RESUMO
Acute kidney injury (AKI) is a systemic inflammatory disease that contributes to remote organ failures. Multiple organ failure is the leading cause of death due to AKI, and lack of understanding of the mechanisms involved has precluded the development of novel therapies. Mitochondrial injury in AKI leads to mitochondrial fragmentation and release of damage-associated molecular patterns, which are known to active innate immune pathways and systemic inflammation. This review presents current evidence suggesting that extracellular mitochondrial damage-associated molecular patterns are mediators of remote organ failures during AKI that have the potential to be modifiable.
Assuntos
Injúria Renal Aguda , Injúria Renal Aguda/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Masculino , Mitocôndrias/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismoRESUMO
Acute respiratory distress syndrome (ARDS) is a common cause of mortality in patients with acute kidney injury (AKI). Inflammatory crosstalk from the kidney to the lung has been shown to contribute to lung injury after AKI, but anti-inflammatory therapies have not been proven beneficial in human studies. Recently, AKI was shown to alter mitochondria and related metabolic pathways in the heart, but the impact of AKI on lung metabolism has not been investigated to our knowledge. In this study, we evaluated the metabolomic profile of the lung following renal ischemia and reperfusion to identify novel pathways that may be modifiable. We randomized C57BL/6 mice to 20 minutes of bilateral renal arterial clamping or sham operation under ketamine/xylazine anesthesia. At 4 hours after reperfusion, we found a significant increase in markers of lung injury, as well as significant metabolomic changes across lung, kidney, plasma and bronchoalveolar lavage fluid (BALF) compared to shams. Comparative analyses revealed that the fatty acid oxidation pathway was the most significantly altered metabolic pathway, a finding which is consistent with mitochondrial dysfunction systemically and in the lung. These metabolomic changes correlated with the extracellular accumulation of the mitochondrial damage associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA) and transcription factor A, mitochondria (TFAM). Finally, we found that intraperitoneal injection of renal mtDAMPs caused metabolomic changes consistent with mitochondrial dysfunction in the lung in vivo. Mitochondrial function and mtDAMPs warrant further investigation as potential therapeutic targets in preventing lung injury because of AKI.
Assuntos
Injúria Renal Aguda/complicações , Alarminas/metabolismo , Lesão Pulmonar/patologia , Metaboloma , Mitocôndrias/patologia , Animais , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismoRESUMO
Sepsis-associated acute kidney injury (s-AKI) has a staggering impact in patients and lacks any treatment. Incomplete understanding of the pathogenesis of s-AKI is a major barrier to the development of effective therapies. We address the gaps in knowledge regarding renal oxygenation, tubular metabolism, and mitochondrial function in the pathogenesis of s-AKI using the cecal ligation and puncture (CLP) model in mice. At 24 h after CLP, renal oxygen delivery was reduced; however, fractional oxygen extraction was unchanged, suggesting inefficient renal oxygen utilization despite decreased glomerular filtration rate and filtered load. To investigate the underlying mechanisms, we examined temporal changes in mitochondrial function and metabolism at 4 and 24 h after CLP. At 4 h after CLP, markers of mitochondrial content and biogenesis were increased in CLP kidneys, but mitochondrial oxygen consumption rates were suppressed in proximal tubules. Interestingly, at 24 h, proximal tubular mitochondria displayed high respiratory capacity, but with decreased mitochondrial content, biogenesis, fusion, and ATP levels in CLP kidneys, suggesting decreased ATP synthesis efficiency. We further investigated metabolic reprogramming after CLP and observed reduced expression of fatty acid oxidation enzymes but increased expression of glycolytic enzymes at 24 h. However, assessment of functional glycolysis revealed lower glycolytic capacity, glycolytic reserve, and compensatory glycolysis in CLP proximal tubules, which may explain their susceptibility to injury. In conclusion, we demonstrated significant alterations in renal oxygenation, tubular mitochondrial function, and metabolic reprogramming in s-AKI, which may play an important role in the progression of injury and recovery from AKI in sepsis.
