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Rhabdomyolysis is characterized by muscle damage and leads to acute kidney injury (AKI). Clinical and experimental studies suggest that glycogen synthase kinase 3ß (GSK3ß) inhibition protects against AKI basically through its critical role in tubular epithelial cell apoptosis, inflammation and fibrosis. Treatment with a single dose of lithium, an inhibitor of GSK3ß, accelerated recovery of renal function in cisplatin and ischemic/reperfusion-induced AKI models. We aimed to evaluate the efficacy of a single dose of lithium in the treatment of rhabdomyolysis-induced AKI. Male Wistar rats were allocated to four groups: Sham, received saline 0.9% intraperitoneally (IP); lithium (Li), received a single IP injection of lithium chloride (LiCl) 80 mg/kg body weight (BW); glycerol (Gly), received a single dose of glycerol 50% 5 mL/kg BW intramuscular (IM); glycerol plus lithium (Gly+Li), received a single dose of glycerol 50% IM plus LiCl IP injected 2 hours after glycerol administration. After 24 hours, we performed inulin clearance experiments and collected blood / kidney / muscle samples. Gly rats exhibited renal function impairment accompanied by kidney injury, inflammation and alterations in signaling pathways for apoptosis and redox state balance. Gly+Li rats showed a remarkable improvement in renal function as well as kidney injury score, diminished CPK levels and an overstated decrease of renal and muscle GSK3ß protein expression. Furthermore, administration of lithium lowered the amount of macrophage infiltrate, reduced NFκB and caspase renal protein expression and increased the antioxidant component MnSOD. Lithium treatment attenuated renal dysfunction in rhabdomyolysis-associated AKI by improving inulin clearance and reducing CPK levels, inflammation, apoptosis and oxidative stress. These therapeutic effects were due to the inhibition of GSK3ß and possibly associated with a decrease in muscle injury.
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Lesión Renal Aguda , Rabdomiólisis , Ratas , Masculino , Animales , Litio/uso terapéutico , Litio/farmacología , Ratas Wistar , Glucógeno Sintasa Quinasa 3 beta , Glicerol/farmacología , Inulina/farmacología , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/tratamiento farmacológico , Rabdomiólisis/complicaciones , Rabdomiólisis/tratamiento farmacológico , Rabdomiólisis/inducido químicamente , Riñón/metabolismo , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , ApoptosisRESUMEN
Acute kidney injury (AKI) alters renal hemodynamics, leading to tubular injury, activating pathways of inflammation, proliferation, and cell death. The initial damage caused to renal tissue after an ischemia/reperfusion (I/R) injury exerts an important role in the pathogenesis of the course of AKI, as well as in the predisposition to chronic kidney disease. Vitamin D deficiency has been considered a risk factor for kidney disease and it is associated with tubulointerstitial damage, contributing to the progression of kidney disease. Obesity is directly related to diabetes mellitus and hypertension, the main metabolic disorders responsible for the progression of kidney disease. Furthermore, the expansion of adipose tissue is described as an important factor for increased secretion of pro-inflammatory cytokines and their respective influence on the progression of kidney disease. We aimed to investigate the influence of vitamin D deficiency and obesity on the progression of renal disease in a murine model of renal I/R. Male Wistar rats underwent renal I/R surgery on day 45 and followed until day 90 of the protocol. We allocated the animals to four groups according to each diet received: standard (SD), vitamin D-depleted (VDD), high fat (HFD), or high fat vitamin D-depleted (HFDV). At the end of 90 days, we observed almost undetectable levels of vitamin D in the VDD and HFDV groups. In addition, HFD and HFDV groups presented alterations in the anthropometric and metabolic profile. The combination of vitamin D deficiency and obesity contributed to alterations of functional and hemodynamic parameters observed in the HFDV group. Moreover, this combination favored the exacerbation of the inflammatory process and the renal expression of extracellular matrix proteins and phenotypic alteration markers, resulting in an enlargement of the tubulointerstitial compartment. All these changes were associated with an increased renal expression of transforming growth factor ß and reduced expression of the vitamin D receptor. Our results show that the synergistic effect of obesity and vitamin D deficiency exacerbated the hemodynamic and morphological changes present in the evolution of renal disease induced by I/R.
