Donald Seldin Lecture

Role of Bile AcidRegulated Nuclear Receptor

FXR and G ProteinCoupled Receptor TGR5 in Regulation
of Cardiorenal Syndrome (Cardiovascular Disease
and Chronic Kidney Disease)
Moshe Levi

t is well known that chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease. In fact,
studies have shown that cardiovascular event rates and allcause mortality increase as a function of CKD as determined
by decrease in estimated glomerular filtration rate and presence
of microalbuminuria.1,2
In recent years, the term cardiorenal syndrome (CRS) has
been proposed to define the relationship between cardiac disease and renal disease. Ronco et al has defined CRS as a pathophysiologic disorder of the heart and kidneys whereby acute or
chronic dysfunction in one organ may induce acute or chronic
dysfunction in the other.36 CRS Type 1: acute CRS is defined
as sudden worsening of cardiac function (acute cardiogenic
shock or acutely decompensated heart failure), leading to acute
kidney injury. CRS Type 2: chronic CRS is defined as chronic
abnormalities in cardiac function (chronic congestive heart
failure) causing progressive and potentially permanent CKD.
CRS Type 3: acute renocardiac syndrome is defined as sudden
worsening of kidney function (acute kidney injury or acute glomerulonephritis) causing acute cardiac disorder (heart failure,
arrhythmia, or ischemia). CRS Type 4: chronic renocardiac
syndrome is defined as CKD contributing to decreased cardiac
function, cardiac hypertrophy, and increased risk of adverse
cardiovascular events. CRS Type 5: secondary CRS is defined
as systemic condition (obesity, diabetes mellitus, sepsis) causing simultaneous cardiac and renal dysfunction.
In this review, I will be discussing mainly the type 5 CRS
associated with obesity and diabetes mellitus and models of
atherosclerosis and vascular calcification. In addition to discussing renal disease, I will also be discussing vascular disease because vascular dysfunction is a well-characterized
complication of renal disease, and vascular dysfunction is also
a leading cause of cardiac disease.

Role for Altered Renal Lipid Metabolism

in the Pathogenesis of Kidney Disease
in Obesity and Diabetes Mellitus
Our work early on determined an important role for altered
renal lipid metabolism in the pathogenesis of kidney disease
in obesity and diabetes mellitus. In a series of studies using

rodent models of type I diabetes mellitus,79 high-fat diet

induced obesity and insulin resistance,10,11 type 2 diabetes
mellitus,12,13 and aging,14,15 we determined that abnormal lipid
metabolism mediated by increased expression and activity of
the sterol regulatory elementbinding proteins (SREBPs) and
carbohydrate regulatory elementbinding protein (ChREBP)
and decreased activity of the peroxisome proliferatoractivated receptor alpha (PPAR) and liver X receptor (LXR)
played an important role in kidney disease (Figures1 and 2).
In streptozotocin-induced diabetes mellitus in the rat,
we found marked increases in SREBP-1 and fatty acid synthase expression, resulting in increased triglyceride accumulation. Treatment of diabetic rats with insulin prevented the
increased renal expression of SREBP-1 and the accumulation
of triglyceride. The role of hyperglycemia in the upregulation
of SREBP-1 was confirmed in renal cells cultured in a high
glucose media. High glucose induced increased expression
of SREBP-1a and -1c mRNA, SREBP-1 protein, and fatty
acid synthase, resulting in increased triglyceride content. To
determine a direct role for SREBP in mediating the increase
in renal lipids and glomerulosclerosis, we studied SREBP-1a
transgenic mice with increased renal expression of SREBP1. The increase in SREBP-1 was associated with increased
expression of fatty acid synthase and acetyl CoA carboxylase,
resulting in increased triglyceride content, increased expression of transforming growth factor-1 and vascular endothelial
growth factor, mesangial expansion, glomerulosclerosis, and
proteinuria. Our study therefore indicated that renal SREBP-1
expression is increased in diabetes mellitus and that SREBP-1
plays an important role in the increased lipid synthesis, triglyceride accumulation, mesangial expansion, glomerulosclerosis,
and proteinuria by increasing the expression of transforming
growth factor- and vascular endothelial growth factor.7
Additional studies were performed in Akita and OVE26
mice, which are 2 genetic models of type 1 diabetes mellitus.
Diabetic nephropathy was characterized by mesangial expansion and loss of podocytes, resulting in glomerulosclerosis
and proteinuria, and is associated with increased expression
of profibrotic growth factors, proinflammatory cytokines, and
increased oxidative stress. We have also found significant