Assuntos
Injúria Renal Aguda/patologia , Rim/lesões , Mitocôndrias/metabolismo , Sepse/complicações , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Animais , Modelos Animais de Doenças , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Camundongos Endogâmicos C57BL , Sepse/metabolismoRESUMO
Electronic (e)-cigarettes theoretically may be safer than conventional tobacco. However, our prior studies demonstrated direct adverse effects of e-cigarette vapor (EV) on airway cells, including decreased viability and function. We hypothesize that repetitive, chronic inhalation of EV will diminish airway barrier function, leading to inflammatory protein release into circulation, creating a systemic inflammatory state, ultimately leading to distant organ injury and dysfunction. C57BL/6 and CD-1 mice underwent nose only EV exposure daily for 3-6 mo, followed by cardiorenal physiological testing. Primary human bronchial epithelial cells were grown at an air-liquid interface and exposed to EV for 15 min daily for 3-5 days before functional testing. Daily inhalation of EV increased circulating proinflammatory and profibrotic proteins in both C57BL/6 and CD-1 mice: the greatest increases observed were in angiopoietin-1 (31-fold) and EGF (25-fold). Proinflammatory responses were recapitulated by daily EV exposures in vitro of human airway epithelium, with EV epithelium secreting higher IL-8 in response to infection (227 vs. 37 pg/ml, respectively; P < 0.05). Chronic EV inhalation in vivo reduced renal filtration by 20% ( P = 0.017). Fibrosis, assessed by Masson's trichrome and Picrosirius red staining, was increased in EV kidneys (1.86-fold, C57BL/6; 3.2-fold, CD-1; P < 0.05), heart (2.75-fold, C57BL/6 mice; P < 0.05), and liver (1.77-fold in CD-1; P < 0.0001). Gene expression changes demonstrated profibrotic pathway activation. EV inhalation altered cardiovascular function, with decreased heart rate ( P < 0.01), and elevated blood pressure ( P = 0.016). These data demonstrate that chronic inhalation of EV may lead to increased inflammation, organ damage, and cardiorenal and hepatic disease.
Assuntos
Barreira Alveolocapilar/efeitos dos fármacos , Sistemas Eletrônicos de Liberação de Nicotina , Inflamação/induzido quimicamente , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/efeitos adversos , Animais , Citocinas/sangue , Feminino , Fibrose/induzido quimicamente , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Cultura Primária de Células , Mucosa Respiratória/citologia , Mucosa Respiratória/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacosRESUMO
The incretin hormone, glucagon-like peptide-1 (GLP-1), is known for responding to dietary fat and carbohydrate. It elicits effects on pancreas, gut, and brain to stabilize blood glucose levels. We have previously reported that the GLP-1 agonist, exenatide, vasodilates the kidney and suppresses proximal reabsorption. The present study was undertaken to determine whether the renal effects of exenatide are mediated by nitric oxide (NO) and/or prostaglandins. Inulin clearance (glomerular filtration rate, GFR) and urine flow rate (UV) were measured in anesthetized rats before and during exenatide infusion (1 nmol/h iv). Animals were pretreated with cyclooxygenase (COX) inhibitor (meclofenamate), NO synthase (NOS) inhibitor (NG-monomethyl-l-arginine, l-NMMA), NO clamp (l-NMMA + sodium nitroprusside), or placebo. Effectiveness of COX inhibition was tested by measuring urinary prostaglandin E2 (UPGE2). Effectiveness of NOS blockade and NO clamp was determined by urinary NO degradation products (UNOx). Exenatide increased GFR, UV, UPGE2, and UNOx. Pretreatment with meclofenamate reduced UPGE2 by 75% and reduced the effect of exenatide on UPGE2 by 30% but did not modify the effects of exenatide on GFR or UV. Pretreatment with l-NMMA reduced UNOx and the impact of exenatide on GFR and UV by 50%. Pretreatment by NO clamp did not prevent UNOx from increasing during exenatide but blunted the effects of exenatide on GFR and UV. In conclusion, exenatide is a potent renal vasodilator and diuretic in the rat. These effects of exenatide are insensitive to COX inhibition but are mediated, in part, by NO.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/agonistas , Óxido Nítrico/metabolismo , Peptídeos/farmacologia , Prostaglandinas/metabolismo , Circulação Renal/efeitos dos fármacos , Peçonhas/farmacologia , Animais , Exenatida , Masculino , Ratos WistarRESUMO
