Reduced tubular proteinuria in hypertensive rats treated with losartan is associated with higher renal cortical megalin expression

Arruda-Junior, Daniel F.; Virgulino, Stephannie G.; Girardi, Adriana C. C.

doi:10.1515/hmbci-2013-0061

Cited by 8 publications

(10 citation statements)

References 41 publications

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“…It is possible to speculate that the RAS is related to these mechanisms. Indeed, it is well known that agents targeting classical components of the RAS exert renoprotective effects beyond their blood pressure lowering effect [ 36 – 38 ], especially regarding the improvement of renal albumin handling [ 12 , 39 ]. In the human glomerulonephritis for example, the long-term antiproteinuric effect of the ACE inhibitor lisinopril could not be acutely reversed by angiotensin II infusion, despite a dose-related fall in renal plasma flow and increase in systolic blood pressure, filtration fraction and renal vascular resistance [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the human glomerulonephritis for example, the long-term antiproteinuric effect of the ACE inhibitor lisinopril could not be acutely reversed by angiotensin II infusion, despite a dose-related fall in renal plasma flow and increase in systolic blood pressure, filtration fraction and renal vascular resistance [ 40 ]. Recently, Arruda-Junior et al [ 39 ] showed that the reduction of tubular proteinuria in SHRs treated with losartan, an AT1 blocker, was accompanied by an increased renal megalin expression and that these beneficial effects were independent of blood pressure reduction. Additionally, studies performed in an experimental model of hypertension and diabetes have shown that treatment with the angiotensin II antagonist irbesartan prevented the development of albuminuria and the down-regulation of nephrin expression, without a prominent influence on blood pressure levels [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

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Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats

et al. 2015

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Several evidences have shown that salt excess is an important determinant of cardiovascular and renal derangement in hypertension. The present study aimed to investigate the renal effects of chronic high or low salt intake in the context of hypertension and to elucidate the molecular mechanisms underlying such effects. To this end, newly weaned male SHR were fed with diets only differing in NaCl content: normal salt (NS: 0.3%), low salt (LS: 0.03%), and high salt diet (HS: 3%) until 7 months of age. Analysis of renal function, morphology, and evaluation of the expression of the main molecular components involved in the renal handling of albumin, including podocyte slit-diaphragm proteins and proximal tubule endocytic receptors were performed. The relationship between diets and the balance of the renal angiotensin-converting enzyme (ACE) and ACE2 enzymes was also examined. HS produced glomerular hypertrophy and decreased ACE2 and nephrin expressions, loss of morphological integrity of the podocyte processes, and increased proteinuria, characterized by loss of albumin and high molecular weight proteins. Conversely, severe hypertension was attenuated and renal dysfunction was prevented by LS since proteinuria was much lower than in the NS SHRs. This was associated with a decrease in kidney ACE/ACE2 protein and activity ratio and increased cubilin renal expression. Taken together, these results suggest that LS attenuates hypertension progression in SHRs and preserves renal function. The mechanisms partially explaining these findings include modulation of the intrarenal ACE/ACE2 balance and the increased cubilin expression. Importantly, HS worsens hypertensive kidney injury and decreases the expression nephrin, a key component of the slit diaphragm.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats

et al. 2015

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“…In addition to the inherited conditions, receptor dysfunction has been suggested in a number of acquired and common disorders associated with proteinuria, such as AKI, chronic = r e v i e w kidney disease, diabetes, and hypertension. Changes in receptor expression have been reported in animal models of acute 105 and chronic renal disease including lipopolysaccharide-induced endotoxemia, 111 ischemia-reperfusion kidney injury, 111,112 Shiga toxin-induced nephropathy, hypertension, 113 chronic kidney disease, [114][115][116] and diabetes. 117,118 Increased urinary excretion of megalin, megalin fragments, and cubilin has been identified in models of Alport syndrome, 119 in experimental as well as human diabetes, 118,[120][121][122] and in IgA nephritis.…”