From the Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado AMC, Aurora.
Correspondence to Moshe Levi, Division of Renal Diseases and Hypertension, University of Colorado AMC, 12700 E 19th Ave, Aurora, CO 80045.
E-mail Moshe.Levi@ucdenver.edu
(Hypertension. 2016;67:1080-1084. DOI: 10.1161/HYPERTENSIONAHA.115.06417.)
2016 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org

DOI: 10.1161/HYPERTENSIONAHA.115.06417

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by guest on June 1, 2016
1080

Levi FXR and TGR5 in Cardiorenal Syndrome 1081

Figure 1. Regulation of triglyceride metabolism in

the kidney.

increases in renal triglyceride and cholesterol content. The

increase in renal triglyceride content was associated with
(1) increased expression of SREBP-1c and ChREBP, which
collectively results in increased fatty acid synthesis, (2)
decreased expression of peroxisome proliferatoractivated
receptor PPAR and PPAR, which results in decreased fatty
acid oxidation, and (3) decreased expression of farnesoid X
receptor (FXR) and small heterodimer partner. The increase in
cholesterol content was associated with (1) increased expression of SREBP-2 and 3-hydroxy-3-methylglutaryl-CoA
reductase, which results in increased cholesterol synthesis and
(2) decreased expression of LXR-, LXR-, and ATP-binding
cassette transporter-1, which results in decreased cholesterol
efflux. Our results had further indicated that in type 1 diabetes mellitus, there is altered renal lipid metabolism favoring
net accumulation of triglycerides and cholesterol, which are
driven by increases in SREBP-1, ChREBP, and SREBP-2 and
decreases in FXR, LXR-, and LXR-, which may also play
a role in the increased expression of profibrotic growth hormones, proinflammatory cytokines, and oxidative stress.9
In addition to diabetes mellitus, obesity and metabolic
syndrome are associated with glomerulosclerosis and proteinuria. Using a model of diet-induced obesity and insulin
resistance, C57BL/6J mice that were fed a high-fat, 60 kcal
% saturated (lard) fat diet developed obesity, hyperglycemia,
and hyperinsulinemia compared with those that were fed a
low-fat, 10 kcal % fat diet. In contrast, A/J mice were resistant when fed the same diet. C57BL/6J mice with high-fat
diet exhibited significantly higher levels of renal SREBP-1

and SREBP-2 expression than those mice with low-fat diet,

whereas in A/J mice, there were no changes with the same
treatment. The increases in SREBP-1 and SREBP-2 expression in C57BL/6J mice resulted in renal accumulation of
triglyceride and cholesterol. There were also significant
increases in the renal expression of plasminogen activator
inhibitor-1, vascular endothelial growth factor, type IV collagen, and fibronectin, resulting in glomerulosclerosis and proteinuria. To determine a role for SREBPs per se in modulating
renal lipid metabolism and glomerulosclerosis, we performed
studies in SREBP-1c (/) mice. In contrast to control mice, in
the SREBP-1c (/) mice with high-fat diet, the accumulation
of triglyceride was prevented, as well as the increases in plasminogen activator inhibitor-1, vascular endothelial growth
factor, type IV collagen, and fibronectin expression. Our
results therefore indicated that diet-induced obesity causes
increased renal lipid accumulation and glomerulosclerosis in
C57BL/6J mice via an SREBP-1c-dependent pathway.10
db/db mice on the friend virus B (FVB) genetic background with loss-of-function mutation of the leptin receptor
(FVB-Lepr(db) mice or FVB db/db) develop severe diabetic
nephropathy, including glomerulosclerosis, tubulointerstitial
fibrosis, increased expression of type IV collagen and fibronectin, and proteinuria, which is associated with increased
renal mRNA abundance of transforming growth factor-,
plasminogen activator inhibitor-1, and vascular endothelial
growth factor. Electron microscopy demonstrated increases
in glomerular basement membrane thickness and foot process (podocyte) length. We found that there is a marked