The pathophysiology of chronic kidney disease (CKD) is driven by alterations in surviving nephrons to sustain renal function with ongoing nephron loss. Oxygen supply-demand mismatch, due to hemodynamic adaptations, with resultant hypoxia, plays an important role in the pathophysiology in early CKD. We sought to investigate the underlying mechanisms of this mismatch. We utilized the subtotal nephrectomy (STN) model of CKD to investigate the alterations in renal oxygenation linked to sodium (Na) transport and mitochondrial function in the surviving nephrons. Oxygen delivery was significantly reduced in STN kidneys because of lower renal blood flow. Fractional oxygen extraction was significantly higher in STN. Tubular Na reabsorption was significantly lower per mole of oxygen consumed in STN. We hypothesized that decreased mitochondrial bioenergetic capacity may account for this and uncovered significant mitochondrial dysfunction in the early STN kidney: higher oxidative metabolism without an attendant increase in ATP levels, elevated superoxide levels, and alterations in mitochondrial morphology. We further investigated the effect of activation of hypoxia-inducible factor-1α (HIF-1α), a master regulator of cellular hypoxia response. We observed significant improvement in renal blood flow, glomerular filtration rate, and tubular Na reabsorption per mole of oxygen consumed with HIF-1α activation. Importantly, HIF-1α activation significantly lowered mitochondrial oxygen consumption and superoxide production and increased mitochondrial volume density. In conclusion, we report significant impairment of renal oxygenation and mitochondrial function at the early stages of CKD and demonstrate the beneficial role of HIF-1α activation on renal function and metabolism.
Assuntos
Aminoácidos Dicarboxílicos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Oxigênio/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Hipóxia Celular , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/metabolismo , Rim/ultraestrutura , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Ratos Wistar , Circulação Renal/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia , Reabsorção Renal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sódio/metabolismo , Superóxidos/metabolismo , Fatores de TempoRESUMO
In critical illness, such as sepsis or the acute respiratory distress syndrome, acute kidney injury (AKI) is common and associated with increased morbidity and mortality. Mechanical ventilation in critical illnesses is also a risk factor for AKI, but it is potentially modifiable. Injurious ventilation strategies may lead to the systemic release of inflammatory mediators from the lung due to ventilator induced lung injury (VILI). The systemic consequences of VILI are difficult to differentiate clinically from other systemic inflammatory syndromes, such as sepsis. The purpose of this study was to identify unique changes in the expression of inflammatory mediators in kidney tissue in response to VILI compared with systemic sepsis to gain insight into direct effects of VILI on the kidney. Four groups of mice were compared-mice with sepsis from cecal ligation and puncture (CLP), mice subjected to injurious mechanical ventilation with high tidal volumes (VILI), mice exposed to CLP followed by VILI (CLP+VILI), and sham controls. Protein expression of common inflammatory mediators in kidneys was analyzed using a proteome array and confirmed by Western blot analysis or ELISA. VEGF and VCAM-1 were found to be significantly elevated in kidneys from VILI mice compared with sham and CLP. Angiopoietin-2 was significantly increased in CLP+VILI compared with CLP alone and was also correlated with higher levels of AKI biomarker, neutrophil gelatinase-associated lipocalin. These results suggest that VILI alters the renal expression of VEGF, VCAM-1, and angiopoietin-2, and these proteins warrant further investigation as potential biomarkers and therapeutic targets.