Section: Acquired Megalin and Cubilin Dysfunction In Acute And Chronimentioning

confidence: 99%

Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease

Nielsen

Christensen

Birn

2016

Kidney International

377

298

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Proximal tubule protein uptake is mediated by 2 receptors, megalin and cubilin. These receptors rescue a variety of filtered ligands, including biomarkers, essential vitamins, and hormones. Receptor gene knockout animal models have identified important functions of the receptors and have established their essential role in modulating urinary protein excretion. Rare genetic syndromes associated with dysfunction of these receptors have been identified and characterized, providing additional information on the importance of these receptors in humans. Using various disease models in combination with receptor gene knockout, the implications of receptor dysfunction in acute and chronic kidney injury have been explored and have pointed to potential new roles of these receptors. Based on data from animal models, this paper will review current knowledge on proximal tubule endocytic receptor function and regulation, and their role in renal development, protein reabsorption, albumin uptake, and normal renal physiology. These findings have implications for the pathophysiology and diagnosis of proteinuric renal diseases. We will examine the limitations of the different models and compare the findings to phenotypic observations in inherited human disorders associated with receptor dysfunction. Furthermore, evidence from receptor knockout mouse models as well as human observations suggesting a role of protein receptors for renal disease will be discussed in light of conditions such as chronic kidney disease, diabetes, and hypertension.

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“…In nephrotic syndrome patients, tubular expression of megalin and cubilin was reduced 8 . Spontaneously hypertensive rats progressively loss megalin and cubilin into the urine 9 and the treatment of hypertension preserves these molecules 10 .…”

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confidence: 99%

Proteinuria is Associated with Urinary Loss of Cubilin and Vitamin D-Binding Protein in Patients with Preeclampsia

Albejante

Kunz

Ferreira

et al. 2020

Sci Rep

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Women with preeclampsia (PE) form a vulnerable group for vitamin D3 deficiency. Reabsorption of vitamin D3 occurs in the proximal tubule after being endocytosed in combination with DBP (vitamin D binding protein) by the megalin/cubilin receptor. Because proteinuria promotes tubule injury and dysfunction, we hypothesized that the proteinuria present in pe could promote the loss of these components into the urine. Twenty preeclamptic patients and ten normal pregnant women with a gestational age greater than 20 weeks composed three groups: NC, normotensive control pregnant patients; PE, non-proteinuric preeclamptic patients; and PPE, preeclamptic patients with proteinuria. When proteinuria was absent, preeclampsia was diagnosed accordingly to the American college of Obstetricians and Gynecologists' (ACOG) guideline. The presence of 24-hour proteinuria equal to or greater than 300 mg was considered to form the PPE group. Urinary cubilin, megalin, and DBP were measured by ELISA and normalized by urinary creatinine. Regarding gestational age, there was no difference between the groups. NC group had arterial pressure within normal values, whereas PE and PPE groups had a significant increase (p < 0.01). As expected, PPE group presented elevated ACR (p < 0.05), accompanied by large amounts of cubilin and DBP in the urine (p < 0.05 vs. NC and PE). No difference was found in urinary megalin. PPE patients showed more chance of shedding cubilin into the urine compared to non-proteinuric patients (odds ratio 12.7 (1.2-136.3). In conclusion, this study further tightens the relationship between pe and vitamin D 3 deficiency, since proteinuria present in pe induces the loss of molecules responsible for renal tubular vitamin D 3 reabsorption for subsequent activation. Combined with other factors, the proteinuria may intensify vitamin D 3 deficiency in PE. Preeclampsia (PE) is a multisystem disorder of pregnancy in which renal damage has a significant contribution. A set level of proteinuria has been used to predict high-risk groups and define treatment for PE. In terms of physiopathology, proteinuria emerges due to processes that disturb the glomerular filtration barrier. Besides the classical mechanisms of glomerular damage such as endotheliosis and loss of podocytes 1,2 , an evidence for tubular injury have also been reported. Markers of proximal tubule injury such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and retinol-binding protein (RBP) were higher in the urine of PE patients than in urine of healthy pregnancies 3 In addition, urinary lysosomal enzyme excretion is elevated in patients with PE compared to a pregnant woman with chronic hypertension 4. Burwick et al. demonstrated that pregnancies affected by severe PE have high amounts of KIM-1 in the urine, which was closely correlated with urinary complement activation products, suggesting that tubular injury in PE is intensified by inflammation-activated complement 5. Direct effects of proteinuria on tubular cell damage have been ...

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Reduced tubular proteinuria in hypertensive rats treated with losartan is associated with higher renal cortical megalin expression

Cited by 8 publications

References 41 publications

Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats

Renal Effects and Underlying Molecular Mechanisms of Long-Term Salt Content Diets in Spontaneously Hypertensive Rats

Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease

Proteinuria is Associated with Urinary Loss of Cubilin and Vitamin D-Binding Protein in Patients with Preeclampsia

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