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Comparative Study
, 125 (11), 1402-13

Renal Sympathetic Denervation Suppresses De Novo Podocyte Injury and Albuminuria in Rats With Aortic Regurgitation

Affiliations
Comparative Study

Renal Sympathetic Denervation Suppresses De Novo Podocyte Injury and Albuminuria in Rats With Aortic Regurgitation

Kazi Rafiq et al. Circulation.

Abstract

Background: The presence of chronic kidney disease is a significant independent risk factor for poor prognosis in patients with chronic heart failure. However, the mechanisms and mediators underlying this interaction are poorly understood. In this study, we tested our hypothesis that chronic cardiac volume overload leads to de novo renal dysfunction by coactivating the sympathetic nervous system and renin-angiotensin system in the kidney. We also examined the therapeutic potential of renal denervation and renin-angiotensin system inhibition to suppress renal injury in chronic heart failure.

Methods and results: Sprague-Dawley rats underwent aortic regurgitation and were treated for 6 months with vehicle, olmesartan (an angiotensin II receptor blocker), or hydralazine. At 6 months, albuminuria and glomerular podocyte injury were significantly increased in aortic regurgitation rats. These changes were associated with increased urinary angiotensinogen excretion, kidney angiotensin II and norepinephrine (NE) levels, and enhanced angiotensinogen and angiotensin type 1a receptor gene expression and oxidative stress in renal cortical tissues. Aortic regurgitation rats with renal denervation had decreased albuminuria and glomerular podocyte injury, which were associated with reduced kidney NE, angiotensinogen, angiotensin II, and oxidative stress. Renal denervation combined with olmesartan prevented podocyte injury and albuminuria induced by aortic regurgitation.

Conclusions: In this chronic cardiac volume-overload animal model, activation of the sympathetic nervous system augments kidney renin-angiotensin system and oxidative stress, which act as crucial cardiorenal mediators. Renal denervation and olmesartan prevent the onset and progression of renal injury, providing new insight into the treatment of cardiorenal syndrome.

