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1.
Kidney Blood Press Res ; 48(1): 114-123, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36791683

RESUMO

INTRODUCTION: Chronic kidney disease (CKD) is a global health problem with increasing incidence which is closely associated with cardiac dysfunction. In CKD, uremic toxins accumulate as kidney function declines. Additionally, high salt intake is a growing health issue worldwide which can exacerbate kidney disease. In this study, we investigated the effect of reducing plasma levels of protein-bound uremic toxins in a rat model of CKD, challenged with high salt intake and compared the effects to those of conventional treatment using an angiotensin-converting enzyme inhibitor (ACEI). METHODS: In rats, the right kidney and 2/3 of the left kidney were surgically removed (5/6 nephrectomy). Animals were fed a normal-salt diet and randomized to either no treatment (control) or chronic treatment with either the oral absorbent AST-120 to reduce plasma levels of protein-bound uremic toxins or the ACEI enalapril to inhibit angiotensin II signaling for 5 weeks. Following treatment, kidney function was measured before and after a week of high salt intake. Cardiac output and markers of oxidative stress were measured at the end of the study period. RESULTS: Treatment with AST-120 resulted in decreased levels of the uremic toxin indoxyl sulfate, improved cardiac output (mL/min: AST-120 44.9 ± 5.4 compared to control 26.6 ± 2.0; p < 0.05), and decreased urinary oxidative stress. ACEI reduced oxidative stress in kidney tissue and improved the glomerular filtration rate in response to high salt intake (mL/min: ACEI 1.5 ± 0.1; compared to control 1.1 ± 0.1; p < 0.05). Both interventions improved intrarenal oxygen availability (mm Hg: AST-120 42.8 ± 0.8; ACEI 43.2 ± 1.9; compared to control 33.4 ± 1.3; p < 0.05). CONCLUSION: AST-120 administered to reduce plasma levels of uremic toxins, such as indoxyl sulfate, has potential beneficial effects on both cardiac and kidney function. Targeting uremic toxins and angiotensin II signaling simultaneously could be an efficient strategy to target both cardiac and kidney dysfunction in CKD, to further slow progression of disease in patients with CKD.


Assuntos
Insuficiência Renal Crônica , Uremia , Animais , Ratos , Angiotensina II , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Débito Cardíaco , Indicã/farmacologia , Rim , Insuficiência Renal Crônica/tratamento farmacológico , Cloreto de Sódio na Dieta , Uremia/tratamento farmacológico , Toxinas Urêmicas
2.
Cardiorenal Med ; 5(4): 278-88, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26648944

RESUMO

OBJECTIVE: We aimed to explore and validate the longitudinal associations between soluble tumor necrosis factor receptor 1 (sTNFR1), glomerular filtration rate (GFR) progression, and chronic kidney disease (CKD) incidence in two independent community-based cohorts of elderly individuals with prespecified subgroup analyses in individuals without prevalent diabetes. RESEARCH DESIGN AND METHODS: Two community-based cohorts of elderly individuals were used with 5-year follow-up data on estimated GFR: the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 437 men; mean age: 78 years) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 703; mean age: 70 years; 51% women). GFR categories were defined as ≥60, 30-60, and <30 ml/min/1.73 m(2). RESULTS: In longitudinal multivariable logistic regression models adjusted for inflammatory markers and established cardiovascular risk factors, higher serum sTNFR1 was significantly associated with an increased risk to progress to a lower GFR category in both ULSAM and PIVUS [odds ratio (OR) per standard deviation (SD) increase 1.28 (95% CI 1.03-1.60) and OR 1.56 (95% CI 1.30-1.87), respectively]. Also, in subgroup analyses in individuals with a GFR ≥60 ml/min/1.73 m(2) at baseline, higher sTNFRs were associated with incident CKD after 5 years in both cohorts [ULSAM: OR per SD increase 1.49 (95% CI 1.16-1.9) and PIVUS: OR 1.84 (95% CI 1.50-2.26)]. Associations were similar in individuals without diabetes. CONCLUSIONS: Higher circulating sTNFR1 independently predicts the progression to a worse GFR category and CKD incidence in elderly individuals even in the absence of diabetes. Further studies are warranted to investigate the underlying mechanisms, and to evaluate the clinical relevance of our findings.

