basal
lamina layer of the glomerulus and composed of glomerular endothelial cells,
glomerular basement membrane (GBM), and glomerular epithelial cells
(podocytes). The interstitium between endothelial cells of the glomerulus is
mesangial cells. Glomerular podocytes are terminally differentiated cells,
consisting of a cell body, major processes and foot processes interlinked by
slit diaphragms. They play a central role in maintaining the filtration barrier
of the glomerulus[8-10]. The endothelial cells of the glomerulus are
highly fenestrated and contain numerous 60-80 nm pores that go through the
cytoplasm[10]. They are also a significant part of the glomerular
filtration barrier. Mesangial cells are specialized smooth muscle cells around
blood vessels in the kidneys, and usually divided into two types:
extraglomerular and intraglomerular mesangial cells. Intraglomerular mesangial
cells provide structural support for glomerulus and regulate blood flow of the
glomerular capillaries by their contractile activity[10]. The tubule
plays a role in the maintenance of fluid and electrolyte composition of our
body by reabsorption and secretion, and produces urine. Renal tubular
epithelial cells lining the tubule establish the polarity of the epithelial
plasma membrane which restricts the apical-basolateral diffusion of membrane
components[11]. Injury or uncontrolled proliferation of renal cells
are the key excretory processes leading to kidney dysfunction and renal disease
progression
Renal disease
progression
Diabetic
nephropathy: Diabetic
nephropathy is clinically characterized by proteinuria, glomerular hypertrophy
and GBM thickening with foot process effacement and is the single most common
cause of end-stage renal disease (ESRD). High glucose in the blood accelerates
glucose uptake, leads to a high metabolic rate and significant succinate
accumulation in the mitochondria, cytosol and interstitium, and activates the
renin angiotensin system that regulates body fluid balance and blood pressure[12,13].
The increases of blood pressure and local growth factors such as angiotensin II
and transforming growth factor , induce podocyte injury[4-7,12-14].
These podocytes become thinner and more elongated, and ultimately cell
hypertrophy, foot process effacement, cell body attenuation, pseudocyst
formation, cytoplasmic overload with reabsorption droplets, and detachment from
the GBM, which finally leads to structural changes such as loss of nephron and
results in loss of barrier function for macromolecules leading to proteinuria
and ESRD[12-14]. Recent studies show that the alteration of the
glomerular endothelial cell surface layer and the communication between
glomerular endothelial cells and mesangial cells, or glomerular endothelial
cells and podocytes also play an important role in the development and
progression of diabetic nephropathy[15].
HIV-associated nephropathy: Human immunodeficiency virus
(HIV) infection is associated with collapsing focal segmental
glomerulosclerosis- a classic histomorphological form of HIV-associated
nephropathy (HIVAN) and immune complex-mediated forms of glomerulonephritis[16].
The mechanisms responsible for HIVAN are initiated by HIV infection of
podocytes and tubular epithelial cells. Glomerular podocytes in HIV-infected
patients undergo dedifferentiation and acquire a proliferative phenotype which
is accompanied by loss of the maturation markers synaptopodin and WT1, and
expression of the proliferation marker Ki-67[17]. Dedifferentiated
podocytes lose their characteristic features, lead to the destruction of
glomerular filtration barrier integrity, reduce their adhesion, and promote
podocyte detachment[16,17]. On the other hand, the most prominent
response to HIV infection in human renal tubular epithelial cells is
up-regulation of pro-inflammatory mediators which cause cell injury[16].
Both podocyte dedifferentiation and tubular epithelial cell injury lead to
progressive renal insufficiency, proteinuria, and focal segmental
glomerulosclerosis.
IgA Nephropathy: The pathogenesis of IgA nephropathy is associated with several
different renal cells. IgA1 binds to the glomerular mesangium, triggering the
local production of cytokines and growth factors which lead to the activation
of mesangial cells and proximal tubular epithelial cells. Mesangial-derived
mediators lead to podocyte and tubulointerstitial injury. One of signs and
symptoms of IgA nephropathy is high blood pressure. This hemodynamic force also
causes podocyte injury, nephron loss and renal failure[18,19].