Assuntos
Angiopoietina-2/metabolismo , Células Endoteliais/metabolismo , Mediadores da Inflamação/metabolismo , Rim/irrigação sanguínea , Respiração Artificial/efeitos adversos , Sepse/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Proteômica/métodos , Sepse/microbiologia , Transdução de Sinais , Regulação para Cima , Molécula 1 de Adesão de Célula Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologiaRESUMO
Renal hypoxia contributes to chronic kidney disease (CKD) progression, as validated in experimental and human CKD. In the early stages, increased oxygen consumption causes oxygen demand/supply mismatch, leading to hypoxia. Hence, early targeting of the determinants and regulators of oxygen consumption in CKD may alter the disease course before permanent damage ensues. Here, we focus on hypoxia inducible factor-1α (HIF-1α) and AMP-activated protein kinase (AMPK) and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1α activation in the subtotal nephrectomy (STN) model of CKD limits protein synthesis, inhibits apoptosis, and activates autophagy, presumably for improved cell survival. AMPK activation was diminished in the STN kidney and was remarkably restored by HIF-1α activation, demonstrating a novel role for HIF-1α in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1α and AMPK on cell survival and death pathways by utilizing pharmacological and knockdown approaches in cell culture models. We found that the effect of HIF-1α activation on autophagy is independent of AMPK, but on apoptosis it is partially AMPK dependent. The effects of HIF-1α and AMPK activation on inhibiting protein synthesis via the mTOR pathway appear to be additive. These various effects were also observed under hypoxic conditions. In conclusion, HIF-1α and AMPK appear to be linked at a molecular level and may act as components of a concerted cellular response to hypoxic stress in the pathophysiology of CKD.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adaptação Fisiológica/fisiologia , Hipóxia Celular/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Modelos Animais de Doenças , Masculino , Nefrectomia , Ratos , Ratos Wistar , Circulação Renal/fisiologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
We previously reported internephron heterogeneity in the tubuloglomerular feedback (TGF) response 1 wk after subtotal nephrectomy (STN), with 50% of STN nephrons exhibiting anomalous TGF (Singh P, Deng A, Blantz RC, Thomson SC. Am J Physiol Renal Physiol 296: F1158-F1165, 2009). Presently, we tested the theory that anomalous TGF is an adaptation of the STN kidney to facilitate increased distal delivery when NaCl balance forces the per-nephron NaCl excretion to high levels. To this end, the effect of dietary NaCl on the TGF response was tested by micropuncture in STN and sham-operated Wistar rats. An NaCl-deficient (LS) or high-salt NaCl diet (HS; 1% NaCl in drinking water) was started on day 0 after STN or sham surgery. Micropuncture followed 8 days later with measurements of single-nephron GFR (SNGFR), proximal reabsorption, and tubular stop-flow pressure (PSF) obtained at both extremes of TGF activation, while TGF was manipulated by microperfusing Henle's loop (LOH) from the late proximal tubule. Activating TGF caused SNGFR to decline by similar amounts in Sham-LS, Sham-HS and STN-LS [ΔSNGFR (nl/min) = -16 ± 2, -11 ± 3, -11 ± 2; P = not significant by Tukey]. Activating TGF in STN-HS actually increased SNGFR by 5 ± 2 nl/min (P < 0.0005 vs. each other group by Tukey). HS had no effect on the PSF response to LOH perfusion in sham [ΔPSF (mmHg) = -9.6 ± 1.1 vs. -9.8 ± 1.0] but eliminated the PSF response in STN (+0.3 ± 0.9 vs. -5.7 ± 1.0, P = 0.0002). An HS diet leads to anomalous TGF in the early remnant kidney, which facilitates NaCl and fluid delivery to the distal nephron.
Assuntos
Retroalimentação Fisiológica/fisiologia , Glomérulos Renais/fisiologia , Túbulos Renais/fisiologia , Rim/fisiologia , Nefrectomia , Cloreto de Sódio na Dieta/farmacologia , Análise de Variância , Animais , Pressão Sanguínea/fisiologia , Proteínas Sanguíneas/metabolismo , Capilares/fisiologia , Dieta , Taxa de Filtração Glomerular/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
There are unique features of renal oxygenation that render the kidney susceptible to oxygen demand-supply mismatch and hypoxia. Renal oxygen consumption by oxidative metabolism is closely coupled to and driven by tubular transport, which is linked to the filtered solute load and glomerular filtration rate (GFR). In turn, filtered solute load and GFR are dependent on the renal blood flow. Hence, changes in renal blood flow increase oxygen delivery but also increase oxygen demand (consumption) simultaneously by increasing the tubular workload of solute transport. The renal blood flow to different regions of kidney is also inhomogeneous, increasing the oxygen demand-supply mismatch in particular areas such as the outer medulla which become more susceptible to injury. Thus, tubular transport and oxidative metabolism by miochondria are closely coupled in the kidney and are the principal determinants of intrarenal oxygenation. Here we review the published literature characterizing renal oxygenation and mitochondrial function in ischemic and sepsis-associated acute kidney injury (AKI). However, the coupling of transport and metabolism in AKI has not been examined. This is a potentially fruitful area of research that should become increasingly active given the emerging data linking renal oxygenation and hypoxia to acute and chronic dysfunction in the kidney.
