Mitochondrial proteomic analysis reveals deficiencies in oxygen utilization in medullary thick ascending limb of Henle in the Dahl salt-sensitive rat

Zheleznova, Nadezhda N.; Yang, Chun; Ryan, Robert P.; Halligan, Brian D.; Liang, Mingyu; Greene, Andrew S.; Cowley, Allen W.

doi:10.1152/physiolgenomics.00060.2012

Cited by 44 publications

(48 citation statements)

References 87 publications

(104 reference statements)

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“…Medullary interstitial infusion of a fumarate precursor in the SS.13 BN rats significantly increased medullary tissue H 2 O 2 and exacerbated salt-induced hypertension. Consistent with these observations, a proteomic analysis of isolated mTAL mitochondria found nine proteins to be reduced in SS rats compared with SS.13 BN rats (203). The downregulation of these proteins was predicted to reduce the efficiency of mitochondrial O 2 utilization, which was confirmed by high-resolution respirometry of the mTAL cells and in mitochondria isolated from the outer medulla of SS rats.…”

Section: Medullary O 2 ·ϫ No and H 2 O 2 As Determinants Of Blood mentioning

confidence: 52%

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Cowley

Abe

Mori

et al. 2015

American Journal of Physiology-Renal Physiology

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logical evidence linking the production of superoxide, hydrogen peroxide, and nitric oxide in the renal medullary thick ascending limb of Henle (mTAL) to regulation of medullary blood flow, sodium homeostasis, and long-term control of blood pressure is summarized in this review. Data obtained largely from rats indicate that experimentally induced elevations of either superoxide or hydrogen peroxide in the renal medulla result in reduction of medullary blood flow, enhanced Na ϩ reabsorption, and hypertension. A shift in the redox balance between nitric oxide and reactive oxygen species (ROS) is found to occur naturally in the Dahl salt-sensitive (SS) rat model, where selective reduction of ROS production in the renal medulla reduces salt-induced hypertension. Excess medullary production of ROS in SS rats emanates from the medullary thick ascending limbs of Henle [from both the mitochondria and membrane NAD(P)H oxidases] in response to increased delivery and reabsorption of excess sodium and water. There is evidence that ROS and perhaps other mediators such as ATP diffuse from the mTAL to surrounding vasa recta capillaries, resulting in medullary ischemia, which thereby contributes to hypertension.superoxide (O 2 ·Ϫ ); hydrogen peroxide (H2O2); nitric oxide (NO); NAD(P)H oxidase; mTAL; medullary blood flow; kidney; Dahl SS rats REACTIVE OXYGEN SPECIES (ROS) are chemically reactive molecules derived from oxygen, whose role as mediators of intracellular signaling cascades is well recognized. The following is a brief review of physiological data linking superoxide (O 2 ·Ϫ ), hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO) production in the medullary thick ascending limbs of Henle (mTAL) to sodium (Na ϩ ) homeostasis, the regulation of medullary blood flow (MBF), and the long-term regulation of arterial blood pressure. MBF to the renal medulla can be importantly controlled by the constriction and dilation of the descending vasa recta (VR) capillaries, which branch from the efferent arterioles of the juxtamedullary glomeruli (49, 147, 149) and whose tone is controlled by the smooth muscle-like pericytes (49, 90, 146 -149). The role of NO cross talk from mTAL to surrounding VR in the renal medulla has been reviewed in detail elsewhere (19, 33) and will be discussed here largely with regard to its ROS-related counterregulatory functions. The present review will first summarize data showing that either the excess endogenous production or reduced scavenging of O 2 ·Ϫ or H 2 O 2 within the renal medulla results in a decrease in MBF and Na ϩ excretion, leading to hypertension and renal injury. Second, evidence will be summarized supporting the hypothesis that a high dietary salt intake results in increased luminal flow and delivery of NaCl to the mTAL, thereby signaling via both mechanical forces (stretch and shear) and increased Na ϩ transport, an increased mitochondrial and membrane NA-D(P)H oxidase production of O 2 ·Ϫ and H 2 O 2 . Third, studies will be reviewed showing that reduction of MBF leads to hypertension a...

