Hypoxia-mediated regulation of mitochondrial transcription factors: Implications for hypertensive renal physiology

AbstractKidneys have a high resting metabolic rate and low tissue partial pressure of oxygen due to enhanced mitochondrial oxygen consumption and ATP production for active solute transport. Enhanced mitochondrial activity leads to progressive hypoxia from the renal cortex to renal medulla. Renal tubulointerstitial hypoxia (TiH) is severe in hypertensive rats due to increased sodium reabsorption within their nephrons. Additionally, these rats display increased energy demand and therefore, require healthy mitochondria for adequate salt reabsorption. Hence, we sought to study the regulation of mitochondrial biogenesis and expression of mitochondrial transcription factors (mtTFs, viz. Tfam, Tfb1m and Tfb2m) during hypoxic conditions and in rodent models of genetic hypertension. We report that the expressions of HIF-1α (hypoxia inducible factor-1α), PGC-1α (peroxisome proliferator activated receptor-γ co-activator-1α), mtTFs and OXPHOS proteins are elevated in hypertensive rats as compared to their normotensive counterparts. Additionally, studies in cultured kidney cells show that acute hypoxia augments the expression of these genes. We also observe a positive correlation between HIF-1α and mtTFs transcripts in human tissues. Furthermore, we report for the first time to our knowledge, that HIF-1α binds to promoters of Tfam, Tfb1m and Tfb2m genes and augments their promoter activities in NRK52e cells subjected to acute hypoxia. Taken together, this study suggests that acute hypoxia may enhance mitochondrial function to meet the energy demand in renal tubular epithelial cells and in young/pre-hypertensive SHR kidneys.Translational StatementOur results suggest that tubulointerstitial hypoxia (TiH) prevailing in prehypertensive rats augments the expression of mitochondrial transcription factors and proteins of electron transport chain. Moreover, previous reports indicate that ATP synthesis in these rats are elevated. Thus, our study provides insights into the molecular mechanism of such enhanced mitochondrial function. We propose that during early stages of kidney diseases (marked by mild TiH) an enhancement of mitochondrial function via stimulation of HIF-1α/PGC-1α production may delay renal tubular damage.

Download Full-text

NHE-1 inhibition improves cardiac mitochondrial function through regulation of mitochondrial biogenesis during postinfarction remodeling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00159.2006 ◽

2006 ◽

Vol 291 (4) ◽

pp. H1722-H1730 ◽

Cited By ~ 28

Author(s):

Sabzali Javadov ◽

Daniel M. Purdham ◽

Asad Zeidan ◽

Morris Karmazyn

Keyword(s):

Transcription Factors ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Marker Gene ◽

Specific Inhibitor ◽

Coronary Artery Ligation ◽

Strong Positive Correlation ◽

Mitochondrial Transcription ◽

Postinfarction Remodeling ◽

Mitochondrial Respiratory

We have recently demonstrated that mitochondrial respiratory dysfunction and mitochondrial permeability transition pore opening during postinfarction remodeling are prevented by the Na+/H+ exchange-1 (NHE-1)-specific inhibitor EMD-87580 (EMD). One of the mechanisms underlying the beneficial effect of NHE-1 inhibition on mitochondria could result from the drug's ability to regulate transcriptional factors responsible for mitochondrial function. In the present study, the effect of EMD on the expression of nuclear factors involved in mitochondrial biogenesis and expression of nuclear (COXNUCSUB IV) and mitochondrial (COXMITSUB I) encoded cytochrome c oxidase subunits has been studied in rat hearts subjected to either 12 or 18 wk of coronary artery ligation (CAL). Remodeling induced an increase in expression of the hypertrophic marker gene atrial natriuretic peptide, especially 12 wk after CAL. The mRNA level of the peroxisome proliferator-activated receptor-γ coactivator-1α and its downstream factors, including nuclear respiratory factor 1 and 2, mitochondrial transcription factor A, COXNUCSUB IV, and COXMITSUB I, were significantly reduced in hearts both 12 and 18 wk after ligation compared with sham-operated hearts. Dietary EMD provided immediately after ligation attenuated downregulation of mitochondrial transcription factors with a parallel decrease of hypertrophic marker gene expression. Regression analysis demonstrated a strong positive correlation between the transcription factors and mitochondrial respiratory function. Thus our study shows that the downregulation of mitochondrial transcription factors induced by postinfarction remodeling can be significantly attenuated by NHE-1 inhibition with a further improvement of mitochondrial function in these hearts.