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Background: Tenofovir disoproxil fumarate (TDF), a widely prescribed component in antiretroviral regimens, has been associated with nephrotoxicity. Nebivolol is a third generation selective ß-1 adrenergic receptor blocker and may protect renal structure and function through the suppression of oxidative stress and enhancement of nitric oxide (NO) synthesis. We aimed to investigate whether nebivolol could be an effective therapeutic strategy to mitigate tenofovir-induced nephrotoxicity. Methods: We allocated Wistar rats to four groups: control (C), received a standard diet for 30 days; NBV, received a standard diet for 30 days added with nebivolol (100 mg/kg food) in the last 15 days; TDF, received a standard diet added with tenofovir (300 mg/kg food) for 30 days; and TDF+NBV, received a standard diet added with tenofovir for 30 days and nebivolol in the last 15 days. Results: Long-term exposure to tenofovir led to impaired renal function, induced hypertension, endothelial dysfunction and oxidative stress. Nebivolol treatment partially recovered glomerular filtration rate, improved renal injury, normalized blood pressure and attenuated renal vasoconstriction. Administration of nebivolol contributed to reductions in asymmetric dimethylarginine (ADMA) levels as well as increases in endothelial nitric oxide sintase (eNOS) accompanied by renin-angiotensin-aldosterone system downregulation and decreases in macrophage and T-cells infiltrate. Furthermore, nebivolol was responsible for the maintenance of the adequate balance of thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and it was associated with reductions in NADPH oxidase (NOX) subunits. Conclusion: Nebivolol holds multifaceted actions that promote an advantageous option to slow the progression of kidney injury in tenofovir-induced nephrotoxicity.
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Chronic kidney disease (CKD) remains a global public health problem. The initial damage after ischemia/reperfusion (I/R) injury plays an important role in the pathogenesis of acute kidney injury (AKI) and predisposition to CKD. Several studies have been showing that nontraditional risk factors such as AKI and hypovitaminosis D could also be involved in CKD progression. Vitamin D deficiency (VDD) is associated with hemodynamic changes, activation of inflammatory pathways and renal disease progression (RDP) following I/R-AKI. Strategies for prevention and/or slowing RDP have been determined and the sufficiency of vitamin D has been emerging as a renoprotective factor in many diseases. Therefore, we investigated the effect of the restoration of vitamin D levels in the progression of I/R injury (IRI) in rats previously deficient in vitamin D. On day 30, male Wistar rats were submitted to bilateral 45 min IRI and divided into three groups: IRI, standard diet for 120 days; VDD+IRI, vitamin D-free diet for 120 days; and VDD+IRI+R, vitamin D-free diet in the first 30 days and just after I/R, we reintroduced the standard diet in the last 90 days. After the 120-day protocol, VDD+IRI+R rats presented an improvement in the renal function and renal protein handling followed by a smaller fractional interstitial area. Furthermore, those animals exhibited a reestablishment regarding the hemodynamic parameters and plasma levels of aldosterone, urea and PTH. In addition, the restoration of vitamin D levels reestablished the amount of MCP1 and the renal expressions of CD68+ and CD3+ cells in the VDD+IRI+R rats. Also, VDD+IRI+R rats showed a restoration regarding the amount of collagen type III and renal expressions of fibronectin, vimentin and α-SMA. Such changes were also accompanied by a reestablishment on the renal expression of VDR, Klotho, JG12, and TGF-ß1. Our findings indicate that the restoration of vitamin D levels not only improved the renal function and hemodynamics but also reduced the inflammation and fibrosis lesions observed in I/R-AKI associated with VDD. Thus, monitoring of vitamin D status as well as its replacement in the early stages of kidney injury may be a therapeutic alternative in the mitigation of renal disease progression.
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Although several studies have demonstrated that the male gender represents an independent risk factor for renal disease, evidence shows that androgens exert renal protective actions. The findings are controversial and no studies have evaluated the effects of orchiectomy and testosterone replacement on glycerol-induced renal injury. Male Wistar rats were submitted to orchiectomy or sham surgery and divided into four groups: SC, sham control rats injected with NaCl; SG, sham rats injected with glycerol; OG, orchiectomized rats injected with glycerol; OGT, orchiectomized rats injected with glycerol and testosterone. Testosterone was administered daily for 14 days in the OGT group. After 11 days of testosterone replacement in the OGT group, SC rats were submitted to a saline injection, while SG, OG and OGT rats received glycerol. All rats were euthanized three days after injections. OG rats presented higher serum creatinine and urea, and sodium excretion, compared to SC and SG, while testosterone attenuated these changes. Acute tubular necrosis was also mitigated by testosterone. Renal immunostaining for macrophages, lymphocytes and NF-κB was higher in OG compared to SC and SG. In addition, renal interleukin-1ß, Caspase 3 and AT1 gene expression was higher in OG rats compared to SG. Testosterone attenuated these alterations, except the NF-κB immunostaining. The renal NO was lower in OG rats compared to SG. Only the OG rats presented decreases in serum NO and renal HO-1, and increased TNF-α, angiotensinogen and AT1 expression compared to SC. We conclude that orchiectomy worsened glycerol-induced kidney injury, while testosterone attenuated this renal damage.