Figure 2. Regulation of cholesterol metabolism in

the kidney.

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1082HypertensionJune 2016
increase in neutral lipid deposits in glomeruli and tubules by
oil red O staining and biochemical analysis for cholesterol
and triglycerides. We also detected a significant increase in
the renal expression of adipocyte differentiationrelated protein (adipophilin), a marker of cytoplasmic lipid droplets. We
examined the expression of SREBP-1 and -2, transcriptional
factors that play an important role in the regulation of fatty
acid, triglyceride, and cholesterol synthesis. We found significant increases in SREBP-1 and -2 protein levels in nuclear
extracts from the kidneys of FVB db/db mice, with increases
in the mRNA abundance of acetyl-CoA carboxylase, fatty
acid synthase, and 3-hydroxy-3-methylglutaryl-CoA reductase, which mediates the increase in renal triglyceride and
cholesterol content. Our results indicate that in FVB db/
db mice, renal triglyceride and cholesterol accumulation is
mediated by increased activity of SREBP-1 and -2.12 Of note,
when the above mice originally generated in Dr Streamson
Chus laboratory at Columbia University were rederived at
Jackson Laboratories, the resulting phenotype was different.16
This may have been because of different FVB strains, diets,
and barrier (pathogen-free conditions, ie, microbiome). We
therefore also performed studies with db/db mice obtained
from Jackson Laboratories in the BKS genetic background.
Our results essentially confirmed our findings with the FVB
db/db mice.13
Parallel studies in aging mice14,15 also indicated a significant role for altered lipid metabolism in modulating renal
disease.

Role for Bile AcidActivated Receptors

in the Pathogenesis of Kidney Disease
in Obesity and Diabetes Mellitus
The above findings of increased SREBP and ChREBP activity
and decreased PPAR activity in obesity and diabetes mellitus
led to the investigation of the role of the bile acidactivated
nuclear hormone receptor FXR in modulation of lipid metabolism and renal disease. There was indeed emerging evidence
in the liver that FXR is an important negative regulator of
SREBP-1 and ChREBP and a positive regulator of PPAR
activity.1719
In diabetic humans, there is decreased FXR expression
in the kidney. In support for FXR playing an important role
in diabetic kidney disease, we found that there is accelerated renal injury in diabetic FXR knockout (KO) mice.8 In
contrast, treatment of the STZ diabetic mice,8 diet-induced
obesity mice,11 or db-db mice13 with the FXR agonist INT747 (6-ethyl-3,7-dihydroxy-5-cholan-24-oic acid)
improved renal injury by decreasing proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis and modulating renal