Conflict of interest statement

Conflict of Interest Disclosures: None

Figures

Figure 1
Figure 1
Systolic blood pressure (SBP), diastolic blood pressure (DBP) and urinary albumin to creatinine ratio (UACR) profiles in protocol 1. (A) SBP (B) DBP. AR- and sham-operated rats have similar SBP, and treatment with olmesartan or hydralazine lowered SBP to equivalent levels. DBP is lower in AR rats than in sham rats. By contrast, DBP is not significantly affected by olmesartan or hydralazine. (C) UACR in protocol 1. AR rats develop marked albuminuria, which is prevented by olmesartan. *P<0.05, **P<0.01, ****P<0.001 vs. sham; ##P<0.01, ####P<0.001 vs. AR.
Figure 2
Figure 2
Plasma and kidney norepinephrine (NE) levels, kidney angiotensin II (AngII) content, mRNA levels of angiotensinogen (AGT) and angiotensin type 1a (AT1a) receptor in renal cortical tissues, and urinary angiotensinogen excretion rate (UAGTV) in protocol 1. (A) Plasma NE levels and (B) kidney tissue NE content at 6 months after the sham or AR operation. AR rats have increased plasma and kidney NE levels. Treatment with olmesartan suppresses the increases in plasma and kidney NE levels in AR rats. (C) Kidney AngII content, (D) AT1a receptor mRNA levels and (E) AGT mRNA levels in renal cortical tissues. AR rats have increased kidney AngII content and mRNA levels of AT1a receptor and AGT. Olmesartan suppresses the increases in AngII levels and the upregulation of AT1a receptor and AGT mRNA levels in AR rats. RT-PCR data are expressed as fold-changes compared with the sham group after normalization for the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). (F) UAGTV is augmented in AR rats, as compared with sham rats. The increase in UAGTV is suppressed by olmesartan in AR rats. *P<0.05, **P<0.01, ***P<0.005, ****P<0.001 vs. sham; #P<0.05, ##P<0.01, ###P<0.005, ####P<0.001 vs. AR.
Figure 3
Figure 3
Podocyte injury, and reactive oxygen species and NADPH oxidase levels in the kidney in protocol 1. (A) Representative immunohistochemical images with staining for desmin, a marker of podocyte injury (original magnification, ×200), and the relative desmin-stained area in glomeruli as a percentage of total glomerular area. (B) Nephrin and (C) podocin mRNA levels in glomeruli. AR rats have a greater desmin-positive area (brown) in the glomeruli, with decreases in glomerular nephrin and podocin mRNA levels. Treatment with olmesartan suppresses the AR-induced increases in the desmin-positive area, and prevents the decreases in glomerular nephrin and podocin mRNA levels. (D) Representative images of dihydroethidium (DHE) staining (original magnification, ×100). (E) Renal cortical tissue thiobarbituric acid reactive substances (TBARS). (F) p22phox and (G) gp91phox mRNA levels in renal cortical tissue. All of these parameters are increased in AR rats compared with sham rats. The increases in renal cortical TBARS, DHE staining, and p22phox and gp91phox mRNA levels in AR rats are attenuated by olmesartan. *P<0.05, **P<0.01, ***P<0.005, ****P<0.001 vs. sham. #P<0.05, ##P<0.01, ###P<0.005 vs. AR.
Figure 4
Figure 4
Systolic blood pressure (SBP), diastolic blood pressure (DBP) and urinary albumin to creatinine ratio (UACR) profiles in protocol 2. (A) UNX and UNX-AR rats have similar SBP. In UNX-AR rats, RDX does not significantly lower SBP. On the other hand, both olmesartan and hydralazine decrease SBP in UNX-RDX-AR rats to equivalent levels. (B) DBP is lower in UNX-AR rats than in UNX rats. RDX alone does not affect DBP in UNX-AR rats, but RDX in combination with olmesartan or hydralazine decreases DBP to equivalent levels in UNX-RDX-AR rats. (C) UNX-AR rats develop marked albuminuria, which is attenuated by RDX. Furthermore, RDX in combination with olmesartan blocks the onset and progression of albuminuria. P< 0.05, ††P< 0.01, †††P< 0.005 vs. UNX; ‡‡P<0.01, ‡‡‡P<0.005, ‡‡‡‡P<0.001 vs. UNX-AR; §§P<0.01 vs. UNX-RDX-AR. UNX: uninephrectomy; RDX: left-side renal denervation.
Figure 5
Figure 5
Plasma and kidney norepinephrine (NE) levels, Kidney angiotensin II (AngII) content and mRNA levels of angiotensinogen (AGT) and AT1a receptor in renal cortical tissues, Urinary angiotensinogen excretion rate (UAGTV) in protocol 2. (A) UNX-AR rats show increased plasma NE levels, which are tends to be decrease by RDX. However, RDX plus olmesartan suppresses the increases in plasma NE levels. (B) UNX-AR rats show markedly increased kidney NE content. By contrast, the kidney NE content in all renal denervated rats is at or below the undetectable range (below 3 ng/g tissue). (C) Kidney AngII content, (D) AT1a receptor mRNA levels and (E) AGT mRNA levels in renal cortical tissues. UNX-AR rats show increased kidney AngII content and AT1a receptor and AGT mRNA levels, which are suppressed by RDX. RDX plus Olmesartan further decreases these renal RAS components. RT-PCR data are expressed as fold-changes compared with UNX after normalization for the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). (F) UAGTV is markedly increased in UNX-AR rats, which is suppressed by RDX. In contrast, RDX plus olmesartan further attenuates UAGTV. P<0.05, ††P<0.01, †††P<0.005, ††††P<0.001 vs. UNX; P<0.05, ‡‡P<0.01, ‡‡‡‡P<0.001 vs. UNX-AR; §P<0.05, §§P<0.01 vs. UNX-RDX-AR. UNX: uninephrectomy; RDX: left-side renal denervation.
Figure 6
Figure 6
Podocyte injury, and reactive oxygen species and NADPH oxidase levels in the kidney in protocol 2. (A) Representative desmin-stained images (original magnification, ×200) and relative desmin-positive area, and (B) nephrin and (C) podocin mRNA levels in glomeruli. UNX-AR rats have a greater desmin-positive area in the glomeruli with reductions in glomerular nephrin and podocin mRNA levels. In these rats, RDX reduces the desmin-positive area and attenuates the reductions in glomerular nephrin and podocin mRNA levels. RDX in combination with olmesartan further enhances these changes. (D) Representative images of dihydroethidium (DHE) staining (original magnification, ×100). (E) Renal cortical tissue thiobarbituric acid reactive substances (TBARS). (F) p22phox and (G) gp91phox mRNA levels in renal cortical tissue. These parameters are increased in UNX-AR rats, while RDX attenuates the AR-induced increases in renal cortical TBARS, DHE staining, and p22phox and gp91phox mRNA levels. These suppressive effects of RDX are further enhanced by olmesartan in UNX-RDX-AR rats. P<0.05, ††P<0.01, ††††P<0.001 vs. UNX; P<0.05, ‡‡P<0.01, ‡‡‡P<0.005, ‡‡‡‡P<0.001 vs. UNX-AR; §P<0.05 vs. UNX-RDX-AR. UNX: uninephrectomy; RDX: left-side renal denervation.
Figure 7
Figure 7
Schematic diagram summarizing the cardio-renal syndrome during conditions of impaired cardiac function. Chronic cardiac volume overload activates the sympathetic nervous system and thereby increases plasma and kidney norepinephrine (NE) levels. In turn, the increased kidney NE stimulates angiotensinogen (AGT) expression and subsequently angiotensin II (AngII) production in the cortical tissues. Activation of the sympathetic nervous system and local AngII stimulates NADPH oxidase-dependent reactive oxygen species (ROS) generation in the kidney. Increases in kidney AngII, NE and oxidative stress lead to podocyte injury and albuminuria. Renal denervation (RDX) plus AngII blockade by an AngII receptor blocker (ARB) suppresses sympathetic nervous activation and the increases in kidney NE, AGT, AngII and oxidative stress, thereby preventing the onset and progression of podocyte injury and albuminuria.

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