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Testosterona , Lesión Renal Aguda , Animales , Glicerol , Masculino , Orquiectomía , Ratas , Ratas WistarRESUMEN
Chronic kidney disease (CKD) has been considered a major public health issue. In addition to cardiovascular diseases and infections, hypovitaminosis D has been considered a non-traditional aggravating factor for CKD progression. Interstitial fibrosis is a hallmark of CKD strongly correlated with deterioration of renal function. Transforming growth factor ß (TGF-ß) is the major regulatory profibrotic cytokine in CKD. Many injurious stimuli converge on the TGF-ß pathway, which has context-dependent pleiotropic effects and interacts with several related renal fibrosis formation (RFF) pathways. Epidermal growth factor receptor (EGFR) is critically involved in CKD progression, exerting a pathogenic role in RFF associated with TGF-ß-related fibrogenesis. Among others, EGFR pathway can be activated by a disintegrin and a metalloproteinase known as tumor necrosis factor α-converting enzyme (TACE). Currently no effective therapy is available to completely arrest RFF and slow the progression of CKD. Therefore, we investigated the effects of a double treatment with losartan potassium (L), an AT1R antagonist, and the tyrosine kinase inhibitor erlotinib (E) on the alternative pathway of RFF related to TACE-dependent EGFR activation in 5/6-nephrectomized rats under vitamin D deficiency (D). During the 90-day protocol, male Wistar rats under D, were submitted to 5/6 nephrectomy (N) on day 30 and randomized into four groups: N+D, no treatment; N+D+L, received losartan (50 mg/kg/day); N+D+E, received erlotinib (6 mg/kg/day); N+D+L+E received losartan+erlotinib treatment. N+D+L+E data demonstrated that the double treatment with losartan+erlotinib not only blocked the TACE-dependent EGF receptor activation but also prevented the expression of TGF-ß, protecting against RFF. This renoprotection by losartan+erlotinib was corroborated by a lower expression of ECM proteins and markers of phenotypic alteration as well as a lesser inflammatory cell infiltrate. Although erlotinib alone has been emerging as a renoprotective drug, its association with losartan should be considered as a potential therapeutic strategy on the modulation of RFF.
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Invasive fungal infections (IFI) is a worldwide serious health problem and Amphotericin B (AmB) has been considered the drug of choice for IFI treatment. Despite its efficacy, clinical use of AmB has been associated with renal toxicity. Some lines of evidence have shown that an extemporaneous lipid emulsion preparation of AmB (AmB/LE) was able to attenuate nephrotoxicity, presenting similar benefits at a lower cost. Studies have been demonstrating that hypovitaminosis D may hasten the progression of kidney disease and reflect on a worse prognosis in cases of drug-induced nephrotoxicity. In view of the high worldwide incidence of hypovitaminosis D, the aim of this study was to investigate whether vitamin D deficiency may induce AmB/LE-related nephrotoxicity. Wistar rats were divided into four groups: control, received a standard diet for 34 days; AmB/LE, received a standard diet for 34 days and AmB/LE (5 mg/kg/day) intraperitoneally in the last 4 days; VDD, received a vitamin D-free diet for 34 days; and VDD+AmB/LE, received a vitamin D-free diet for 34 days and AmB/LE as described. At the end of the protocol, animals were euthanized and blood, urine and renal tissue samples were collected in order to evaluate AmB/LE effects on renal function and morphology. Association of AmB/LE and vitamin D deficiency led to diminished glomerular filtration rate and increased tubular injury, evidenced by reduced renal protein expression of NaPi-IIa and TRPM6 leading to hyperphosphaturia / hypermagnesuria. VDD+AmB/LE rats also presented alterations in the PTH-Klotho-FGF-23 signaling axis, urinary concentrating defect and hypertension, probably due to an inappropriate activation of the renin-angiotensin-aldosterone system. Hence, it is important to monitor vitamin D levels in AmB/LE treated patients, since vitamin D deficiency induces AmB/LE nephrotoxicity.
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Anfotericina B/efectos adversos , Antifúngicos/efectos adversos , Riñón/efectos de los fármacos , Deficiencia de Vitamina D/complicaciones , Animales , Pruebas de Función Renal , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Masculino , Ratas Wistar , Factores de RiesgoRESUMEN
IMPACT STATEMENT: To date, no studies have been found evaluating the effects of physical exercise on renal function and structure changes in ovariectomized rats with type 1 diabetes. Therefore, this work emerges with an important tool for strengthening and expanding innovative research on exercise with potential for the prevention of renal diseases in ovariectomized diabetic rats, and future development of studies that seek to increase scientific knowledge about the beneficial effects of physical exercise on renal diseases in humans.