Polycystic kidney disease: Polycystic kidney disease (PKD)
is one of the most common life-threatening genetic diseases and is caused by a
broad array of genetic mutations. Recent findings link cystogenesis in ciliary
functions, planar cell polarity, and centrosome integrity in early disease
development. The dysregulation of Ca2+ signaling leads to aberrant
structure and function of the collecting ducts in the kidney, but the most
important characteristics of PKD are the neoplastic-like epithelial cell
proliferation and over-activation of epidermal growth factor/epidermal growth
factor receptor (EGF/EGFR) signaling[20-23]. High blood pressure is
also the most common and noticeable sign of PKD. On the other hand, PKD cysts
slowly replace and accumulate in the kidneys, reducing kidney function and
leading to kidney failure.
Renal cell carcinoma: Renal cell carcinoma (RCC), the most common form
(more than 90 %) of primary kidney tumors, arises from the convoluted tubules
with the development of metastatic disease in the lung, bone, liver, and brain[24-26].
In the unstressed kidney, renal tubule epithelial cells which are maintained in
G0-G1 phase divide at a very low rate[27]. The new tubular
epithelial cells only replace the loss of old tubular epithelial cells under
physiological conditions. The turnover rate is under tight control as even a
small imbalance between cell loss and cell division would soon lead to the
significant changes of kidney size over time. Upon tumorigenesis, the tubular
epithelial cells reenter the cell cycle, produce high levels of Cyclin D and A,
cycline-dependent kinase 2 and 4, and proliferate out of control[24-28].
Enhanced cell proliferation occurs in every form of RCC and different stages of
renal tumorigenesis[24-26].
Although
different renal cells play different roles in the regulation of kidney function
and different renal diseases are caused by different reasons, the progression
of different renal diseases are always associated with either renal cell
apoptosis or uncontrolled proliferation. More and more studies indicate that
mTOR signaling plays an important role in the regulation of cell growth,
proliferation and apoptosis, and is involved in the progression of different
renal diseases[29-31]. It is important to understand the regulation
of mTOR signaling in renal cells and the association with renal disease
progression.
mTOR signaling
The mTOR signaling
plays a central role in the regulation of cell growth (cell size and
proliferation), stress response (apoptosis, autophagy, and necroptosis) and
cell metabolism (nutrients and energy balance), and can be activated in
response to nutrients, growth factors, stress, and cellular energy[29-38].
The mTOR protein is a highly conserved 289 kDa serine/threonine kinase which
nucleates at least two distinct multi-protein complexes: mTOR complex 1
(mTORC1) and mTOR complex 2 (mTORC2)[32-34]. In addition to mTOR,
both complexes contain the small adaptors: deptor (DEP domain-containing
mTOR-interacting protein) and mLST8 (mammalian lethal with SEC13 protein 8)/GβL (G protein β subunit-like protein), and the
defined adaptors: raptor (regulatory-associated protein of mTOR) for mTORC1 and
rictor (rapamycin-insensitive companion of mTOR) for mTORC2. Two well
characterized effectors of mTORC1 are ribosomal S6 kinase (S6K), and the
eukaryotic translation initiation factor-4E (eIF4E) binding proteins (4E-BP),
which regulate mRNA translation (Figure 1)[37]. Both S6K and 4E-BP
are recruited by the raptor to mTORC1 for phosphorylation[38]. By
phosphorylation of S6K and 4E-BP1, mTORC1 activates the translation of key
proteins such as hypoxia-inducible factor (HIF) and cyclin D and regulates gene
translation to modulate cell growth, proliferation, differentiation, death,
metabolism, and energy balance[32-38]. Like mTORC1, mTORC2
phosphorylates SGK1, Akt, and PKCα, activates Rho GTPases, and regulates
cytoskeletal organization, metabolism, proliferation, and survival[39-45].
Recent data also indicate that mTORC2 regulates cell motility via focal
adhesion proteins and actin cytoskeleton[39, 40,46].
Phosphatidic acid,
rapamycin and mTOR
Both phosphatidic acid (PA) and rapamycin can directly bind to mTOR.
