diabetes and inflammasomes in the bladder - surgery.duke.edu · retinopathy, nephropathy. dbd not...
TRANSCRIPT
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Diabetes and Inflammasomes in the Bladder
J Todd Purves MD, PhD Duke University Medical Center
Division of Urology
Disclosures: None
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Introduction
• Diabetic Bladder Dysfunction (DBD) is the most common complication seen in diabetic patients.
• DBD is a progressive complication
– Early DBD = irritative voiding symptoms (diminished sensation, frequency, urge incontinence)
– Chronic DBD = decompensated bladder (insensate bladder, poor compliance, overflow incontinence)
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Endocrine referral-DONE!!(?) • Normalize blood sugars; stop diuresis • 58% of patients achieve ADA goals1
• DCCT found strict glycemic control decreased retinopathy, nephropathy. DBD not so much! 2,3,4
• What else can we do?
1 Selvin E et al. Ann Intern Med 2014; 160(8): 517-25 2 Genuth S Endocr Pract 2006; 12 Suppl 1:34-41 3 Sarma AV et al. Urology 2009; 73(6): 1203-9 4 Van den Eden SK et al Diabetes Care 2009; 32(4): 664-70
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Bladder Damage from Diabetes
• Neuropathy • Smooth muscle dysfunction • Urothelial (barrier) dysfunction
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DBD as manifestation of Peripheral Neuropathy
• PN correlates with OAB in diabetic women Variable OAB syndrome Without OAB syndrome P-value
No. of patients 26 (32.5) 54 (67.5) Polyneuropathy 0.003* With 22 (27.5) 27 (33.8) Without 4 (5.0) 27 (33.8) Retinopathy 0.763 With 5 (6.3) 9 (11.3) Without 21 (26.3) 45 (56.3) Nephropathy 0.572 With 7 (8.8) 11 (13.8) Without 19 (23.8) 43 (53.8)
Tanik, et al. Int Neurourol J 2016 Sep; 20(3):232-9
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DBD as manifestation of Peripheral Neuropathy
• PN correlates with OAB in diabetic men
Tanik, et al. Int Neurourol J 2016 Sep; 20(3):232-9
Variable OAB syndrome Without OAB syndrome P-value
No. of patients 14 (35.0) 26 (65.0) Polyneuropathy 0.022* With 11 (27.5) 10 (25.0) Without 3 (7.5) 16 (40.0) Retinopathy 0.115 With 3 (7.5) 1 (2.5) Without 11 (27.5) 25 (62.5) Nephropathy 0.089 With 8 (20.0) 7 (17.5) Without 6 (15.0) 19 (47.5)
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Rodent Studies • Decrease in myelinated nerve density
Time point Group Muscle NF200-IR area, mm2
Muscle NF200-IR/muscle area
1 week Control 0.110 ± 0.013 0.017 ± 0.001 Diabetic 0.112 ± 0.005 0.013 ± 0.001 Diuretic 0.114 ± 0.023 0.011 ± 0.002
9 week Control 0.129 ± 0.007 0.019 ± 0.001
Diabetic 0.112 ± 0.013 0.012 ± 0.001*
Diuretic 0.128 ± 0.013 0.012 ± 0.001*
20 week Control 0.128 ± 0.001 0.021 ± 0.001
Diabetic 0.108 ± 0.008 0.010 ± 0.001*
Diuretic 0.129 ± 0.004 0.011 ± 0.001*
Liu, et al. BJUI 2011Jun 113(4):1988-93.