Assuntos
Injúria Renal Aguda/fisiopatologia , Rim/metabolismo , Mitocôndrias/fisiologia , Oxigênio/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Animais , Transporte Biológico , Hipóxia Celular , Modelos Animais de Doenças , Metabolismo Energético , Taxa de Filtração Glomerular , Humanos , Rim/irrigação sanguínea , Túbulos Renais Proximais/metabolismo , Dinâmica Mitocondrial , Oxirredução , Consumo de Oxigênio , Circulação Renal , Traumatismo por Reperfusão/metabolismo , Sepse/complicações , Sepse/fisiopatologia , Sódio/metabolismo , VasoconstriçãoRESUMO
The incretin hormone glucagon-like peptide-1 (GLP-1) is released from the gut in response to fat or carbohydrate and contributes to negative feedback control of blood glucose by stimulating insulin secretion, inhibiting glucagon, and slowing gastric emptying. GLP-1 receptors (GLP-1R) are also expressed in the proximal tubule, and possibly elsewhere in the kidney. Presently, we examined the effect of a GLP-1R agonist on single-nephron glomerular filtration rate (GFR; SNGFR), proximal reabsorption (Jprox), tubuloglomerular feedback (TGF) responses, and urine flow rate in hydropenic male Wistar and Wistar-Froemter rats. Micropuncture and whole-kidney data were obtained before and during infusion of the GLP-1 agonist exenatide (1 nmol/h iv). SNGFR and Jprox were measured by late proximal collection at both extremes of TGF activation, which was achieved by perfusing Henle's loop at 0 or 50 nl/min. Primary changes in Jprox were revealed by analysis of covariance for Jprox with SNGFR as a covariate. Effects on TGF activation were determined in a separate set of experiments by comparing early distal and late proximal collections. Exenatide increased SNGFR by 33-50%, suppressed proximal tubular reabsorption by 20-40%, doubled early distal flow rate, and increased urine flow rate sixfold without altering the efficiency of glomerulotubular balance, TGF responsiveness, or the tonic influence of TGF. This implies that exenatide is both a proximal diuretic and a renal vasodilator. Since the natural agonist for the GLP-1R is regulated by intake of fat and carbohydrate, but not by salt or fluid, the control of salt excretion by the GLP-1R system departs from the usual negative-feedback paradigm for regulating salt balance.
Assuntos
Taxa de Filtração Glomerular/fisiologia , Hipoglicemiantes/farmacologia , Túbulos Renais Proximais/fisiologia , Peptídeos/farmacologia , Receptores de Glucagon/metabolismo , Peçonhas/farmacologia , Animais , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1 , Masculino , Ratos , Ratos Wistar , Receptores de Glucagon/agonistas , Receptores de Glucagon/genética , Cloreto de Sódio/metabolismo , Equilíbrio HidroeletrolíticoRESUMO
Acute kidney injury (AKI) is a major burden on health systems and may arise from multiple initiating insults, including ischaemia-reperfusion injury, cardiovascular surgery, radiocontrast administration and sepsis. Similarly, the incidence and prevalence of chronic kidney disease (CKD) continues to increase, with significant morbidity and mortality. Moreover, an increasing number of AKI patients survive to develop CKD and end-stage renal disease. Although the mechanisms for the development of AKI and progression to CKD remain poorly understood, initial impairment of oxygen balance likely constitutes a common pathway, causing renal tissue hypoxia and ATP starvation that, in turn, induce extracellular matrix production, collagen deposition and fibrosis. Thus, possible future strategies for one or both conditions may involve dopamine, loop diuretics, atrial natriuretic peptide and inhibitors of inducible nitric oxide synthase, substances that target kidney oxygen consumption and regulators of renal oxygenation, such as nitric oxide and heme oxygenase-1.