3.
J Am Soc Nephrol ; 26(2): 328-38, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25183809

RESUMO

Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetes-induced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/fisiopatologia , Fator 1 Induzível por Hipóxia/fisiologia , Animais , Antioxidantes/farmacologia , Cobalto/farmacologia , Óxidos N-Cíclicos/farmacologia , Modelos Animais de Doenças , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Ratos , Ratos Sprague-Dawley , Marcadores de Spin
4.
J Diabetes Sci Technol ; 8(3): 453-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24876605

RESUMO

The incidence of insulinopenic diabetes mellitus is constantly increasing, and in addition, approximately a third of all hyperinsulinemic diabetic patients develop insulinopenia. Optimal glycemic control is essential to minimize the risk for diabetes-induced complications, but the majority of diabetic patients fail to achieve proper long-term glucose levels even in clinical trials, and even more so in clinical practice. Compliance with a treatment regimen is likely to be higher if the procedure is simple, painless, and discreet. Thus, insulin has been suggested for nasal, gastrointestinal, and inhalation therapy, but so far with considerable downsides in effect, side effects, or patient acceptance. The stratum corneum is the main barrier preventing convenient drug administration without the drawbacks of subcutaneous injections. Recently, devices with miniaturized needles have been developed that combine the simplicity and discretion of patch-based treatments, but with the potential of peptide and protein administration. As this review describes, initial comparisons with subcutaneous administration now suggest microneedle patches for active insulin delivery are efficient in maintaining glycemic control. Hollow microneedle technology could also prove to be efficient in systemic as well as local delivery of other macromolecular drugs, such as vaccines.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Sistemas de Liberação de Medicamentos/instrumentação , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Agulhas , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Desenho de Equipamento , Humanos , Injeções Intradérmicas , Miniaturização , Resultado do Tratamento
5.
Adv Exp Med Biol ; 812: 157-163, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24729228

RESUMO

Oxidative stress is closely associated with renal dysfunction following diabetes and hypertension. Angiotensin II (Ang II) can activate the NADPH-oxidase, increasing oxidative stress that is thought to blunt proximal tubular electrolyte transport and thereby oxygen consumption (QO2). We investigated the effect of Ang II on QO2 in immortalized mouse proximal tubular cells over-expressing the NADPH oxidase subunit p22(phox); a model of increased oxidative stress. Cultured cells were exposed to either Ang II or H2O2 for 48 h. QO2 was determined during baseline (113 mmol/l NaCl; transport-dependent QO2) and during sodium-free conditions (transport-independent QO2). Ang II reduced transport-dependent QO2 in wild-types, but not in p22(phox) which also displayed increased QO2 at baseline. Transport-independent QO2 was increased in p22(phox) and Ang II had no additional effect, whereas it increased QO2 in wild-type. Addition of H2O2 reduced transport-dependent QO2 in wild-types, but not in p22(phox). Transport-independent QO2 was unaffected by H2O2. The similar effects of Ang II and H2O2 to reduce transport-dependent QO2 suggest a direct regulatory role of oxidative stress. In accordance, the transport-dependent QO2 was reduced in p22(phox) already during baseline. The effects of Ang II on transport-independent QO2 was not replicated by H2O2, indicating direct regulation via Ang II-receptors independently of oxidative stress. However, the Ang II effect was absent in p22(phox), suggesting that oxidative stress also modulates normal Ang II signaling. In conclusion, Ang II affects both transport-dependent and transport-independent QO2 in proximal tubular cells and may be an important pathway modulating renal QO2.


