Nebivolol Attenuates Redox-Sensitive Glomerular and Tubular Mediated Proteinuria in Obese Rats

Habibi, Javad; Hayden, Melvin R.; Sowers, James R.; Pulakat, Lakshmi; Tilmon, Roger D.; Manrique, Camila; Lastra, Guido; DeMarco, Vincent G.; Whaley‐Connell, Adam

doi:10.1210/en.2010-1038

Cited by 42 publications

(42 citation statements)

References 42 publications

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“…Circulating CRP was significantly higher in the female diabetic rats but did not change in the male diabetic group. Although serum CRP is considered a marker of inflammation, CRP may directly contribute to vascular dysfunction through reduced nitric oxide or increased oxidative stress (17,38,44). Vascular relaxation to acetylcholine and estrogen were significantly reduced in the diabetic mRen2.Lewis females, which would support a role for CRP; however, the mechanism for the attenuated relaxation response awaits further study.…”

Section: Discussionmentioning

confidence: 93%

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

Yamaleyeva¹,

Gilliam-Davis

Almeida³

et al. 2012

American Journal of Physiology-Renal Physiology

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Yamaleyeva LM, Gilliam-Davis S, Almeida I, Brosnihan KB, Lindsey SH, Chappell MC. Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes. Am J Physiol Renal Physiol 302: F1374 -F1384, 2012. First published February 29, 2012 doi:10.1152/ajprenal.00656.2011We examined the impact of early diabetes on the circulating and kidney renin-angiotensin system (RAS) in male and female mRen2.Lewis (mRen2) hypertensive rats. Diabetes (DB) was induced by streptozotocin (STZ; 65 mg/kg) at 11 wk of age for 4 wk without insulin replacement. Systolic blood pressures were not increased in DB males or females compared with controls (CON). Circulating angiotensinconverting enzyme 2 (ACE2) increased ninefold (P Ͻ 0.05) in DB females and threefold (P Ͻ 0.05) in DB males, but circulating ACE and ANG II were higher in the DB groups. Serum C-reactive protein was elevated in DB females but not DB males, and the vascular responses to acetylcholine and estradiol were attenuated in the DB females. Proteinuria, albuminuria, and angiotensinogen excretion increased to a similar extent in both DB females and males. Glomerular VEGF expression also increased to a similar extent in both DB groups. Renal inflammation (CD68 ϩ cells) increased only in DB females although males exhibited greater inflammation that was not different with DB. Cortical ACE2 did not change in DB females but was reduced (30%) in DB males. Renal neprilysin activity (Ͼ75%, P Ͻ 0.05) was markedly reduced in the DB females to that in the DB and CON males. ACE activity was significantly lower in both female (75%, P Ͻ 0.05) and male (50%; P Ͻ 0.05) DB groups, while cortical ANG II and Ang-(1-7) levels were unchanged. In conclusion, female mRen2 rats are not protected from vascular damage, renal inflammation, and kidney injury in early STZ-induced diabetes despite a marked increase in circulating ACE2 and significantly reduced ACE within the kidney.angiotensin; kidney; neprilysin; hypertension; proteinuria ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2), a homolog of ACE, is recognized as an important enzymatic component of the renin-angiotensin system (RAS) that may regulate functional output of this hormonal system (5,7,8,14,28,30,51,50). Although ACE2 was originally characterized for its ability to hydrolyze ANG I to Ang-(1-9), subsequent studies revealed a very high catalytic activity to convert ANG II to Ang-(1-7) (41,44,45,56,58). Indeed, ACE2 inhibition or genetic knockout studies reveal a heightened sensitivity to ANG II-induced increases in blood pressure, as well as an exacerbation of end-organ damage in these experimental models (31,32,46,48,52,60). In contrast to ACE, circulating ACE2 is low to nondetectable in rodents and humans, and tissue sources of the enzyme are more likely to influence the local RAS (12, 40). Diabetic renal injury is generally associated with a reduction in the activity and/or expression of renal tissue ACE2, which may contribute to a deleterious imbalance in the relative expression of ANG I...