Download Full-text

Early urinary biomarkers for renal tubular damage in spontaneously hypertensive rats on a high salt intake

Hypertension Research ◽

10.1038/hr.2015.103 ◽

2015 ◽

Vol 39 (1) ◽

pp. 19-26 ◽

Cited By ~ 15

Author(s):

Keiko Hosohata ◽

Daisuke Yoshioka ◽

Akira Tanaka ◽

Hitoshi Ando ◽

Akio Fujimura

Keyword(s):

Spontaneously Hypertensive Rats ◽

Salt Intake ◽

High Salt ◽

Urinary Biomarkers ◽

Tubular Damage ◽

Hypertensive Rats ◽

Renal Tubular Damage ◽

Spontaneously Hypertensive ◽

High Salt Intake ◽

Renal Tubular

Download Full-text

Impact of endurance training on murine spontaneous activity, muscle mitochondrial DNA abundance, gene transcripts, and function

Journal of Applied Physiology ◽

10.1152/japplphysiol.00791.2006 ◽

2007 ◽

Vol 102 (3) ◽

pp. 1078-1089 ◽

Cited By ~ 54

Author(s):

Lisa S. Chow ◽

Laura J. Greenlund ◽

Yan W. Asmann ◽

Kevin R. Short ◽

Shelly K. McCrady ◽

...

Keyword(s):

Mitochondrial Dna ◽

Transcription Factors ◽

Glucose Tolerance ◽

Mitochondrial Function ◽

Aerobic Exercise Training ◽

Gene Transcript ◽

Related Gene ◽

Mitochondrial Transcription ◽

Transcript Levels ◽

Gene Transcripts

We hypothesized that enhanced skeletal muscle mitochondrial function following aerobic exercise training is related to an increase in mitochondrial transcription factors, DNA abundance [mitochondrial DNA (mtDNA)], and mitochondria-related gene transcript levels, as well as spontaneous physical activity (SPA) levels. We report the effects of daily treadmill training on 12-wk-old FVB mice for 5 days/wk over 8 wk at 80% peak O2 consumption and studied the training effect on changes in body composition, glucose tolerance, muscle mtDNA muscle, mitochondria-related gene transcripts, in vitro muscle mitochondrial ATP production capacity (MATPC), and SPA levels. Compared with the untrained mice, the trained mice had higher peak O2 consumption (+18%; P < 0.001), lower percentage of abdominal (−25.4%; P < 0.02) and body fat (−19.5%; P < 0.01), improved glucose tolerance ( P < 0.04), and higher muscle mitochondrial enzyme activity (+19.5–43.8%; P < 0.04) and MATPC (+28.9 to +32.4%; P < 0.01). Gene array analysis showed significant differences in mRNAs of mitochondria-related ontology groups between the trained and untrained mice. Training also increased muscle mtDNA (+88.4 to +110%; P < 0.05), peroxisome proliferative-activated receptor-γ coactivator-1α protein (+99.5%; P < 0.04), and mitochondrial transcription factor A mRNA levels (+21.7%; P < 0.004) levels. SPA levels were higher in trained mice ( P = 0.056, two-sided t-test) and significantly correlated with two separate substrate-based measurements of MATPC ( P < 0.02). In conclusion, aerobic exercise training enhances muscle mitochondrial transcription factors, mtDNA abundance, mitochondria-related gene transcript levels, and mitochondrial function, and this enhancement in mitochondrial function occurs in association with increased SPA.

Download Full-text

Hypoxia-mediated regulation of mitochondrial transcription factors in renal epithelial cells: implications for hypertensive renal physiology

Hypertension Research ◽

10.1038/s41440-020-00539-4 ◽

2020 ◽

Author(s):

Bhargavi Natarajan ◽

Vikas Arige ◽

Abrar A. Khan ◽

S. Santosh Reddy ◽

Manoj K. Barthwal ◽

...

Keyword(s):

Transcription Factors ◽

Epithelial Cells ◽

Renal Physiology ◽

Mitochondrial Transcription ◽

Renal Epithelial Cells

Download Full-text

High Doses of Essential Oil of Croton Zehntneri Induces Renal Tubular Damage

Plants ◽

10.3390/plants10071400 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1400

Author(s):

Katarine F. Silva ◽

Diogo B. Peruchetti ◽

Gabriela M. Sirtoli ◽

Christina M. Takiya ◽

Ana Acacia S. Pinheiro ◽

...

Keyword(s):

Essential Oil ◽

Biological Activities ◽

Kidney Injury ◽

Sodium Reabsorption ◽

Tubular Damage ◽

Collagen Deposition ◽

Renal Tubular Damage ◽

Cont Group ◽

High Doses ◽

Renal Tubular

The essential oil of Croton zehntneri (EOCZ) and its major compounds are known to have several biological activities. However, some evidence shows potential toxic effects of high doses of EOCZ (>300 mg/kg) in amphibian and human kidneys. The aim of the present work was to investigate the effects on renal function of EOCZ at 300 mg/kg/day in healthy Swiss mice and a subclinical acute kidney injury (subAKI) animal model, which presents tubule-interstitial injury (TII). Four experimental groups were generated: (1) CONT group (control); (2) EOCZ, mice treated with EOCZ; (3) subAKI; (4) subAKI+EOCZ, subAKI treated simultaneously with EOCZ. EOCZ treatment induced TII measured by increases in (1) proteinuria; (2) cortical tubule-interstitial space; (3) macrophage infiltration; (4) collagen deposition. A decrease in tubular sodium reabsorption was also observed. These results were similar and nonadditive to those observed in the subAKI group. These data suggest that treatment with EOCZ at higher concentrations induces TII in mice, which could be mediated by protein overload in the proximal tubule.