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Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/prevención & control , Ovariectomía , Condicionamiento Físico Animal , Animales , Glucemia/análisis , Creatinina/sangre , Estradiol/sangre , Terapia por Ejercicio , Femenino , Ovariectomía/efectos adversos , Ratas , Ratas WistarRESUMEN
The pathogenesis of chronic kidney disease (CKD) involves a very complex interaction between hemodynamic and inflammatory processes, leading to glomerular/vascular sclerosis, and fibrosis formation with subsequent evolution to end-stage of renal disease. Despite efforts to minimize the progression of CKD, its incidence and prevalence continue to increase. Besides cardiovascular diseases and infections, several studies demonstrate that vitamin D status could be considered as a non-traditional risk factor for the progression of CKD. Therefore, we investigated the effects of vitamin D deficiency (VDD) in the course of moderate CKD in 5/6 nephrectomized rats (Nx). Adult male Wistar rats underwent Sham surgery or Nx and were subdivided into the following four groups: Sham, receiving standard diet (Sham); Sham VDD, receiving vitamin D-free diet (VDD); Nx, receiving standard diet (Nx); and VDD+Nx, receiving vitamin D-free diet (VDD+Nx). Sham or Nx surgeries were performed 30 days after standard or vitamin D-free diets administration. After validation of vitamin D depletion, we considered only Nx and VDD+Nx groups for the following studies. Sixty days after surgeries, VDD+Nx rats exhibited hypertension, a greater decline in renal function and plasma FGF-23 levels, renal hypertrophy, as well as higher plasma levels of PTH and aldosterone. In addition, those animals presented more significant chronic tubulointerstitial changes (cortical interstitial expansion/inflammation/fibrosis), higher expression of collagen IV, fibronectin and α-smooth muscle actin, and lower expressions of JG12 and M2 macrophages. Also, VDD+Nx rats had greater infiltration of inflammatory cells (M1 macrophages and T-cells). Such changes were accompanied by higher expression of TGF-ß1 and angiotensinogen and decreased expression of VDR and Klotho protein. Our observations indicate that vitamin D deficiency impairs the renal function and worsens the renovascular and morphological changes, aggravating the features of moderate CKD in 5/6 nephrectomized rats.
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The aim of this study is to evaluate the effects of regular moderate exercise training initiated previously or after induction of diabetes mellitus on renal oxidative stress and inflammation in STZ-induced diabetic female rats. For this purpose, Wistar rats were divided into five groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD), trained diabetic (TD), and previously trained diabetic (PTD). Only the PTD group was submitted to treadmill running for 4 weeks previously to DM induction with streptozotocin (40 mg/kg, i.v). After confirming diabetes, the PTD, TD, and TC groups were submitted to eight weeks of exercise training. At the end of the training protocol, we evaluated the following: glycosuria, body weight gain, plasma, renal and urinary levels of nitric oxide and thiobarbituric acid reactive substances, renal glutathione, and immunolocalization of lymphocytes, macrophages, and nuclear factor-kappa B (NF-κB/p65) in the renal cortex. The results showed that exercise training reduced glycosuria, renal TBARS levels, and the number of immune cells in the renal tissue of the TD and PTD groups. Of note, only previous exercise increased weight gain and urinary/renal NO levels and reduced NF-κB (p65) immunostaining in the renal cortex of the PTD group. In conclusion, our study shows that exercise training, especially when initiated previously to diabetes induction, promotes protective effects in diabetic kidney by reduction of renal oxidative stress and inflammation markers in female Wistar rats.
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Diabetes Mellitus Experimental/metabolismo , Inflamación/metabolismo , Riñón/metabolismo , Estrés Oxidativo/fisiología , Condicionamiento Físico Animal/fisiología , Animales , Biomarcadores/metabolismo , Glucemia/metabolismo , Peso Corporal/fisiología , Femenino , FN-kappa B/metabolismo , Ratas , Ratas WistarRESUMEN
BACKGROUND: Mesenchymal stromal cells (MSCs) represent an option for the treatment of acute kidney injury (AKI). It is known that young stem cells are better than are aged stem cells at reducing the incidence of the senescent phenotype in the kidneys. The objective of this study was to determine whether AKI leads to premature, stress-induced senescence, as well as whether human umbilical cord-derived MSCs (huMSCs) can prevent ischaemia/reperfusion injury (IRI)-induced renal senescence in rats. METHODS: By clamping both renal arteries for 45 min, we induced IRI in male rats. Six hours later, some rats received 1 × 106 huMSCs or human adipose-derived MSCs (aMSCs) intraperitoneally. Rats were euthanised and studied on post-IRI days 2, 7 and 49. RESULTS: On post-IRI day 2, the kidneys of huMSC-treated rats showed improved glomerular filtration, better tubular function and higher expression of aquaporin 2, as well as less macrophage infiltration. Senescence-related proteins (ß-galactosidase, p21Waf1/Cip1, p16INK4a and transforming growth factor beta 1) and microRNAs (miR-29a and miR-34a) were overexpressed after IRI and subsequently downregulated by the treatment. The IRI-induced pro-oxidative state and reduction in Klotho expression were both reversed by the treatment. In comparison with huMSC treatment, the treatment with aMSCs improved renal function to a lesser degree, as well as resulting in a less pronounced increase in the renal expression of Klotho and manganese superoxide dismutase. Treatment with huMSCs ameliorated long-term kidney function after IRI, minimised renal fibrosis, decreased ß-galactosidase expression and increased the expression of Klotho. CONCLUSIONS: Our data demonstrate that huMSCs attenuate the inflammatory and oxidative stress responses occurring in AKI, as well as reducing the expression of senescence-related proteins and microRNAs. Our findings broaden perspectives for the treatment of AKI.