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Section: Discussionmentioning

confidence: 93%

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

Yamaleyeva¹,

Gilliam-Davis

Almeida³

et al. 2012

American Journal of Physiology-Renal Physiology

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“…The young ZO rat model of insulin resistance and obesity develops microalbuminuria and therefore may serve as a good model of early renal disease in the CRS [20,21,23,31,32,33,34]. The kidney glomerulus undergoes marked ultrastructural remodeling consisting of glomerular hypertrophy and widening of Bowman’s space, inflammation, loss of podocytes (podocytopenia), and podocyte remodeling (fig.…”

Section: Kidney As a Target Organ: Ckd And End-stage Kidney Failurementioning

confidence: 99%

“…The kidney proximal tubule cells also undergo marked ultrastructural remodeling consisting of loss of basolateral polarity, loss of elongated mitochondria with spherical rounded mitochondria (mitochondrial fragmentation), abnormal mitochondrial cristae and matrix, decreased basilar invaginating canalicular infoldings, and chronic inflammation (fig. 6) [34]. In the young ZO rat model, we refer to these proximal tubule cell remodeling changes as obesity-related tubulopathy.…”

Section: Kidney As a Target Organ: Ckd And End-stage Kidney Failurementioning

confidence: 99%

Childhood-Adolescent Obesity in the Cardiorenal Syndrome: Lessons from Animal Models

Hayden

Sowers²

2011

Cardiorenal Med

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Background/Aims: Childhood-adolescent overweight and obesity have grown to pandemic proportions during the past decade. The onset of obesity in younger adults will likely be manifested as earlier onset of myocardial and renal end-organ disease in younger adults. For the first time, it is estimated that the current generation may not live to be as old as their parents. Thus, it is important to develop animal models of childhood obesity to understand fundamental pathological organ changes. Methods: In this regard, we utilize transmission electron microscopy evaluation to evaluate early remodeling changes of two adolescent rodent obesity models: the Zucker obese (fa/fa) rat and the db/db mouse models of obesity. We have concentrated on the initial ultrastructural remodeling (obese adipose tissue, skeletal muscle, and islet remodeling) and the associated changes in target end organs (including the myocardium and kidney) in young rodent models of obesity and insulin resistance, collectively manifesting as the cardiorenal metabolic syndrome (CRS). Results: Briefly, tissues revealed the following ultrastructural remodeling abnormalities: inflammation, hypertrophy, and early fibrosis in adipose tissue; loss of mitochondria in skeletal muscles, hyperplasia, fibrosis, and depletion of insulin-secretory granules in pancreatic islets; increased intramyocardial lipid accumulation, fibrosis, and mitochondrial deposition in the myocardium, and obesity-related glomerulopathy and tubulopathy in the kidney. Conclusion: Based on the current knowledge and ultrastructural observations of organ pathology, we propose mechanisms whereby obesity appears to be the driving force behind the development of the CRS.

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“…Four micrometers of paraffin-embedded sections of kidney were deparaffinized in CitriSolv, rehydrated in ethanol series and Hepes buffer [30,31]. Epitopes were retrieved (antigen retrieval) in citrate buffer pH 6 for 25 min at 95°C.…”

Section: Methodsmentioning

confidence: 99%

Mineralocorticoid Receptor-Dependent Proximal Tubule Injury Is Mediated by a Redox-Sensitive mTOR/S6K1 Pathway

Whaley‐Connell¹,

Habibi²,

Nistala³

et al. 2011

Am J Nephrol

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Background/Aims: The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics. Methods: Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks. Results: Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β-aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin. Conclusions: Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.

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Nebivolol Attenuates Redox-Sensitive Glomerular and Tubular Mediated Proteinuria in Obese Rats

Cited by 42 publications

References 42 publications

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

Childhood-Adolescent Obesity in the Cardiorenal Syndrome: Lessons from Animal Models

Mineralocorticoid Receptor-Dependent Proximal Tubule Injury Is Mediated by a Redox-Sensitive mTOR/S6K1 Pathway

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