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Rodent Studies • Afferent nerve conduction velocity is decreased
Aizawa, N et al. J Urol 2013 Apr 189(4): 1580-1587
Velo
city
(m/s
ec)
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DM and Smooth Muscle Dysfunction • Smooth muscle contractility changes according
to compensated versus de-compensated state
Daneshgari, et al. J Urol Jul 176(1): 380-6
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DM effects on urothelial barrier
Hanna-Mitchell et al. Am J Physiol Integr Comp Physiol 2013 Jan 304(2): R84-93
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Etiology of Diabetic Bladder Dysfunction
• Osmotic diuresis (polyuria)
• Hyperglycemia
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Polyuria and hyperglycemia • Diuresis causes bladder hypertrophy
Xiao N, et al. J Urol 2013 Mar 189(3): 1130-6
Diabetes +
Diversion
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Polyuria and hyperglycemia • Diabetes/hyperglycemia, but not diuresis alone,
leads to oxidative stress
Xiao N, et al. J Urol 2013 Mar 189(3): 1130-6
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What is the molecular mechanism?
• Brownlee’s Unified Theory
• Inflammation
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Brownlee’s Unified Theory of Diabetic Complications
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Inflammation
Diabetic metabolites uric acid lipids
ROS mitochondrial dysfunction
K+ cellular efflux
NLRP3 Activation INFLAMMATION
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Canonical Pathway -Activation The NLRP3 Inflammasome
Activating DAMPs and PAMPS
ROS
Pyroptosis
IL-1β
IL-18
Gasdermin D pore K+ efflux
K+
Active Caspase-1
NLRP3 Inflammasome
Pro-IL-1β Pro-IL-18
Gasdermin D
NEK7 NEK7
Ca2+
IP3
ER
Ca2+
Inouye et al. Curr Urol (2017) in press
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NLRP3 mediates DM complications
• Retinopathy • Nephropathy • Cardiomyopathy • Neuropathy • Endothelial dysfunction
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Inflammasomes in the bladder? • NLRP3 found in human bladder (Tschopp 2007) • Rat urothelium (Hughes 2014)
This image cannot currently be displayed.
And in the mouse!!
NLRP3
Wild Type
This image cannot currently be displayed. This image cannot currently be displayed.
Diabetic
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NLRP3 in urothelium
Hyperglycemia
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Inflammasomes and sterile cystitis
• NLRP3 mediates inflammation in cyclophosphamide induced cystitis and BOO
• NLRP3 inhibitor (glyburide) prevents inflammationpreserves tissue and function
Hughes et al. Am J Physiol-Renal (2017) 313:F603-F610 Lutolf et al. Neurourol Urodyn (2017) in press Hughes et al. J. Urol (2016) 195:1598-1605 Hughes et al. Am J Physiol-renal (2014) 306:F299-308
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Does NLRP3-induced inflammation lead to DBD?
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Diabetic metabolites activate NLRP3
6
10
12
14
16
Glucose
0 3 6 9 12
Glucose (mM added)
8
**
** **
** **
Cas
p-1
Act.
(R
FUs
x 10
00)
0
15
MSU
0 0.3 0.6 0.9 1.2
MSU (µg/ml)
10
Cas
p-1
Act.
(%
max
ATP
res
pons
e)
5
** ** ** *
0
15
HMGB1
0 1 2 3 4
HMGB1 (µg/ml)
10
Cas
p-1
Act.
(%
max
ATP
res
pons
e)
5
** ** **
0
15
AGE
0 50 100 150 250
AGE (gly-BSA; µg/ml)
10
Cas
p-1
Act.