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Section: Medullary O 2 ·ϫ No and H 2 O 2 As Determinants Of Blood mentioning

confidence: 52%

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Cowley

Abe

Mori

et al. 2015

American Journal of Physiology-Renal Physiology

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“…28 Chromosome 13 contains several critical genes such as genes encoding renin and NADPH subunit p67 phox and several studies utilizing this model illustrate its critical role in BP regulation. [28][29][30][31][32][33] After 3 weeks on a HS diet, MAP was significantly lower in SS. 13 BN rats compared with SS rats, as Figure 1.…”

Section: Enac Plays a Role In Development Of Salt-sensitive Hypertensmentioning

confidence: 96%

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Pavlov¹,

Levchenko²,

O’Connor³

et al. 2013

Journal of the American Society of Nephrology

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Various stimuli, including hormones and growth factors, modulate epithelial sodium channels (ENaCs), which fine-tune Na + absorption in the kidney. Members of the EGF family are important for maintaining transepithelial Na + transport, but whether EGF influences ENaC, perhaps mediating salt-sensitive hypertension, is not well understood. Here, the ENaC inhibitor benzamil attenuated the development of hypertension in Dahl salt-sensitive rats. Feeding these salt-sensitive rats a high-salt diet led to lower levels of EGF in the kidney cortex and enhanced the expression and activity of ENaC compared with feeding a lowsalt diet. To directly evaluate the role of EGF in the development of hypertension and its effect on ENaC activity, we infused EGF intravenously while continuously monitoring BP of the salt-sensitive rats. Infusion of EGF decreased ENaC activity, prevented the development of hypertension, and attenuated glomerular and renal tubular damage. Taken together, these findings indicate that cortical EGF levels decrease with a high-salt diet in salt-sensitive rats, promoting ENaC-mediated Na + reabsorption in the collecting duct and the development of hypertension. More than 76 million American adults have high BP 1 and the likelihood of developing hypertension significantly increases with age. Nearly 40% of African Americans aged .20 years exhibit hypertension and nearly 70% of these individuals have a form of hypertension that is highly sensitive to salt intake. A reduced ability to maintain sodium homeostasis and normal levels of arterial pressure is a hallmark of all forms of hypertension. 2 In the kidney, discretionary Na + reabsorption in response to endocrine input to the aldosterone-sensitive distal nephron (ASDN) is a determinant of the pressurenatriuresis relationship, which is of fundamental importance in the long-term control of arterial pressure. 2,3 Although sodium transport in ASDN accounts for a small proportion of renal sodium transport (,10%), ENaC activity is the rate-limiting step for this discretionary Na + reabsorption. 4 The Dahl salt-sensitive (SS) rat strain used in this study is a genetic animal model of hypertension and kidney disease that reveals disease traits similar to those observed in humans. This inbred strain exhibits a low-renin, sodium-sensitive form of hypertension that is associated with severe and progressive proteinuria, glomerulosclerosis, and renal interstitial fibrosis. [5][6][7] The EGF and related hormones are multipotent agents [8][9][10][11] involved in regulation of various renal

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“…Downregulation of proteins connected with energy metabolism predicted reduction of oxygen utilization in mitochondria in medullary thick ascending limb of Henle's loop of salt sensitive rats 94 . 86 .…”

Section: Hypertensionmentioning

confidence: 95%

“…Using salt-sensitive rats as model organism for hypertension, effect of salt-induced hypertension on mitochondria of thick ascending limb of Henle's loop was tested by proteomics 94 . Downregulation of proteins connected with energy metabolism predicted reduction of oxygen utilization in mitochondria in medullary thick ascending limb of Henle's loop of salt sensitive rats 94 .…”

Section: Hypertensionmentioning

confidence: 99%

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Proteomic approaches to the study of renal mitochondria

Tůma¹,

Kuncová²,

Mareš³

et al. 2016

BIOMED PAP

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Background and Aims. Dysfunction of kidney mitochondria plays a critical role in the pathogenesis of a number of renal diseases. Proteomics represents an untargeted attempt to reveal the remodeling of mitochondrial proteins during disease. Combination of separation methods and mass spectrometry allows identification and quantitative analysis of mitochondrial proteins including protein complexes. The aim of this review is to summarize the methods and applications of proteomics to renal mitochondria. Methods. Using keywords "mitochondria", "kidney", "proteomics", scientific databases (PubMed and Web of knowledge) were searched from 2000 to August 2015 for articles describing methods and applications of proteomics to analysis of mitochondrial proteins in kidney. Included were publications on mitochondrial proteins in kidneys of humans and animal model in health and disease. Results and Conclusion. Proteomics of renal mitochondria has been/is mostly used in diabetes, hypertension, acidosis, nephrotoxicity and renal cancer. Integration of proteomics with other methods for examining protein activity is promising for insight into the role of renal mitochondria in pathological states. Several challenges were identified: selection of appropriate model organism, sensitivity of analytical methods and analysis of mitochondrial proteome in different renal zones/biopsies in the course of various kidney disorders.

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Mitochondrial proteomic analysis reveals deficiencies in oxygen utilization in medullary thick ascending limb of Henle in the Dahl salt-sensitive rat

Cited by 44 publications

References 87 publications

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Deficiency of Renal Cortical EGF Increases ENaC Activity and Contributes to Salt-Sensitive Hypertension

Proteomic approaches to the study of renal mitochondria

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