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Lesión Renal Aguda/terapia , Sangre Fetal/metabolismo , Glucuronidasa/genética , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Daño por Reperfusión/terapia , Lesión Renal Aguda/genética , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Animales , Acuaporina 2/genética , Acuaporina 2/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Sangre Fetal/citología , Regulación de la Expresión Génica , Tasa de Filtración Glomerular , Glucuronidasa/metabolismo , Humanos , Riñón/irrigación sanguínea , Riñón/metabolismo , Riñón/patología , Proteínas Klotho , Masculino , Células Madre Mesenquimatosas/citología , MicroARNs/genética , MicroARNs/metabolismo , Estrés Oxidativo , Ratas , Ratas Endogámicas WKY , Arteria Renal/lesiones , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Trasplante Heterólogo , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismoRESUMEN
BACKGROUND: Severe scorpion envenomation can evolve to lung injury and, in some cases, death. The lung injury could be attributed to acute left ventricular failure and increased pulmonary vascular permeability secondary to the release of inflammatory mediators. In clinical practice, corticosteroids have been administered to reduce the early side effects of the anti-venom. We propose to study the effects of Tityus serrulatus venom and dexamethasone on pulmonary expression of sodium and water transporters, as well as on the inflammatory response. METHODS: Wistar rats were injected intraperitoneally with saline (control group), dexamethasone, and saline (2.0 mg/kg body weight-60 min before saline injection; dexamethasone + saline group), venom (T. serrulatus venom-3.8 mg/kg body weight), or dexamethasone and venom (2.0 mg/kg body weight-60 min before venom injection; dexamethasone + venom group). At 60 min after venom/saline injection, experiments were performed in ventilated and non-ventilated animals. We analyzed sodium transporters, water transporters, and Toll-like receptor 4 (TLR4) by Western blotting, macrophage infiltration by immunohistochemistry, and serum interleukin (IL) by cytokine assay. RESULTS: In the lung tissue of non-ventilated envenomed animals, protein expression of the epithelial sodium channel alpha subunit (α-ENaC) and aquaporin 5 (AQP5) were markedly downregulated whereas that of the Na-K-2Cl cotransporter (NKCC1) and TLR4 was elevated although expression of the Na,K-ATPase alpha 1 subunit was unaffected. Dexamethasone protected protein expression of α-ENaC, NKCC1, and TLR4 but not that of AQP5. We found that IL-6, IL-10, and tumor necrosis factor alpha were elevated in the venom and dexamethasone + venom groups although CD68 expression in lung tissue was elevated only in the venom group. Among the ventilated animals, both envenomed groups presented hypotension at 50 min after injection, and the arterial oxygen tension/fraction of inspired oxygen ratio was lower at 60 min than at baseline. CONCLUSIONS: Our results suggest that T. serrulatus venom and dexamethasone both regulate sodium transport in the lung and that T serrulatus venom regulates sodium transport via the TLR4 pathway.
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Vitamin D deficiency (VDD) is widespread in the general population. Iodinated (IC) or gadolinium-based contrast media (Gd) may decrease renal function in high-risk patients. This study tested the hypothesis that VDD is a predisposing factor for IC- or Gd-induced nephrotoxicity. To this end, male Wistar rats were fed standard (SD) or vitamin D-free diet for 30 days. IC (diatrizoate), Gd (gadoterate meglumine), or 0.9% saline was then administered intravenously and six groups were obtained as the following: SD plus 0.9% saline (Sham-SD), SD plus IC (SD+IC), SD plus Gd (SD+Gd), vitamin D-free diet for 30 days plus 0.9% saline (Sham-VDD30), vitamin D-free diet for 30 days plus IC (VDD30+IC), and vitamin D-free diet for 30 days plus Gd (VDD30+Gd). Renal hemodynamics, redox status, histological, and immunoblot analysis were evaluated 48 h after contrast media (CM) or vehicle infusion. VDD rats showed lower levels of total serum 25-hydroxyvitamin D [25(OH)D], similar plasma calcium and phosphorus concentration, and higher renal renin and angiotensinogen protein expression compared with rats fed SD. IC or Gd infusion did not affect inulin clearance-based estimated glomerular filtration rate (GFR) in rats fed SD but significantly decreased GFR in rats fed vitamin D-free diet. Both CM increased renal angiotensinogen, and the interaction between VDD and CM triggered lower renal endothelial nitric oxide synthase abundance and higher renal thiobarbituric acid reactive substances-to-glutathione ratio (an index of oxidative stress) on VDD30+IC and VDD30+Gd groups. Conversely, worsening of renal function was not accompanied by abnormalities on kidney structure. Additionally, rats on a VDD for 60 days displayed a greater fall in GFR after CM administration. Collectively, our findings suggest that VDD is a potential risk factor for IC- or Gd-induced nephrotoxicity most likely due to imbalance in intrarenal vasoactive substances and oxidative stress.