Download Full-text

AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

Scientific Reports ◽

10.1038/s41598-019-55550-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Yongjun Zhu ◽

Hongwang Cui ◽

Jie Lv ◽

Haiqin Liang ◽

Yanping Zheng ◽

...

Keyword(s):

Angiotensin Ii ◽

Renal Injury ◽

Critical Role ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Tubular Cell ◽

Tubular Damage ◽

Renal Tubular Cell ◽

Ang Ii ◽

Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

Download Full-text

Fractional excretion of magnesium as an early indicator of renal tubular damage in normotensive diabetic nephropathy

Turkish Journal of Biochemistry ◽

10.1515/tjb-2019-0232 ◽

2020 ◽

Vol 45 (5) ◽

pp. 543-551

Author(s):

Fatih Ozcelik ◽

Serif Kactas ◽

Halime Hanim Pence ◽

Saadet Kurcenli ◽

Erdim Sertoglu ◽

...

Keyword(s):

Fractional Excretion ◽

Study Patient ◽

Control Group ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular ◽

Excretion Rates ◽

Urine And Serum ◽

Diagnostic And Prognostic Value

AbstractObjectivesThe aim of the present study is to evaluate the diagnostic powers of fractional magnesium, sodium and potassium as markers of renal tubular damage in normotensive type 2 diabetes mellitus (T2DM) patients with respect to microalbuminuria and estimated glomerular filtration rate (eGFR).Materials and methodsForty healthy volunteers and 91 normotensive T2DM patients were included in the study. Patient group was divided into two according to albuminuria level; 49 were normoalbuminuric and 42 were microalbuminuric. In addition to albumin in urine, urine and serum Na, K, Mg and creatinine values were measured to calculate fractional electrolyte excretion rates.ResultsIn normoalbuminuric and microalbuminuric groups, fractional excretion of magnesium (FEMg) values were found to be significantly higher than the control group (p < 0.05). There was a moderate correlation between FEMg and albümin to cratinin ratio (ACR) (Spearman r = 0.3215, p < 0.05). In the ROC analysis for eGFR and FEMg based on microalbuminuria, the areas under the curve were 0.625 and 0.732, respectively (diagnostic sensitivity 59.52% and 66.67%; specificity 70.79% and 77.53%, p < 0.05).ConclusionFor renal tubular damage predicted by microalbuminuria, FEMg could be accepted as a candidate biochemical marker with diagnostic and prognostic value.

Download Full-text

Tactical approaxhes to diagnosis and treatment of hepatorenal syndrome in patients with blastomatous obstructive jaundice

Problems of Uninterrupted Medical Training and Science ◽

10.31071/promedosvity2021.02.028 ◽

2021 ◽

Vol 42 (2) ◽

pp. 28-31

Author(s):

S. V. Kosulin ◽

◽

Ju. O. Vinnik ◽

Ju. V. Ivanova ◽

◽

...

Keyword(s):

Obstructive Jaundice ◽

Hepatorenal Syndrome ◽

Resistance Index ◽

Doppler Imaging ◽

Coagulation System ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular ◽

Neutrophil Gelatinase

The article discusses problems of early diagnosis and, accordingly, treatment of hepatorenal syndrome (HRS) in case of obstructive jaundice of blastomatous origin. The results of a comprehensive examination of 37 patients with blastomatous obstructive jaundice (OJ) with clinical and laboratory signs of HRS were analyzed. Patients were evaluated for clinical and biochemical parameters of blood and urine, blood electrolytes, indicators of the blood coagulation system according to unified methods. The main work is devoted to the determination of the biomarker of renal tubular damage, neutrophil-gelatinase-associated lipocaine (s-NGAL) as a marker and indicator of HRS severity, careful and detailed analysis, monitoring of levels (s-NGAL) and other bioactive substances as an indicator of treatment efficacy. Introduction of active ultrasound as a replacement for contrast computer tomography to reduce the load on precompromised kidneys. It has been proven that the level of renal tubular damage, neutrophil-gelatinase-associated lipocaine s-NGAL is an early marker of renal damage whose function is to reduce the severity of damage to the proximal tubules of the kidneys, normalize damaged tissue by participating in apoptosis, increase survival of damaged restoration of damaged epithelium, stimulation of differentiation and structural reorganization of renal epithelial cells. The fact that s-NGAL was not significantly reduced in the stage of recovery of diuresis, confirms the presence of patients with blastomatous MF severe and persistent toxic tubulointerstitial disorders. Based on this determination of the biomarker (s-NGAL) in the serum of patients with blastomatous mechanical jaundice and performing in them at primary ultrasound color Doppler mapping and pulsed wave Doppler imaging of the kidneys with the calculation of the resistance index may serve as early signs of damage.

Download Full-text