They are positive and negative regulators of mTOR[39,40,47]. By
analyzing NMR structure, Veverka et al reported that the phospho group
of PA interacts with Arg2109 in FRB (FKBP12-rapamycin-binding) domain of mTOR[48].
PA binds to FRB domain of mTOR in a manner that is competitive with
rapamycin-FKBP12[49] and activates either mTORC1 or mTORC2 in the
cells[32-35]. Rapamycin binds to FKBP12 (a 12 kDa FK506-binding
protein), and the complex specifically binds to FRB domain of mTOR, and
inhibits mTORC1 activation by preventing the interaction of mTOR with raptor,
but does not bind to preformed mTORC2 (Figure 1, red box)[39,40].
One recent report showed that prolonged rapamycin treatment also inhibit the
interaction of mTORC2 and rictor in some cell lines, and further attenuate Akt
activity[50].
Tuberous
sclerosis complex (TSC) plays an important role in the regulation of mTOR
signaling via activating phospholipase D (PLD) and generating PA[51-53].
TSC consists of hamartin (TSC1) and tuberin (TSC2), and is an autosomal
disorder that causes significant complications in multiple organs such as kidney,
brain, heart, and lung[51,54]. Under the normal condition, TSC1
binds to TSC2, and forms a functional complex. TSC2 serves as a GTPase
regulator for ras homolog enriched in brain (Rheb, a ras-related small GTPase)
and the active form of Rheb (Rheb-GTP) stimulates PLD activity[55-58].
The activation of AMP-activated protein kinase (AMPK, an energy- and
nutrient-sensing kinases) leads to increased phosphorylation of TSC2 at S1345,
S1387 and T1227 that results in Rheb-GTP hydrolysis and inactivate Rheb (Rheb-GDP
form)[59,60]. The inactive TSC2 which is phosphorylated by Akt at
T1462 and S939 allows Rheb at GTP form to activate PLD and produce PA[61-64].
Other protein kinases such as ERK, S6K, GSK-3, PKC, and p38-MK2 kinase also
phosphorylate TSC2 at specific sites to regulate mTOR activity (Figure 1, blue
box)[65-70].
PA is
generated by PLD which can be stimulated by a variety of extracellular signals
including hormones, growth factors, neurotransmitters, cancer-causing agents,
and bioactive lipids as well as the factors that can induce podocyte injury.
PLD activation is regulated by multiple signaling pathways via tyrosine kinase
receptors, G protein coupled receptors and others that act through Arf, Rho,
Ral, PKC, ERK, p38MAPK, PI3K, Pyk2 and Src[71-74]. Many of these
signaling pathways may be independent to TSC2/Rheb/PLD pathway. PA can also be
produced by diacylglycerol kinase (DGK) which is regulated by ionic detergents,
phospholipids (PIP2 and PIP3) and many enzymes such as
PKC, Src, and mTOR (Figure 1 green box)[75,76]. Based on PA binding
to mTOR[32-35,48,49], signaling pathways that regulate PA production
are associated with the activation of mTOR signaling.
The role of mTOR signaling in progressive renal diseases
The role of mTOR signaling in the physiological condition links to
development and autophagy regulation in the kidney. The mTOR integrates signals
to coordinate cell growth (mass and size) and cell cycle progression with
sufficiency of nutrients, energy, and growth factors during kidney development
and recovery, and is also a key player in the regulation of autophagy activity
by stimulating cellular catabolism and anabolism in the response to kidney
nutrients and growth factors[53,54]. Recently, a growing body of
evidence suggests that mTOR plays a crucial role in renal disease progression[29-35].
Diabetic
nephropathy: A sustained exposure of high glucose results in diabetic nephropathy[7].
High glucose milieu up-regulates expression of matrix proteins leading to
glomerular matrix accumulation and thickening of the GBM and induces the
hypertrophy of glomerular podocytes, mesangial cells, and proximal tubular
epithelial cells resulting in apoptosis, albuminuria, and glomerulosclerosis[5-7].