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Medios de Contraste/efectos adversos , Nefropatías Diabéticas/inducido químicamente , Gadolinio/efectos adversos , Enfermedades Renales/metabolismo , Riñón/metabolismo , Deficiencia de Vitamina D/metabolismo , Animales , Modelos Animales de Enfermedad , Enfermedades Renales/fisiopatología , Masculino , Estrés Oxidativo/fisiología , Ratas Wistar , Factores de Riesgo , Vitamina D/análogos & derivados , Vitamina D/farmacologíaRESUMEN
Vitamin D deficiency (VDD) increases the risk of death in hospitalized patients. Renal ischemia/reperfusion injury (IRI) induces acute kidney injury (AKI), which activates cell cycle inhibitors, including p21, a cyclin-dependent kinase inhibitor and genomic target of 25-hydroxyvitamin D, which is in turn a potent immunomodulator with antiproliferative effects. In this study, we assess the impact of VDD in renal IRI. Wistar rats were divided into groups, each evaluated for 30 days: control (receiving a standard diet); VDD (receiving a vitamin D-free diet); IRI (receiving a standard diet and subjected to 45-min bilateral renal ischemia on day 28); and VDD + IRI (receiving a vitamin D-free diet and subjected to 45-min bilateral renal ischemia on day 28). At 48 h after IRI, animals were euthanized; blood, urine, and kidney tissue samples were collected. Compared with IRI rats, VDD + IRI rats showed a more severe decrease in glomerular filtration rate, greater urinary protein excretion, a higher kidney/body weight ratio and lower renal aquaporin 2 expression, as well as greater morphological damage, characterized by increased interstitial area and tubular necrosis. Our results suggest that the severity of tubular damage in IRI may be associated with downregulation of vitamin D receptors and p21. VDD increases renal inflammation, cell proliferation and cell injury in ischemic AKI.
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BACKGROUND: Despite a significant improvement in the management of chronic kidney disease (CKD), its incidence and prevalence has been increasing over the years. Progressive renal fibrosis is present in CKD and involves the participation of several cytokines, including Transforming growth factor-ß1 (TGF-ß1). Besides cardiovascular diseases and infections, several studies show that Vitamin D status has been considered as a non-traditional risk factor for the progression of CKD. Given the importance of vitamin D in the maintenance of essential physiological functions, we studied the events involved in the chronic kidney disease progression in rats submitted to ischemia/reperfusion injury under vitamin D deficiency (VDD). METHODS: Rats were randomized into four groups: Control; VDD; ischemia/reperfusion injury (IRI); and VDD+IRI. At the 62 day after sham or IRI surgery, we measured inulin clearance, biochemical variables and hemodynamic parameters. In kidney tissue, we performed immunoblotting to quantify expression of Klotho, TGF-ß, and vitamin D receptor (VDR); gene expression to evaluate renin, angiotensinogen, and angiotensin-converting enzyme; and immunohistochemical staining for ED1 (macrophages), type IV collagen, fibronectin, vimentin, and α-smooth mucle actin. Histomorphometric studies were performed to evaluate fractional interstitial area. RESULTS: IRI animals presented renal hypertrophy, increased levels of mean blood pressure and plasma PTH. Furthermore, expansion of the interstitial area, increased infiltration of ED1 cells, increased expression of collagen IV, fibronectin, vimentin and α-actin, and reduced expression of Klotho protein were observed. VDD deficiency contributed to increased levels of plasma PTH as well as for important chronic tubulointerstitial changes (fibrosis, inflammatory infiltration, tubular dilation and atrophy), increased expression of TGF-ß1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals. CONCLUSION: Through inflammatory pathways and involvement of TGF-ß1 growth factor, VDD could be considered as an aggravating factor for tubulointerstitial damage and fibrosis progression following acute kidney injury induced by ischemia/reperfusion.
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Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo , Daño por Reperfusión/etiología , Deficiencia de Vitamina D/complicaciones , Actinas/metabolismo , Lesión Renal Aguda , Angiotensinógeno/metabolismo , Animales , Progresión de la Enfermedad , Fibronectinas/metabolismo , Riñón , Masculino , Ratas , Ratas Wistar , Receptores de Calcitriol/metabolismo , Insuficiencia Renal Crónica/patología , Renina/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Factor de Crecimiento Transformador beta , Factor de Crecimiento Transformador beta1/metabolismo , Deficiencia de Vitamina D/metabolismo , Deficiencia de Vitamina D/fisiopatologíaRESUMEN
Vitamin D deficiency (VDD) is prevalent among HIV-infected individuals. Vitamin D has been associated with renal and cardiovascular diseases because of its effects on oxidative stress, lipid metabolism and renin-angiotensin-aldosterone system (RAAS). Tenofovir disoproxil fumarate (TDF), a widely used component of antiretroviral regimens for HIV treatment, can induce renal injury. The aim of this study was to investigate the effects of VDD on TDF-induced nephrotoxicity. Wistar rats were divided into four groups: control, receiving a standard diet for 60 days; VDD, receiving a vitamin D-free diet for 60 days; TDF, receiving a standard diet for 60 days with the addition of TDF (50 mg/kg food) for the last 30 days; and VDD+TDF receiving a vitamin D-free diet for 60 days with the addition of TDF for the last 30 days. TDF led to impaired renal function, hyperphosphaturia, hypophosphatemia, hypertension and increased renal vascular resistance due to downregulation of the sodium-phosphorus cotransporter and upregulation of angiotensin II and AT1 receptor. TDF also increased oxidative stress, as evidenced by higher TBARS and lower GSH levels, and induced dyslipidemia. Association of TDF and VDD aggravated renovascular effects and TDF-induced nephrotoxicity due to changes in the redox state and involvement of RAAS.