lipid metabolism, macrophage infiltration, and renal expression of SREBPs, profibrotic growth factors, and oxidative
stress enzymes.
Additional work from other laboratories has also confirmed our results. Administration of chenodeoxycholic acid,
an FXR agonist, prevents kidney fibrosis, inflammation, and
oxidative stress in high fructosefed rats.20 FXR activation
also prevents cisplatin-induced kidney injury through its antifibrotic, anti-inflammatory, and antiapoptotic effects.21In addition, FXR agonist protects against kidney disease induced by
high fat feeding in uninephrectomized mice.22,23
In addition to FXR, a bile acidactivated G proteincoupled receptor TGR5 has also been identified.2426 We found that
treatment of diabetic db/db mice with the selective TGR5 agonist INT-777 (6-ethyl-23(S)-methyl-3,7,12-trihydroxy5-cholan-24-oic acid) decreased proteinuria, podocyte
injury, mesangial expansion, fibrosis, and CD68 macrophage
infiltration in the kidney. INT-777 also induced renal expression of master regulators of mitochondrial biogenesis, inhibitors of oxidative stress, and inducers of fatty acid -oxidation,
including sirtuin 1, sirtuin 3, and Nrf-1. Increased activity of
sirtuin 3 was evidenced by normalization of the increased
acetylation of mitochondrial superoxide dismutase 2 and isocitrate dehydrogenase 2 observed in untreated db/db mice.
Accordingly, INT-777 decreased mitochondrial H2O2 generation and increased the activity of superoxide dismutase 2,
which associated with decreased urinary levels of H2O2 and
thiobarbituric acid reactive substances. Furthermore, INT-777
decreased renal lipid accumulation. INT-777 also prevented
kidney disease in mice with diet-induced obesity. In human
podocytes cultured with high glucose, INT-777 induced mitochondrial biogenesis, decreased oxidative stress, and increased
fatty acid -oxidation. Compared with normal kidney biopsy
specimens, kidney specimens from patients with established
ORG or DN expressed significantly less TGR5 mRNA, and
the levels correlated with disease progression. Our results
indicate that TGR5 activation induces mitochondrial biogenesis and prevents renal oxidative stress and lipid accumulation,
establishing a role for TGR5 in inhibiting kidney disease in
obesity and diabetes mellitus27 (Figures3 and 4).
In view of important roles for FXR and TGR5 in modulating kidney disease in obesity and in diabetes mellitus
in collaboration with the Intercept scientists, we have also
characterized a dual FXR-TGR5 agonist INT-767 (6-ethyl3,7,23-trihydroxy-24-nor-5-cholan-23-sulfate sodium
salt).28 We found that INT-767 is a potent agonist for
both FXR (mean EC(50), 30 nmol/L by PerkinElmer
AlphaScreen assay) and TGR5 (mean EC(50), 630 nmol/L
by time resolved-fluorescence resonance energy transfer),

Figure 3. Role of farnesoid X receptor (FXR) and

TGR5 in regulation of triglyceride metabolism in
the kidney.

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Levi FXR and TGR5 in Cardiorenal Syndrome 1083

with INT-767 had significantly lower levels of active nuclear
factor kappa-B, resulting in cytokine production in response
to LPS through a PKA-dependent mechanism. This study
demonstrates that concurrent activation of FXR and TGR5
attenuates atherosclerosis by reducing both circulating lipids
and inflammation.

Summary

Figure 4. Role of TGR5 in regulating mitochondrial biogenesis

and activity, fatty acid beta-oxidation, and oxidative stress in the
kidney.

the first compound described to date to potently and selectively activate both BA receptors.
In preliminary studies in streptozotocin diabetic mice and
db-db mice, we have found that treatment of mice INT-767
has significant effects to prevent development of albuminuria
and glomerular disease.