Evidence from different laboratories has demonstrated that high glucose
stimulates PLD activity[77,78] and enhances mTOR activation and
morphological changes[79-81]. Direct evidence from mice with TSC1
deletion specifically in podocytes recapitulates many features of diabetic
nephropathy, including podocyte loss, GBM thickening, mesangial expansion, and
proteinuria[82]. The partially TSC2(+/-)-deficient diabetic rats
significantly increase the kidney mass[83]. Genetic deletion of
raptor (mTORC1) in mouse podocytes induces proteinuria and progressive
glomerulosclerosis, while simultaneous deletion of both raptor and rictor
(mTORC2) from mouse podocytes aggravates the glomerular lesions, revealing the
importance of both mTOR complexes for podocyte homeostasis (podocyte
development and podocyte maintenance)[84]. Deletion of S6K 1
inhibits renal hypertrophy following either contralateral nephrectomy or
induction of diabetes[85]. 4E-BP1 knockout mice have not been used
to address the important of 4E-BP1 in hypertrophic renal growth[86].
Taken together, these genetic data support that mTOR signaling plays an
important role in the progression of diabetic nephropathy.
HIV-associated nephropathy: The mTOR regulates cell growth
and proliferation by promoting the biosynthesis of proteins, lipids and nucleic
acids. HIV-infection enhances the biosynthesis of DNA and protein. Increased
extracellular matrix synthesis leads to GBM thickening and mesangial expansion.
Increased proliferation of glomerular podocyte cells occurs with loss of
maturation markers (synaptopodin and WT1) and the destruction of glomerular
filtration barrier integrity and tubular cells that lead to the significant
changes in kidney size[30,31,34,69,70]. So far, there is no genetic
evidence linking mTOR signaling components to HIVAN, however, the
phosphorylation of mTOR is significantly increased in both glomerular and
tubular epithelial cells of HIV-1 transgenic mice and HIVAN patients, and the
renal tissues of transgenic mice enhance the phosphorylation of p70S6 kinase
and 4E-BP1[87,88]. On the other hand, rapamycin can attenuate the
progression of glomerular and tubular lesions in Tg26 mice[89].
Epithelial mesenchymal transition of renal cells has been demonstrated to
contribute to the pathogenesis of proliferative HIVAN[90]. Recent
studies have found that abnormal mTORC1 activation also causes alteration of
slit diaphragm protein distribution and induces an epithelial-mesenchymal
transition-like phenotypic switch with enhanced endoplasmic reticulum stress in
podocytes[82].
IgA nephropathy and PKD: Most of IgA nephropathy presents with progressive
mesangioproliferative glomerulosclerosis and causes ESRD within 20 years of
onset[91]. ERK activation through mesangial IgA1 receptor (CD71)
controls pro-inflammatory cytokine secretion and alters mesangial cell-podocyte
crosstalk[92]. Rapamycin can attenuate the progression of
mesangioproliferative glomerulosclerosis, prevent an additional increase in
proteinuria and protect kidney function in a rat IgA nephropathy model induced
by injection of high dose anti-thy1 antibody[91,92]. Many PKD
patients have a large deletion of chromosome 16 encompassed by both the PKD1
gene and the adjacent TSC2 gene[20-23]. Using a PKD mouse model
created by knocking out TSC1 in a subset of renal tubular cells, one recent
study reported that extensive renal cyst formation in these mice is accompanied
by broadly elevated mTORC1 activity[93]. It is clear that cyst
development requires mTORC1 activation and can be blocked by low dosage of
rapamycin administration[93,94].
RCC and others: The mTOR signaling promoting cell proliferation under energy or
nutrient-rich conditions is dysregulated in many cancers, including RCC[33-35].
The activation of mTOR correlates with aggressive behavior and poor prognosis
in RCC and the inhibition of mTOR signaling by rapamycin and its analogs shows
promising efficacy against RCC[95-97]. One recent study demonstrated
that activation of mTORC2 up-regulates E-cadherin expression and promotes cell
motility during HIF-2α down-regulation in renal carcinoma cells[98].