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Fármacos Anti-VIH , Dislipidemias/complicaciones , Hipertensión/complicaciones , Enfermedades Renales/complicaciones , Estrés Oxidativo/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Tenofovir , Deficiencia de Vitamina D/complicaciones , Animales , Dislipidemias/inducido químicamente , Dislipidemias/metabolismo , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Masculino , Ratas , Ratas Wistar , Receptores de Angiotensina/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Deficiencia de Vitamina D/metabolismoRESUMEN
BACKGROUND: Nephropathic cystinosis is an autosomal recessive systemic severe disease characterized by intralysosomal cystine storage. Cysteamine is an essential component of treatment. There is solid evidence that cystine accumulation itself is not responsible for all abnormalities in cystinosis; there is also a deficiency of glutathione in the cytosol. Patients with cystinosis can be more susceptible to oxidative stress. CASE-DIAGNOSIS/TREATMENT: The patient cohort comprised 23 cystinosis patients (16 males) aged <18 years (mean age 8.0 ± 3.6 years) with chronic kidney disease class I-IV with good adherence to treatment, including cysteamine. Oxidative stress was evaluated based on the levels of serum thiobarbituric acid-reactive substances (TBARS), and renal function was evaluated based on serum creatinine and cystatin C levels and creatinine clearance (Schwartz formula). N-Acetylcysteine (NAC), an antioxidant drug was given to all patients for 3 months (T1) at 25 mg/kg/day divided in three doses per day. The measured values at just before the initiation of NAC treatment (T0) served as the control for each patient. RESULTS: Median serum TBARS levels at T0 and T1 were 6.92 (range 3.3-29.0) and 1.7 (0.6-7.2) nmol/mL, respectively (p < 0.0001). In terms of renal function at T0 and T1, serum creatinine levels (1.1 ± 0.5 vs. 0.9 ± 0.5 mg/dL, respectively; p < 0.0001), creatinine clearance (69.7 ± 32.2 vs. T1 = 78.5 ± 33.9 mL/min/1.73 m(2), respectively; p = 0.006), and cystatin c level (1.33 ± 0.53 vs. 1.15 ± 0.54 mg/l, respectively; p = 0.0057) were all significantly different at these two time points. Serum creatinine measurements at 6 (T -6) and 3 months (T -3) before NAC initiation and at 3 (T +3) and 6 months (T +6) after NAC had been withdrawn were also evaluated. CONCLUSION: During the 3-month period that our 23 cystinosis patients were treated with NAC, oxidative stress was reduced and renal function significantly improved. No side-effects were detected. Larger and controlled studies are needed to confirm these findings.
Asunto(s)
Acetilcisteína/uso terapéutico , Antioxidantes/uso terapéutico , Cistinosis/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Niño , Cisteamina/uso terapéutico , Depletores de Cistina/uso terapéutico , Femenino , Humanos , Pruebas de Función Renal , MasculinoRESUMEN
The aim of this study was to evaluate the effects of N-acetylcysteine (NAC) on renal function, as well as on sodium and water transporters, in the kidneys of aged rats. Normal, 8-month-old male Wistar rats were treated (n=6) or not (n=6) with NAC (600 mg/L in drinking water) and followed for 16 months. At the end of the follow-up period, we determined inulin clearance, serum thiobarbituric acid reactive substances (TBARS), serum cholesterol, and urinary phosphate excretion. In addition, we performed immunohistochemical staining for p53 and for ED-1-positive cells (macrophages/monocytes), together with Western blotting of kidney tissue for NKCC2, aquaporin 2 (AQP2), urea transporter A1 (UT-A1) and Klotho protein. At baseline, the two groups were similar in terms of creatinine clearance, proteinuria, cholesterol, and TBARS. At the end of the follow-up period, NAC-treated rats presented greater inulin clearance and reduced proteinuria, as well as lower serum cholesterol, serum TBARS, and urinary phosphate excretion, in comparison with untreated rats. In addition, NAC-treated rats showed upregulated expression of NKCC2, AQP2, and UT-A1; elevated Klotho protein expression, low p53 expression, and few ED-1 positive cells. In conclusion, we attribute these beneficial effects of NAC (the significant improvements in inulin clearance and in the expression of NKCC2, AQP2, and UT-A1) to its ability to decrease oxidative stress, inhibit p53 expression, minimize kidney inflammation, and stimulate Klotho expression.