Assuntos
Angiotensina II/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Animais , Linhagem Celular Transformada , Túbulos Renais Proximais/metabolismo , Camundongos , Estresse Oxidativo
6.
Adv Exp Med Biol ; 789: 9-14, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23852470

RESUMO

Intrarenal tissue hypoxia is an acknowledged common pathway to end-stage renal disease in clinically common conditions associated with development of chronic kidney disease, such as diabetes and hypertension. In diabetic kidneys, increased oxygen metabolism mediated by mitochondrial uncoupling results in decreased kidney oxygen tension (PO2) and contributes to the development of diabetic nephropathy. The present study investigated whether increased intrarenal oxygen metabolism per se can cause intrarenal tissue hypoxia and kidney damage, independently of confounding factors such as hyperglycemia and oxidative stress. Male Sprague-Dawley rats were untreated or treated with either triiodothyronine (T3, 10 g/kg bw/day, subcutaneously for 10 days) or the mitochondria uncoupler dinitrophenol (DNP, 30 mg/kg bw/day, oral gavage for 14 days), after which in vivo kidney function was evaluated in terms of glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Transonic, PAH clearance), cortical PO2 (Clark-type electrodes), kidney oxygen consumption (QO2), and proteinuria. Administration of both T3 and DNP increased kidney QO2 and decreased PO2 which resulted in proteinuria. However, GFR and RBF were unaltered by either treatment. The present study demonstrates that increased kidney metabolism per se can cause intrarenal tissue hypoxia which results in proteinuria. Increased kidney QO2 and concomitantly reduced PO2 may therefore be a mechanism for the development of chronic kidney disease and progression to end-stage renal disease.


Assuntos
Dinitrofenóis/farmacologia , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Nefropatias/metabolismo , Tri-Iodotironina/farmacologia , Animais , Hipóxia Celular/fisiologia , Córtex Renal/patologia , Nefropatias/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Oxigênio/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/fisiologia , Ratos , Ratos Sprague-Dawley
7.
Clin Exp Pharmacol Physiol ; 40(2): 138-47, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23360244

RESUMO

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/patologia
8.
Adv Exp Med Biol ; 765: 185-193, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22879032

RESUMO

Sustained hyperglycemia is closely associated with increased risk to develop nephropathy. We have previously reported alterations in the intrarenal oxygen metabolism already after the early onset of diabetes. Furthermore, formation of advanced glycation end-products (AGE) is postulated as a major contributor to diabetic nephropathy. We therefore investigated the possible relationship between altered oxygen metabolism and AGE in diabetic kidneys.Normoglycemic and streptozotocin-diabetic rats with and without chronic treatment with aminoguanidine (AGE inhibitor; 600 mg/kg bw/24 h in drinking water) or L-N(6)-(1-Iminoethyl)lysine (L-NIL, iNOS inhibitor, 1 mg/kg bw/24 h in drinking water) were studied 2 weeks after induction of diabetes. Glomerular filtration rate (GFR) was estimated by inulin clearance, oxygen tension (pO(2)) and interstitial pH by microelectrodes and regional renal blood flow (RBF) by laser-Doppler. Histological changes were evaluated on fixed tissue.Glomerular hyperfiltration was unaffected by aminoguanidine, whereas L-NIL normalized GFR in diabetic rats. pO(2) and interstitial pH, but not RBF, were lower in both kidney cortex and medulla compared to control rats, but was unaffected by both chronic treatments. Urinary protein excretion was higher in diabetic rats and unaffected by L-NIL, whereas aminoguanidine paradoxically increased this parameter. Damage scores were similar in all groups.In conclusion, diabetes-induced alterations in intrarenal oxygen metabolism are independent of the AGE pathway, and precede any morphological changes. These findings highlight the early stage of diabetes as being a metabolic disorder also in the kidney.