High blood
pressure is one of signs and symptoms of diabetic nephropathy, IgA nephropathy
and PKD. We and others recently demonstrated that mechanical forces can induce
mTOR activation[99-102], and the activation of mTOR leads to
podocyte apoptosis[28-36]. Kusma et al[103]
reported that the nephrotoxicity caused by brown spider venom leads to
glomerular foot process effacement and cell detachment via a PLD-dependent
action. This suggests that mTOR is also involved in the repair and recovery of
renal function after acute kidney injury caused by acute toxic factors. The
decrease in phosphatidylcholine and the increase in serum free choline in
chronic hemodialysis patients and ESRD patients could be associated with PLD
action in renal disease progression[104-107]. There are convincing
data that the renin-angiotensin system is a major mediator of renal injury[108-111].
Angiotensin II stimulates PLD activity in the activation of mTOR signaling in
different renal cells and plays a central role in glomerular hemodynamic
adaptation and injury[112-116]. Taken together, the dysregulation of
mTOR signaling is associated with renal disease progression.
mTOR signaling
and therapeutic implications
Given the accumulated knowledge that mTOR signaling promotes cell
proliferation and regulates apoptosis, mTOR has emerged as an attractive
therapeutic target for treatment of different renal diseases, including
diabetic nephropathy, HIVAN, IgA nephropathy, PKD, acute kidney injury, and RCC[29-34].
A number of clinically important drugs appear to be effective because of the
inhibition of mTOR signaling. Meanwhile, some new agents which can inhibit
different components in mTOR signaling are potential therapeutic drugs for
renal diseases (Table 1).
Rapamycin and its analogs: The
inhibition of the mTOR activity by rapamycin can reduce podocyte injury[117],
attenuates unilateral ureteral obstruction-induced renal fibrosis[118]
and slows progression of diabetic nephropathy[82,84], HIVAN[119,120],
IgA nephropathy[121] and PKD[122-128]. Rapamycin also attenuates
both glomerular and tubular lesions in Tg26 mice by induced modulation of miRNA
expression[119] and decreased transcription of HIV genes[120].
The therapeutic benefit of mTOR inhibition in RCC is likely due to inhibition
of cell growth and proliferation[129,130]. Rapamycin (also known as
sirolimus) is an immunosuppressive drug and has helped to identify mTOR
signaling. Due to problems with rapamycin stability, three analogs
[temsirolimus, everolimus and ridaforolimus (also known as deforolimus)] with
superior pharmacokinetic and biological properties have been synthesized and
introduced to clinical trials for treatment of renal diseases and different
cancers (NCT01083368, NCT01174199, NCT01155258, NCT01020305, NCT00512668,
NCT01026623, NCT00887640, NCT01206036, NCT00777959, NCT00110188). Ku0063794, a
small molecule that inhibits both mTORC1 and mTORC2, and MLN0128 (INK128), a
potent mTOR ATP-competitive inhibitor, have also been used in clinical trials
or pre-clinical stage to evaluate the efficacy of renal disease and cancer
treatment[123-130].
Kinase modulators: Multiple kinases are involved in the regulation of mTOR signaling
(Figure 1, blue box). Up- or down-regulation of kinase activity could turn on
or off mTOR signaling in the treatment of renal diseases. For instance,
metformin, a well-known anti-diabetic drug, stimulates AMPK activity and
inhibits mTOR activity[131] that can slow progression of diabetic
nephropathy. By activating AMPK, metformin inhibits mTORC1 resulting in decreased
cell proliferation, which leads to the recent discovery of metformin’s
anti-cancer properties[131,132]. Resveratrol, a phenolic compound
found in plants, can promote transcription factor nuclear factor-erythroid
2-related factor 2 (Nrf2) activation, reduce mTOR pathway signaling through the
activation of AMPK[133], and also shows promise for the treatment of
cancer and type 2 diabetes[134]. Some new resveratrol analogues can
attenuate renal ischemic injury in rats[135]. Many growth factors
are involved in the progression of renal diseases, and growth factor receptors
are receptor tyrosine kinases which are up-stream regulators of mTOR signaling.
Recently, a variety of studies focused on targeting novel receptor tyrosine
kinases in cancer therapy including RCC, and screening the next generation of
tyrosine kinase inhibitors as potential therapeutic drugs[136-138].