Assuntos
Injúria Renal Aguda/metabolismo , Hemodinâmica/fisiologia , Rim/metabolismo , Consumo de Oxigênio/fisiologia , Insuficiência Renal Crônica/metabolismo , Injúria Renal Aguda/patologia , Animais , Humanos , Rim/patologia , Insuficiência Renal Crônica/patologiaRESUMO
Nephron loss in a diseased kidney invokes adaptations in the remaining nephrons. Whether and how these adaptations condition the response of the kidney to injury is not known. We examined the susceptibility of the kidney after subtotal (5/6th) nephrectomy (STN) to ischemic injury in rats. GFR in STN kidneys did not significantly change after ischemia reperfusion (IR), whereas GFR fell by 70% after IR in unilateral nephrectomy controls. In micropuncture experiments, single-nephron GFR responses mirrored the whole-kidney responses: in STN, single-nephron GFR decreased by 7% after IR compared with 28% in controls. Furthermore, we found that tubuloglomerular feedback, a mechanism that links proximal tubular injury to a fall in GFR, was inoperative in STN but was normal in controls. Restoration of normal feedback in STN attenuated the functional resistance to IR. In addition to the functional resilience, the morphology of the kidney was better preserved in STN. In STN kidneys, the S3 segment of the proximal tubule, normally injured after ischemia, constitutively expressed hypoxia-inducible factor-1α (HIF-1α), which is cytoprotective in ischemia. Inducing HIF before IR improved GFR in control animals, and inhibiting the HIF target heme-oxygenase-1 before IR reduced GFR in STN animals. Taken together, these data suggest that fewer functioning nephrons in a diseased kidney do not increase the susceptibility to injury, but rather, hemodynamic and molecular adaptations in the remnant nephrons precondition them against ischemic injury.
Assuntos
Retroalimentação Fisiológica/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Glomérulos Renais/fisiologia , Túbulos Renais Proximais/fisiologia , Nefrectomia , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/fisiopatologia , Adaptação Fisiológica/fisiologia , Animais , Taxa de Filtração Glomerular/fisiologia , Rim/patologia , Rim/cirurgia , Glomérulos Renais/patologia , Túbulos Renais Proximais/patologia , Masculino , Modelos Animais , Néfrons/fisiologia , Punções , Ratos , Ratos Wistar , Transdução de Sinais/fisiologiaRESUMO
Kidney tubules have high metabolic activity to support solute transport and other cellular functions. Energy generation in the kidney is largely dependent on mitochondrial oxidative phosphorylation, particularly in the proximal tubules. Important alterations in the pathways of energy generation and cellular metabolism have been identified in early and late stages of kidney disease. This review provides a succinct summary of the current literature on the central role of energy metabolism in the pathophysiology of acute and chronic kidney disease.
Assuntos
Rim , Insuficiência Renal Crônica , Humanos , Rim/metabolismo , Metabolismo Energético , Túbulos Renais Proximais/metabolismo , Insuficiência Renal Crônica/metabolismo , Túbulos Renais/metabolismoRESUMO
Temporal adaptation of tubuloglomerular feedback (TGF) permits readjustment of the relationship of nephron filtration rate [single nephron glomerular filtration rate (SNGFR)] and early distal tubular flow rate (V(ED)) while maintaining TGF responsiveness. We used closed-loop assessment of TGF in hydropenia and after acute saline volume expansion (SE; 10% body wt over 1 h) to determine whether 1) temporal adaptation of TGF occurs, 2) adenosine A(1) receptors (A(1)R) mediate TGF responsiveness, and 3) inhibition of TGF affects SNGFR, V(ED), or urinary excretion under these conditions. SNGFR was evaluated in Fromter-Wistar rats by micropuncture in 1) early distal tubules (ambient flow at macula densa), 2) recollected from early distal tubules while 12 nl/min isotonic fluid was added to late proximal tubule (increased flow to macula densa), and 3) from proximal tubules of same nephrons (zero flow to macula densa). SE increased both ambient SNGFR and V(ED) compared with hydropenia, whereas TGF responsiveness (proximal-distal difference in SNGFR, distal SNGFR response to adding fluid to proximal tubule) was maintained, demonstrating TGF adaptation. A(1)R blockade completely inhibited TGF responsiveness during SE and made V(ED) more susceptible to perturbation in proximal tubular flow, but did not alter ambient SNGFR or V(ED). Greater urinary excretion of fluid and Na(+) with A(1)R blockade may reflect additional effects on the distal nephron in hydropenia and SE. In conclusion, A(1)R-independent mechanisms adjust SNGFR and V(ED) to higher values after SE, which facilitates fluid and Na(+) excretion. Concurrently, TGF adapts and stabilizes early distal delivery at the new setpoint in an A(1)R-dependent mechanism.