Assuntos
Complicações do Diabetes/etiologia , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Produtos Finais de Glicação Avançada/metabolismo , Hipóxia/patologia , Rim/patologia , Animais , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Inibidores Enzimáticos/uso terapêutico , Taxa de Filtração Glomerular , Guanidinas/uso terapêutico , Hipóxia/metabolismo , Rim/metabolismo , Testes de Função Renal , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Endogâmicos WF
9.
PLoS One ; 7(7): e39635, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22768304

RESUMO

Increased O(2) metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O(2) consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (-30-50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Canais Iônicos/metabolismo , Córtex Renal/metabolismo , Mitocôndrias/metabolismo , Translocases Mitocondriais de ADP e ATP/metabolismo , Proteínas Mitocondriais/metabolismo , Estresse Oxidativo , Difosfato de Adenosina/genética , Difosfato de Adenosina/metabolismo , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Técnicas de Silenciamento de Genes , Guanosina Difosfato/genética , Guanosina Difosfato/metabolismo , Canais Iônicos/genética , Córtex Renal/patologia , Masculino , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/genética , Mitocôndrias/patologia , Translocases Mitocondriais de ADP e ATP/genética , Proteínas Mitocondriais/genética , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína Desacopladora 2
10.
Am J Physiol Regul Integr Comp Physiol ; 301(5): R1229-41, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21832206

RESUMO

Hypertension is closely associated with progressive kidney dysfunction, manifested as glomerulosclerosis, interstitial fibrosis, proteinuria, and eventually declining glomerular filtration. The postulated mechanism for development of glomerulosclerosis is barotrauma caused by increased capillary pressure, but the reason for development of interstitial fibrosis and the subsequently reduced kidney function is less clear. However, it has been hypothesized that tissue hypoxia induces fibrogenesis and progressive renal failure. This is very interesting, since recent reports highlight several different mechanisms resulting in altered oxygen handling and availability in the hypertensive kidney. Such mechanisms include decreased renal blood flow due to increased vascular tone induced by ANG II that limits oxygen delivery and increases oxidative stress, resulting in increased mitochondrial oxygen usage, increased oxygen usage for tubular electrolyte transport, and shunting of oxygen from arterial to venous blood in preglomerular vessels. It has been shown in several studies that interventions to prevent oxidative stress and to restore kidney tissue oxygenation prevent progression of kidney dysfunction. Furthermore, inhibition of ANG II activity, by either blocking ANG II type 1 receptors or angiotensin-converting enzyme, or by preventing oxidative stress by administration of antioxidants also results in improved blood pressure control. Therefore, it seems likely that tissue hypoxia in the hypertensive kidney contributes to progression of kidney damage, and perhaps also persistence the high blood pressure.


Assuntos
Hipertensão/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , Estresse Oxidativo , Consumo de Oxigênio , Oxigênio/metabolismo , Angiotensina II/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Progressão da Doença , Fibrose , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipóxia/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Nefropatias/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo
11.
Diabetes Metab Res Rev ; 27(7): 697-704, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21618400

RESUMO

BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether the genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2 h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and real-time quantitative polymerase chain reaction. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p < 0.01) after 2 h of C-peptide exposure, with the majority of these genes repressed (83%). Real-time quantitative polymerase chain reaction validation supported a trend of several G protein-coupled receptors being activated, and certain transcription factors being repressed. Also, C-peptide repressed the transcription of genes associated with the pathways of circulatory and inflammatory diseases. CONCLUSION: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type 1 diabetes, and support a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.


Assuntos
Peptídeo C/farmacologia , Diabetes Mellitus Experimental/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/metabolismo , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
12.
Clin Exp Pharmacol Physiol ; 38(7): 474-80, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21545630