(%
max
ATP
res
pons
e)
5
** **
***
200
***
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Akita Mouse Model
• Type 1 DM mouse • Heterozygous Ins2 mutation
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Materials and Methods • Female Ins2 (Akita) mice were compared to age-matched controls for
the following end-points:
• Voiding Dysfunction: Cystometry • Active Caspase-1 Activity: FAM-FLICA assay
o Surrogate for activated NLRP3 inflammasome
• Inflammation: Evans Blue extravasation assay
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DBD Occurs by Week 15 in Akita Mice
5
15
25
35
45
55
Bla
dder
Pre
ssur
e (c
m H
2O)
Wildtype Mouse Bladder Pressure Tracing
5
15
25
35
45
55
0 300 600 900 1200 1500
Bla
dder
Pre
ssur
e (c
m H
2O)
Time (s)
Diabetic Mouse Bladder Pressure Tracing
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DBD Occurs by Week 15 in Akita Mice
0 20 40 60 80
100 120 140 160 180 200
Wildtype Diabetic
Volu
me
(ul)
Void Volume
0
2
4
6
8
10
12
Wildtype Diabetic
Freq
uenc
y (v
oids
/hr)
Frequency
*
**
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Increased Caspase-1 Activity at 15 Weeks
14
16
18
20
22
Wildtype Diabetic
Mea
n Fl
uore
scen
ce In
tens
ity
(RFU
s)
Active Caspase-1 *
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Increased Bladder Inflammation at Week 15
*
0
500
1000
1500
2000
2500
Wildtype Diabetic
Conc
entr
atio
n in
Bla
dder
(n
g/m
g)
Evans Blue Extravasation
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DBD in Akita Mice
• Early DBD appears at 15 weeks in Akita mice • Early DBD associated with
– Inflammation – Activation of Caspase-1
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So what happens without NLRP3?
Akita diabetic mouse with NLRP3 knocked out
Akita/NLRP3 KO
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Blo
od g
lc (
mg/
dL)
wt KO wt KO
0 50
200
300 350
150
250
100
NLRP3:
Diabetic wild type
*** ***
Akita/NLRP3 KO - No change in hyperglycemia
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Void Volume
µl
***
0
50
100
150
200 ###
### ###
Frequency
Mic
turit
ions
/hr ***
0
2.5
5
7.5
10 ***
* ### ###
###
µL
0
50
100
150
200
**
# ##
##
PVR
wt KO wt KO NLRP3:
Diabetic wild type wt KO wt KO NLRP3:
Diabetic wild type
wt KO wt KO NLRP3:
Diabetic wild type
Akita/NLRP3 KO - DBD is attenuated
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# ne
rves
/µm
2 (x1
06)
wt KO wt KO 0
10
40
50
30
20
NLRP3:
Diabetic wild type
Akita/NLRP3 KO - Nerve density is preserved
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NRP3 inflammation and DBD
High Glucose
DBD
IL-1β
DAMPs
NLRP3
Neuropathy Smooth muscle hypertrophy
Urothelia dysfunction
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NLRP3 and Neuropathy
• Rat BOO model • BOO (pressure, stretch, hypoxia) activates NLRP3 • Decrease in bladder nerve density • IL1β causes neuronal apoptosis
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Gly Ana
Nerve Density
Control Sham Veh 0
10
20
30
40
BOO
* * *
*
Ner
ve D
ensi
ty
(# n
erve
s x
10-6
)/µm
2 )
Gly Ana
Gly Ana
*
Control Sham Veh 0
50
100
150
200
BOO
Tot
al n
umbe
r of N
erve
s
# Nerves
*
Control Sham Veh 0
4
8
12
16
Bla
dder
Are
a (x
106 µ
m2 )
BOO
Bladder Area
IL-1𝑏𝑏 Apoptosis **
*
Apo
ptot
ic/T
otal
cel
ls (%
)
0 100 250 500 0
10
20
30
40
50
IL-1β (ng/ml)
Pelvic Ganglion Nerves
Apoptosis
Conclusion The NLRP3/IL-1β pathway mediates denervation during BOO
IL-1β
DAMPs (ATP)
NLR
Inflammasome
Casp-1
Adaptor
IL-1β
Pro-IL-1β
Pyroptosis
High pressure
Stretch Hypoxia/reperfusion
NLRP3 Mediates Denervation during BOO IL-1β Induces Apoptosis in Pelvic Neurons in vitro
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Future Work • NLRP3 impact on:
– Neuropathy – Smooth muscle dysfunction – Urothelium/barrier function
• Natural course: DM vs. DM/NLRP3-/-
• NLRP3 inhibition as adjunct to Glycemic control
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Acknowledgements