Assuntos
Taxa de Filtração Glomerular/efeitos dos fármacos , Glomérulos Renais/metabolismo , Túbulos Renais Distais/metabolismo , Túbulos Renais Proximais/metabolismo , Néfrons/metabolismo , Receptor A1 de Adenosina/metabolismo , Cloreto de Sódio/farmacologia , Antagonistas do Receptor A1 de Adenosina/farmacologia , Animais , Retroalimentação Fisiológica , Inulina/metabolismo , Glomérulos Renais/efeitos dos fármacos , Túbulos Renais Distais/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Néfrons/efeitos dos fármacos , Potássio/metabolismo , Ratos , Ratos Wistar , Receptor A1 de Adenosina/efeitos dos fármacos , Sódio/metabolismo , Xantinas/farmacologiaRESUMO
Tubuloglomerular feedback (TGF) stabilizes nephron function from minute to minute and adapts to different steady-state inputs to maintain this capability. Such adaptation inherently renders TGF less efficient at buffering long-term disturbances, but the magnitude of loss is unknown. We undertook the present study to measure the compromise between TGF and TGF adaptation in transition from acute to chronic decline in proximal reabsorption (Jprox). As a tool, we blocked proximal tubule sodium-glucose cotransport with the SGLT2 blocker dapagliflozin in hyperglycemic rats with early streptozotocin diabetes, a condition in which a large fraction of proximal fluid reabsorption owes to SGLT2. Dapagliflozin acutely reduced proximal reabsorption leading to a 70% increase in early distal chloride, a saturated TGF response, and a major reduction in single nephron glomerular filtration rate (SNGFR). Acute and chronic effects on Jprox were indistinguishable. Adaptations to 10-12 days of dapagiflozin included increased reabsorption by Henle's loop, which caused a partial relaxation in the increased tone exerted by TGF that could be explained without desensitization of TGF. In summary, TGF contributes to long-term fluid and salt balance by mediating a persistent decline in SNGFR as the kidney adapts to a sustained decrease in Jprox.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Glomérulos Renais/fisiologia , Túbulos Renais/fisiologia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Compostos Benzidrílicos , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Glucosídeos/farmacologia , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Glomérulos Renais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Transportador 2 de Glucose-Sódio/fisiologia , Estreptozocina/efeitos adversosRESUMO
BACKGROUND/AIMS: Acute kidney injury (AKI) contributes to significant morbidity and mortality in the intensive care unit (ICU). Plasma levels of interleukin (IL)-6 predict the development of AKI and are associated with higher mortality in ICU patients with AKI. Most studies in AKI have focused on the tubulo-interstitium, despite evidence of glomerular involvement. In the following study, our goals were to investigate the expression of IL-6 and its downstream mediators in septic-induced AKI. METHODS: Podocytes were treated in vitro with lipopolysaccharide (LPS) and mice were treated with LPS, and we evaluated IL-6 expression by real-time PCR, ELISA and in situ RNA hybridization. RESULTS: Following LPS stimulation, IL-6 is rapidly and highly induced in cultured podocytes and in vivo in glomeruli and infiltrating leukocytes. Surprisingly, in direct response to exogenous IL-6, podocytes produce lipocalin-2/neutrophil gelatinase-associated lipocalin (Lcn2/Ngal). LPS also potently induces Lcn2/Ngal expression in podocytes in culture and in glomeruli in vivo. Intense Lcn2/Ngal expression is also observed in IL-6 knockout mice, suggesting that while IL-6 may be sufficient to induce glomerular Lcn2/Ngal expression, it is not essential. CONCLUSIONS: The glomerulus is involved in septic AKI, and we demonstrate that podocytes secrete key mediators of AKI including IL-6 and Lcn2/Ngal.