RESUMO

1. Intrarenal oxygen availability is the balance between supply, mainly dependent on renal blood flow, and demand, determined by the basal metabolic demand and the energy-requiring tubular electrolyte transport. Renal blood flow is maintained within close limits in order to sustain stable glomerular filtration, so increased intrarenal oxygen consumption is likely to cause tissue hypoxia. 2. The increased oxygen consumption is closely linked to increased oxidative stress, which increases mitochondrial oxygen usage and reduces tubular electrolyte transport efficiency, with both contributing to increased total oxygen consumption. 3. Tubulointerstitial hypoxia stimulates the production of collagen I and α-smooth muscle actin, indicators of increased fibrogenesis. Furthermore, the hypoxic environment induces epithelial-mesenchymal transdifferentiation and aggravates fibrosis, which results in reduced peritubular blood perfusion and oxygen delivery due to capillary rarefaction. 4. Increased oxygen consumption, capillary rarefaction and increased diffusion distance due to the increased fibrosis per se further aggravate the interstitial hypoxia. 5. Recently, it has been demonstrated that hypoxia simulates the infiltration and maturation of immune cells, which provides an explanation for the general inflammation commonly associated with the progression of chronic kidney disease. 6. Therapies targeting interstitial hypoxia could potentially reduce the progression of chronic renal failure in millions of patients who are otherwise likely to eventually present with fully developed end-stage renal disease.


Assuntos
Nefropatias/metabolismo , Nefrite Intersticial/metabolismo , Animais , Hipóxia Celular/fisiologia , Humanos , Nefropatias/patologia , Nefrite Intersticial/patologia , Oxigênio/metabolismo , Circulação Renal/fisiologia
13.
Am J Physiol Renal Physiol ; 299(2): F380-6, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20519374

RESUMO

In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. To elucidate the pathophysiology of uremic states, we investigated the effect of indoxyl sulfate (IS), a representative uremic toxin, on oxygen metabolism in tubular cells. We demonstrated an increase in oxygen consumption by IS in freshly isolated rat and human proximal tubules. Studies utilizing ouabain, the Na-K-ATPase inhibitor, and apocynin, the NADPH oxidase inhibitor, as well as the in vivo gene-silencing approach to knock down p22(phox) showed that the increase in tubular oxygen consumption by IS is dependent on Na-K-ATPase and oxidative stress. We investigated whether the enhanced oxygen consumption led to subsequent hypoxia of the kidney. An increase in serum IS concentrations in rats administered indole was associated with a decrease in renal oxygenation (8 h). The remnant kidney in rats developed hypoxia at 16 wk. Treatment of the rats with AST-120, an oral adsorbent that removes uremic toxins, reduced serum IS levels and improved oxygenation of the kidney. Amelioration of hypoxia in the remnant kidney was associated with better renal functions and less histological injury. Reduction of serum IS levels also led to a decrease in oxidative stress in the kidney. Our ex vivo and in vivo studies implicated that uremic states may deteriorate renal dysfunction via dysregulating oxygen metabolism in tubular cells. The abnormal oxygen metabolism in tubular cells by uremic toxins was, at least in part, mediated by oxidative stress.


Assuntos
Indicã/metabolismo , Falência Renal Crônica/metabolismo , Túbulos Renais Proximais/metabolismo , Estresse Oxidativo , Consumo de Oxigênio , Uremia/metabolismo , Acetofenonas/farmacologia , Animais , Carbono/farmacologia , Hipóxia Celular , Modelos Animais de Doenças , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Humanos , Indicã/sangue , Indóis , Falência Renal Crônica/etiologia , Falência Renal Crônica/fisiopatologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/fisiopatologia , Masculino , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Nefrectomia , Ouabaína/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Óxidos/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/metabolismo , Fatores de Tempo , Uremia/etiologia , Uremia/fisiopatologia
14.
Diabetes Metab Res Rev ; 26(3): 193-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20225182