Role for Bile AcidActivated Receptors in the

Pathogenesis of Atherosclerosis and Vascular
Calcification in Apolipoprotein E KO and
Low-Density Lipoprotein Receptor KO
Mice With CKD
We found that FXR also play an important role on vascular calcification on apolipoprotein E (ApoE) knockout mice
(KO) with 5/6 nephrectomy-induced CKD.29 We found that
FXR was highly induced during osteogenic differentiation of
bovine calcifying vascular cells (CVCs) and in the aorta of
ApoE KO mice with CKD, which are common tissue culture
and mouse model, respectively, for aortic calcification. FXR
activation by a synthetic FXR agonist, 6alpha-ethyl chenodeoxycholic acid (INT-747), inhibited phosphate-induced
mineralization and triglyceride accumulation in CVCs. FXRdominant negative expression augmented mineralization of
CVCs and blocked the anticalcific effect of INT-747, whereas
VP16FXR that is a constitutively active form reduced mineralization of CVCs. INT-747 treatment also increased phosphorylated c-Jun N-terminal kinase. SP600125 (specific c-Jun
N-terminal kinase inhibitor) significantly induced mineralization of CVCs and alkaline phosphatase expression, suggesting
that the anticalcific effect of INT-747 is attributable to c-Jun
N-terminal kinase activation. We also found that INT-747
ameliorates CKD-induced vascular calcification in ApoE KO
mice with 5/6 nephrectomy, without affecting the development of atherosclerosis.29
In additional studies, we have treated ApoE KO mice and
low-density lipoprotein receptor KO mice with the FXRTGR5 dual agonist INT-767. INT-767 treatment drastically
reduced serum cholesterol levels and significantly reduced
atherosclerotic plaque formation in both ApoE KO and lowdensity lipoprotein receptor KO mice.30 INT-767 decreased
the expression of proinflammatory cytokines and chemokines
in the aortas of ApoE KO mice through the inactivation of
nuclear factor kappa-B. In addition, J774 macrophages treated

In summary, our studies indicate an important role for altered

lipid metabolism mediated by significant alterations in nuclear
hormone receptors, transcription factors, and G protein
coupled receptors in modulating kidney disease in diabetes
mellitus, obesity and aging, and atherosclerosis and vascular
calcification in low-density lipoprotein receptor KO and ApoE
KO mice with 5/6 nephrectomy-induced CKD. Studies discussed in this review indicate that in these conditions, FXR
and TGR5 agonists play an important role in preventing progression of kidney disease, atherosclerosis, and vascular calcification. Future studies will also need to determine whether
FXR and TGR5 agonists have similar beneficial effects in preventing cardiac dysfunction in CKD.

Acknowledgments
It is a great honor for me to have been selected for the KCVD Donald
Seldin Lecturer Award by the Council for Kidney in Cardiovascular
Disease of the American Heart Association. From the time I joined
the faculty at the University of Texas Southwestern Medical Center
in 1983 and until I moved to the University of Colorado in 2002, Dr
Seldin was my Chair of Medicine and then my mentor, colleague,
and friend. He was an exemplary leader who has encouraged vertical
and creative thinking. His influence and friendship continued even
after my move to the University of Colorado where I continued to
see him and seek his advice on a regular basis. I thank Dr Tao Jiang
for overseeing the studies with SREBPs, Dr Xiaoxin Wang for overseeing the studies with FXR and TGR5, and Dr Makoto Miyazaki
for overseeing the studies with atherosclerosis and vascular calcification. Our progress in this area would not have been possible
without their dedicated and excellent work. The studies have been
supported by grants from the National Institutes of Health, Veterans
Administration, American Heart Association, Juvenile Diabetes
Research Foundation, and Intercept Pharmaceuticals. Special thanks
to Dr Mark Pruzanski and Dr Luciano Adorini who continue to collaborate with us with the FXR- and TGR5-related projects.

Sources of Funding
The studies discussed here were supported by grant support from the
National Institutes of Health, Veterans Administration, and Intercept
to M. Levi.

Disclosures
M. Levi has received a medical schooladministered research grant
from Intercept.

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Role of Bile AcidRegulated Nuclear Receptor FXR and G ProteinCoupled Receptor

TGR5 in Regulation of Cardiorenal Syndrome (Cardiovascular Disease and Chronic
Kidney Disease)
Moshe Levi
Hypertension. 2016;67:1080-1084; originally published online April 4, 2016;
doi: 10.1161/HYPERTENSIONAHA.115.06417
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2016 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563

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