Assuntos
Injúria Renal Aguda/metabolismo , Proteínas de Fase Aguda/biossíntese , Interleucina-6/biossíntese , Glomérulos Renais/metabolismo , Lipocalinas/biossíntese , Lipopolissacarídeos/toxicidade , Proteínas Oncogênicas/biossíntese , Podócitos/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Proteínas de Fase Aguda/metabolismo , Animais , Linhagem Celular Transformada , Células Cultivadas , Interleucina-6/metabolismo , Lipocalina-2 , Lipocalinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Oncogênicas/metabolismo , Podócitos/efeitos dos fármacosRESUMO
Acute kidney injury (AKI) significantly contributes to morbidity and mortality in critically ill patients. AKI is also an independent risk factor for the development and progression of chronic kidney disease. Effective therapeutic strategies for AKI are limited, but emerging evidence indicates a prominent role of mitochondrial dysfunction and altered tubular metabolism in the pathogenesis of AKI. Therefore, a comprehensive, mechanistic understanding of mitochondrial function and renal metabolism in AKI may lead to the development of novel therapies in AKI. In this review, we provide an overview of current state of research on the role of mitochondria and tubular metabolism in AKI from both pre-clinical and clinical studies. We also highlight current therapeutic strategies which target mitochondrial function and metabolic pathways for the treatment of AKI.
RESUMO
The 5/6(th) nephrectomy or ablation/infarction (A/I) preparation has been used as a classic model of chronic kidney disease (CKD). We observed increased kidney oxygen consumption (Q(O2)) and altered renal hemodynamics in the A/I kidney that were normalized after combined angiotensin II (ANG II) blockade. Studies suggest hypoxia inducible factor as a protective influence in A/I. We induced hypoxia-inducible factor (HIF) and HIF target proteins by two different methods, cobalt chloride (CoCl(2)) and dimethyloxalyglycine (DMOG), for the first week after creation of A/I and compared the metabolic and renal hemodynamic outcomes to combined ANG II blockade. We also examined the HIF target proteins expressed by using Western blots and real-time PCR. Treatment with DMOG, CoCl(2), and ANG II blockade normalized kidney oxygen consumption factored by Na reabsorption and increased both renal blood flow and glomerular filtration rate. At 1 wk, CoCl(2) and DMOG increased kidney expression of HIF by Western blot. In the untreated A/I kidney, VEGF, heme oxygenase-1, and GLUT1 were all modestly increased. Both ANG II blockade and CoCl(2) therapy increased VEGF and GLUT1 but the cobalt markedly so. ANG II blockade decreased heme oxygenase-1 expression while CoCl(2) increased it. By real-time PCR, erythropoietin and GLUT1 were only increased by CoCl(2) therapy. Cell proliferation was modestly increased by ANG II blockade but markedly after cobalt therapy. Metabolic and hemodynamic abnormalities were corrected equally by ANG II blockade and HIF therapies. However, the molecular patterns differed significantly between ANG II blockade and cobalt therapy. HIF induction may prove to be protective in this model of CKD.
Assuntos
Angiotensina II/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Falência Renal Crônica/metabolismo , Rim/efeitos dos fármacos , Aminoácidos Dicarboxílicos/farmacologia , Animais , Anidrase Carbônica IX , Anidrases Carbônicas/metabolismo , Cobalto/farmacologia , Indução Enzimática , Transportador de Glucose Tipo 1/biossíntese , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos WistarRESUMO
PURPOSE OF REVIEW: We review some basic homeostatic principles that are frequently disregarded to provide boundary conditions to test any new theory containing new details. Homeostasis as applied to total body salt is discussed with a linear model for salt homeostasis that is extraordinarily simple wherein total body salt drives the salt excretion. The basics of tubuloglomerular feedback (TGF) and its implications for salt homeostasis are then reviewed. RECENT FINDINGS: Advances in the field discussed include new details on the apical and basolateral transport of sodium chloride (NaCl) in the macula densa cells during TGF response, direct evidence of contribution of TGF to renal autoregulation and the description of vasodilatory adenosine A2b receptors in the 'efferent' TGF response. Finally, recent information about the role of proximal tubular microvilli as mechanosensors in the flow-dependent tubular reabsorption as a mechanism to explain glomerulotubular balance is reviewed. SUMMARY: Notwithstanding the complexity of salt balance at a molecular level, the overall salt homeostasis is simple. Various natritropic nerves and hormones stabilize any disturbance in salt balance. A change in glomerular filtration rate (GFR) brought about by these natritropes will be partially counteracted by the impact of TGF on nephron function. Thus, by stabilizing GFR, TGF reduces the usefulness of GFR as an instrument of salt balance, and lessens the efficiency of salt homeostasis.