RESUMO

AIMS/HYPOTHESIS: C-peptide reduces renal damage in diabetic patients and experimental animal models. In vitro studies suggest that the renal effects of C-peptide may, in part, be explained by stimulation of Na(+)/K(+)-ATPase activity. However, the responses of Na(+)/K(+)-ATPase expression in the kidney of diabetic animals to C-peptide administration remain unclear. The aim of this study was to clarify the responses. METHODS: Type 1 diabetic rats were produced by injecting streptozotocin (STZ), and some of the rats were treated with either C-peptide or insulin by the aid of an osmotic pump for 1 week. The mRNA expression and immunohistochemical localization of Na(+)/K(+)-ATPase alpha1-, alpha2- and beta3-subunits were investigated in the kidney of these rats. RESULTS: Na(+)/K(+)-ATPase alpha1-subunit was abundantly expressed in the medullary collecting ducts of control animals, but the expression was markedly decreased in the diabetic state with concomitant decrease in its mRNA expression. Similar decreases were observed in the insulin-treated diabetic rats, whereas in the C-peptide-treated diabetic rats, there was no reduction in the alpha1-expression. The beta3-subunit was expressed in podocytes and parietal cells in the glomeruli, vascular endothelial cells, and cortical collecting ducts, but lesser signals were observed in the proximal and distal tubules. However, the beta3-subunit did not appear to be affected by the diabetic state. CONCLUSIONS: Diabetes selectively reduced Na(+)/K(+)-ATPase alpha1-subunit expression and abundance. Chronic administration of C-peptide prevented this decrease. This implies a role for C-peptide in the long-term regulation of Na(+)/K(+)-ATPase function.


Assuntos
Peptídeo C/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Rim/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Análise de Variância , Animais , Glicemia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/genética , Ensaio de Imunoadsorção Enzimática , Hipoglicemiantes/uso terapêutico , Imuno-Histoquímica , Insulina/sangue , Insulina/uso terapêutico , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , ATPase Trocadora de Sódio-Potássio/genética
15.
Rev Diabet Stud ; 6(3): 203-10, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20039009

RESUMO

Proinsulin C-peptide has been found to exert beneficial effects in many tissues affected by diabetic microvascular complications, including the kidneys. Glomerular hyperfiltration and microalbuminuria are early markers of diabetic nephropathy. C-peptide at physiological concentrations effectively reduces diabetes-induced glomerular hyperfiltration via constriction of the afferent arteriole, dilation of the efferent arteriole, and inhibition of tubular reabsorption in experimental models of type 1 diabetes. The glomerular hypertrophy and mesangial matrix expansion seen in early diabetes can be reduced or prevented by C-peptide administration, possibly via interference with TGF-beta1 and TNFalpha signaling. Several of C-peptide's reno-protective effects have been confirmed in human studies; reduced glomerular hyperfiltration and diminished urinary albumin excretion have been documented in type 1 diabetes patients receiving replacement doses of C-peptide for periods of up to 3 months. In this review, we critically summarize the current state of knowledge regarding C-peptide's renal effects, and discuss possible mechanisms of its beneficial effects in diabetic nephropathy.

16.
Am J Physiol Renal Physiol ; 297(5): F1265-72, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19741019

RESUMO

C-peptide reduces diabetes-induced glomerular hyperfiltration in diabetic patients and experimental animal models. However, the mechanisms mediating the beneficial effect of C-peptide remain unclear. We investigated whether altered renal afferent-efferent arteriole tonus or alterations in tubular Na+ transport (T(Na)) in response to C-peptide administration mediate the reduction of diabetes-induced glomerular hyperfiltration. Glomerular filtration rate, filtration fraction, total and cortical renal blood flow, total kidney O2 consumption (QO2), T(Na), fractional Na+ and Li+ excretions, and tubular free-flow and stop-flow pressures were measured in anesthetized adult male normoglycemic and streptozotocin-diabetic Sprague-Dawley rats. The specific effect of C-peptide on transport-dependent QO2 was investigated in vitro in freshly isolated proximal tubular cells. C-peptide reduced glomerular filtration rate (-24%), stop-flow pressure (-8%), and filtration fraction (-17%) exclusively in diabetic rats without altering renal blood flow. Diabetic rats had higher baseline T(Na) (+40%), which was reduced by C-peptide. Similarly, C-peptide increased fractional Na+ (+80%) and Li+ (+47%) excretions only in the diabetic rats. None of these parameters was affected by vehicle treatments in either group. Baseline QO2 was 37% higher in proximal tubular cells from diabetic rats than controls and was normalized by C-peptide. C-peptide had no effect on ouabain-pretreated diabetic cells from diabetic rats. C-peptide reduced diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of the glomerular net filtration pressure. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.