Tyrosine kinase inhibitors (tivozanib, dovitinib, regorafenib, cabozantinib,
tivantinib, sunitinib, sorafenib, erlotinib, lapatinib, dasatinib, pazopanib
and vemurafenib) have been introduced to clinical trials (NCT02111889,
NCT01636908, NCT01098500 and NCT02321293).
PLD inhibitors: PLD generates PA which binds to mTOR and activates mTORC1 and mTORC2.
Several PLD inhibitors (NOPT, N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)ethyl]-2-naphthalenecarboxamide,
NBOD,
N-[2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-1-methylethyl]-2-naphthalenecarboxamide,
RBPC, (1R,2R)-N-([S]-1-{4-[5-bromo-2-oxo-2,3-dihydro-1H-benzo(d)imidazol-1-yl]piperidin-1-yl}
propan-2-yl)-2- phenylcyclopropanecarboxamide, FIPI,
N-[2-[4-(2,3-Dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethy]-(5-fluoro-1H-indole-2-carboxamide;
other name: 5-Fluoro-2-Indolyl des-Chlorohalopemide, VU0359595 and VU0364739)
have been characterized during last several years[139-143]. In vitro
experiments, targeting PLD by small molecule inhibitors blocked mTOR signaling
and reduced PKD cell proliferation, and the blocking PLD activity also enhanced
the sensitivity of PKD cells to rapamycin[144]. Using PLD
inhibitors, Mathew et al. recently identify a novel regulatory role for PLD
activity in Malignant Gliomas[142]. It is clear that PLD inhibitors
have a promising potential as therapeutic drugs for renal disease in the
future.
Other inhibitors: High glucose, hemodynamic force and HIV-infection are associated with
angiotensin II-induced podocyte injury[141-143]. The effects of
Angiotensin II are mediated through the angiotensin receptor to stimulate PLD
activity and generate PA which could activate mTOR[109-113,134], and
plays an important role in the pathogenesis of renal injury[108,109].
Angiotensin-converting enzyme inhibitor (ACEI) is a primary drug used for the
treatment of hypertension and congestive heart failure. Several animal models
and clinical trials have clearly demonstrated the effectiveness of ACEI therapy
to improve glomerular/tubulointerstitial damage, reduce proteinuria, and
decrease the progression of chronic kidney disease[145-147]. In rat
PKD model, tolvaptan (a vasopressin V2 receptor antagonist) and rapamycin
caused a similar significant reduction in cyst volume density[148].
Tolvaptan delays the increase in total kidney volume, slows the decline in
renal function, reduces kidney pain, and has been demonstrated in the
pharmacologic, preclinical, and phase II and III clinical trial studies[149].
Somatostatin analogues (octreotide, lanreotide, pasireotide) and others are
also used therapeutically by alteration of receptor binding, kinase activity
and mTOR signaling[125,128].
Conclusions and
prospective
The progression of renal disease is very complex and is regulated by a
complex signaling network in different renal cells. The mTOR lies at the center
of this signaling network and regulates many fundamental cell processes in
glomerulus and tubule, including renal cell growth, proliferation, autophagy,
and apoptosis. The mTOR signaling network responds to extracellular signaling
such as hormones, growth factors, glucose, hemodynamic, immune factors, toxins,
cancer causing agents and alteration of energy and nutrient, and leads to
regulation of downstream metabolic pathways. In many renal diseases, the
current data support the concept that alteration of mTOR activity could turn
renal cells from physiological functions into disease-driving progression. This
provides an important theoretical basis for mTOR as a therapeutic target for
treatment of renal diseases. Given the complex of mTOR signaling network, we
need further insight into the regulation of mTOR signaling, identify the key
modulators in different renal cells as novel target(s) for pharmacologic
consideration, develop precise, specific and effective drugs for renal
diseases, and search new therapeutic strategies for patients with renal disease.
CONFLICT OF INTERESTS
The authors declare no conflict
of interest.
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Peer
reviewer: James Stockand, PhD, Department of
Physiology, University of Texas Health Science Center, 7703 Floyd Curl Drive,
San Antonio, TX, the United States.
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