Asunto(s)
Acetilcisteína/farmacología , Envejecimiento/metabolismo , Antioxidantes/farmacología , Senescencia Celular , Riñón/efectos de los fármacos , Factores de Edad , Envejecimiento/patología , Animales , Acuaporina 2/metabolismo , Biomarcadores/metabolismo , Western Blotting , Colesterol/sangre , Ectodisplasinas/metabolismo , Glucuronidasa/metabolismo , Inmunohistoquímica , Inulina/metabolismo , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Proteínas Klotho , Masculino , Proteínas de Transporte de Membrana/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosfatos/orina , Ratas , Ratas Wistar , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Miembro 1 de la Familia de Transportadores de Soluto 12 , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Transportadores de UreaRESUMEN
BACKGROUND: Leptospirotic renal lesions frequently produce a polyuric form of acute kidney injury with a urinary concentration defect. Our study investigated a possible effect of the glycolipoprotein, (GLPc) extracted from L. interrogans, on vasopressin (Vp) action in the guinea pig inner medullary collecting duct (IMCD). METHODS: The osmotic water permeability (Pf µm/s) was measured by the microperfusion in vitro technique. AQP2 protein abundance was determined by Western Blot. Three groups were established for study as follows: Group I, IMCD from normal (ngp, nâ=â5) and from leptospirotic guinea-pigs (lgp-infected with L. interrogans serovar Copenhageni, GLPc, nâ=â5); Group II, IMCD from normal guinea-pigs in the presence of GLPc (GLPc group, nâ=â54); Group III, IMCD from injected animals with GLPc ip (nâ=â8). RESULTS: In Group I, PFS were: ngp--61.8±22.1 and lgp--8.8±12.4, p<0.01 and the urinary osmolalities were: lgp--735±64 mOsm/Kg and ngp--1,632±120 mOsm/Kg. The lgp BUN was higher (176±36 mg%) than the ngp (56±9 mg%). In Group II, the Pf was measured under GLPc (250 µg/ml) applied directly to the bath solution of the microperfused normal guinea-pig IMCDs. GLPc blocked Vp (200 pg/ml, nâ=â5) action, did not block cAMP (10(-4) M), and Forskolin (Fors--10(-9) M) action, but partially blocked Cholera Toxin (ChT--10(-9) M) action. GLP from L.biflexa serovar patoc (GLPp, non pathogenic, 250 µg) did not alter Vp action. In Group III, GLPc (250 µg) injected intraperitoneally produced a decrease of about 20% in IMCD Aquaporin 2 expression. CONCLUSION: The IMCD Pf decrease caused by GLP is evidence, at least in part, towards explaining the urinary concentrating incapacity observed in infected guinea-pigs.
Asunto(s)
Proteínas Bacterianas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glicoproteínas/farmacología , Túbulos Renales Colectores/efectos de los fármacos , Leptospira interrogans/metabolismo , Leptospirosis/patología , Equilibrio Hidroelectrolítico/efectos de los fármacos , Animales , Acuaporina 2/metabolismo , Western Blotting , Regulación de la Expresión Génica/fisiología , Glicoproteínas/aislamiento & purificación , Cobayas , Túbulos Renales Colectores/fisiología , Leptospirosis/microbiología , Permeabilidad , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
Sepsis is a common cause of acute kidney injury (AKI) and acute lung injury. Oxidative stress plays as important role in such injury. The aim of this study was to evaluate the effects that the potent antioxidant N-acetylcysteine (NAC) has on renal and pulmonary function in rats with sepsis. Rats, treated or not with NAC (4.8 g/l in drinking water), underwent cecal ligation and puncture (CLP) 2 days after the initiation of NAC treatment, which was maintained throughout the study. At 24 h post-CLP, renal and pulmonary function were studied in four groups: control, control + NAC, CLP, and CLP + NAC. All animals were submitted to low-tidal-volume mechanical ventilation. We evaluated respiratory mechanics, the sodium cotransporters Na-K-2Cl (NKCC1) and the α-subunit of the epithelial sodium channel (α-ENaC), polymorphonuclear neutrophils, the edema index, oxidative stress (plasma thiobarbituric acid reactive substances and lung tissue 8-isoprostane), and glomerular filtration rate. The CLP rats developed AKI, which was ameliorated in the CLP + NAC rats. Sepsis-induced alterations in respiratory mechanics were also ameliorated by NAC. Edema indexes were lower in the CLP + NAC group, as was the wet-to-dry lung weight ratio. In CLP + NAC rats, α-ENaC expression was upregulated, whereas that of NKCC1 was downregulated, although the difference was not significant. In the CLP + NAC group, oxidative stress was significantly lower and survival rates were significantly higher than in the CLP group. The protective effects of NAC (against kidney and lung injury) are likely attributable to the decrease in oxidative stress, suggesting that NAC can be useful in the treatment of sepsis.