Assuntos
Peptídeo C/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Túbulos Renais/metabolismo , Sódio/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Arteríolas/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Túbulos Renais/efeitos dos fármacos , Lítio/metabolismo , Masculino , Tono Muscular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Ouabaína/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Circulação Renal/efeitos dos fármacos
17.
Adv Exp Med Biol ; 645: 193-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19227471

RESUMO

Exogenous C-peptide administration has beneficial effects in many of the tissues commonly affected by diabetic complications. Diabetes-induced circulatory impairments such as decreased blood flow are prevented by C-peptide, possibly via Ca2+-mediated effects on nitric oxide release. C-peptide also improves diabetes-induced erythrocyte deformability, which likely improves oxygen availability and uptake in affected tissues. Furthermore, C-peptide prevents diabetic neuropathy via improvements of endoneural blood flow and by preventing axonal swelling. In the kidney, C-peptide normalizes the diabetes-induced increase in oxygen consumption via inhibition of the Na+/K+-ATPase. Surprisingly, C-peptide has also been shown to prevent complications in patients with type II diabetes. Taken together, these results may indicate that C-peptide treatment has the potential to reduce the prevalence of diabetic complications. In this paper, the current knowledge regarding these beneficial effects of C-peptide administered to diabetic subjects will be reviewed briefly.


Assuntos
Peptídeo C/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Insulina/metabolismo , Oxigênio/metabolismo , Animais , Humanos , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico/metabolismo
18.
Adv Exp Med Biol ; 645: 205-12, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19227473

RESUMO

Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively. UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls. In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Saúde , Canais Iônicos/metabolismo , Rim/metabolismo , Proteínas Mitocondriais/metabolismo , Animais , Estudos de Casos e Controles , Diabetes Mellitus Experimental/induzido quimicamente , Regulação da Expressão Gênica , Canais Iônicos/genética , Masculino , Proteínas Mitocondriais/genética , Isoformas de Proteínas/metabolismo , Ratos , Ratos Wistar , Estreptozocina/farmacologia , Proteína Desacopladora 1 , Proteína Desacopladora 2 , Proteína Desacopladora 3
19.
Adv Exp Med Biol ; 645: 219-25, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19227475

RESUMO

Tubular electrolyte transport accounts for a major part of the oxygen consumed by the normal kidney. We have previously reported a close association between diabetes and increased oxygen usage, partly due to increased tubular electrolyte transport secondary to glomerular hyperfiltration during the early onset of diabetes. Several studies have shown that acute administration of C-peptide to diabetic rats with glomerular hyperfiltration results in normalized glomerular filtration rate (GFR). In this study, we validated a novel method for precise and repetitive GFR measurements in conscious rats and used C-peptide injection in diabetic rats for evaluation. First, GFR was determined in normoglycemic control rats before and after C-peptide administration. Thereafter, all rats were made diabetic by an i.v. streptozotocin injection. Fourteen days later, GFR was again determined before and after C-peptide administration. GFR was estimated from plasma clearance curves using a single bolus injection of FITC-inulin, followed by serial blood sampling over 155 min. FITC-inulin clearance was calculated using non-compartmental pharmacokinetic data analysis. Baseline GFR in normoglycemic controls was 2.10 +/- 0.18 ml/min, and was unaffected by C-peptide (2.23 +/- 0.14 ml/min). Diabetic rats had elevated GFR (3.06 +/- .034 ml/min), which was normalized by C-peptide (2.35 +/- 0.30 ml/min). In conclusion, the used method for estimation of GFR in conscious animals result in values that are in good agreement with those obtained from traditional GFR measurements on anaesthetized rats. However, multiple measurements from the same conscious subject can be obtained using this method. Furthermore, as previously shown on anaesthetized rats, C-peptide also normalizes GFR in hyperfiltrating conscious diabetic rats.


Assuntos
Peptídeo C/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley
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