Angiotensin II overcomes strain-dependent resistance of rapid CKD progression in a new remnant kidney mouse model

Leelahavanichkul, Asada; Qin, Yan; Hu, Xiaobang; Eisner, Christoph; Huang, Yuning; Chen, Richard; Mizel, Diane; Zhou, Hua; Wright, Elizabeth C.; Kopp, Jeffrey B.; Schnermann, Jürgen; Yuen, Peter S.T.; Star, Robert A.

doi:10.1038/ki.2010.287

Cited by 137 publications

(168 citation statements)

References 81 publications

(85 reference statements)

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“…The spectrum of glomerular pathologies associated with the nephrin-Y3F mutation is portrayed on both the CD-1 and C57BL/6 backgrounds, despite the differences in onset and severity. C57BL/6 mice have lower BPs than age-matched CD-1 mice, 50 which may reflect reduced glomerular strain, although this is unlikely to be the sole determinant, and identification of modifier alleles within these backgrounds remains an area of intense interest. It is noteworthy that the nephrin-Y3F protein seems to have a dominant negative effect in the heterozygous state, and this may be relevant in patients with nephrotic syndrome who carry only a single nephrin mutation and those who present outside the neonatal period.…”

Section: Discussionmentioning

confidence: 99%

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

New¹,

Martín²,

Scott

et al. 2016

JASN

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Podocytes are specialized epithelial cells of the kidney blood filtration barrier that contribute to permselectivity via a series of interdigitating actin-rich foot processes. Positioned between adjacent projections is a unique cell junction known as the slit diaphragm, which is physically connected to the actin cytoskeleton via the transmembrane protein nephrin. Evidence indicates that tyrosine phosphorylation of the intracellular tail of nephrin initiates signaling events, including recruitment of cytoplasmic adaptor proteins Nck1 and Nck2 that regulate actin cytoskeletal dynamics. Nephrin tyrosine phosphorylation is altered in human and experimental renal diseases characterized by pathologic foot process remodeling, prompting the hypothesis that phosphonephrin signaling directly influences podocyte morphology. To explore this possibility, we generated and analyzed knockin mice with mutations that disrupt nephrin tyrosine phosphorylation and Nck1/2 binding (nephrin Y3F/Y3F mice). Homozygous nephrin Y3F/Y3F mice developed progressive proteinuria accompanied by structural changes in the filtration barrier, including podocyte foot process effacement, irregular thickening of the glomerular basement membrane, and dilated capillary loops, with a similar but later onset phenotype in heterozygous animals. Furthermore, compared with wild-type mice, nephrin Y3F/Y3F mice displayed delayed recovery in podocyte injury models. Profiling of nephrin tyrosine phosphorylation dynamics in wild-type mice subjected to podocyte injury indicated site-specific differences in phosphorylation at baseline, injury, and recovery, which correlated with loss of nephrin-Nck1/2 association during foot process effacement. Our results define an essential requirement for nephrin tyrosine phosphorylation in stabilizing podocyte morphology and suggest a model in which dynamic changes in phosphotyrosine-based signaling confer plasticity to the podocyte actin cytoskeleton.

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Section: Discussionmentioning

confidence: 99%

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

New¹,

Martín²,

Scott

et al. 2016

JASN

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“…18 Three weeks after 5/6 Nx, the SBP from the Nx group was higher than the sham control group (Figure 5). At Week 7, the SBP from the NxþHS group was significantly lower when compared with the Nx group ( Figure 5).…”

Section: Effects Of Hibiscus Sabdariffa (Hs) Aqueous Extracts On Hypementioning

confidence: 99%

“…To determine the severity of the kidney injury, the percentage of the glomerular expansion from the PAS staining and the area of the interstitial fibrosis from Masson's trichrome stained histology were used to gauge the extent of the glomerular injury and renal interstitial damage. [18][19][20] Injured glomeruli were defined as more than 50% expansion of the glomerular lesion at 400Â magnification. The severity of the glomerular injury was determined by the percentage of the injured glomeruli (Figure 3), whereas the renal interstitial injury was estimated by the number of areas with tubulointerstitial expansion at 200Â magnification using 10 randomly selected fields for each rat by three pathologists who were blinded from knowing which group the rats belonged to.…”

Section: Histologymentioning

confidence: 99%

“…The semiquantitative criteria used to score the renal interstitial injury were as follows: 0 areas with tubulointerstitial expansion was equivalent to <5% damage, 1 area with tubulointerstitial expansion was equivalent to 5-10% damage, 2 areas with tubulointerstitial expansion was equivalent to 10-25% damage, 3 areas with tubulointerstitial expansion was equivalent to 25-50% damage, and 4 areas with tubulointerstitial expansion was equivalent to >50% damage. 18,20 Masson's trichrome stained sections were used to estimate the kidney interstitial fibrosis at 200Â magnification by using the ImageJ 1.36b program (National Institutes of Health, Bethesda, MD, USA) as detailed in http://imagej.nih.gov/ij. In brief, 20 different but randomly selected interstitial areas at 200Â magnification without glomeruli and large vessels were captured and converted into black and white colors (HSB stack).…”

Section: Histologymentioning

confidence: 99%

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Hibiscus SabdariffaLinnaeus Aqueous Extracts Attenuate the Progression of Renal Injury in 5/6 Nephrectomy Rats

et al. 2012

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Hibiscus sabdariffa Linn. (HS) is a tropical wild plant with antioxidant, antibacterial, antihypertensive, and lipid-lowering properties. In several animal models, HS aqueous extracts reduced the severity of the multi-organ injuries such as hypertension and diabetic nephropathy. One of the multiorgan injuries is chronic kidney disease (CKD), which results from the loss of nephron function. HS was used in a 5/6 nephrectomy (5/6 Nx) rat model to determine if it could attenuate the progression of CKD. HS (250 mg/kg/day) or placebo was orally administered to 5/6 Nx male Sprague-Dawley rats. The NxþHS group had fewer renal injuries as measured by blood urea nitrogen, serum creatinine, creatinine clearance, and renal pathology when compared with the Nx group. In order to determine which property of HS, either vasodilatory and/or antioxidant, was important in attenuating the progression of CKD, systolic blood pressure (SBP) and serum levels of malondialdehyde (MDA) were assessed. In the NxþHS group, the SBP and the serum levels of MDA were significantly lower at Week 7. In conclusion, through either antihypertensive and/or antioxidant properties, HS was able to attenuate the progression of renal injury after 5/6 Nx. Hence, HS should be considered as one of the new, promising drugs that can be used to attenuate the progression of CKD.

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“…One week later (week 0), the intact right kidney was removed via a right flank incision, as previously described. 18,19 One week after the operation (week 1), the 5/6NX mice were randomized and divided into different groups (n Z 6 to 8 in each group): i) sham control; ii) 5/6NX mice injected with empty vector pcDNA3 (designated as 5/6NX group); and iii) 5/6NX mice injected with pV5-sKlotho plasmid (designated as 5/6NXþK group). In vivo expression of secreted Klotho in mice was performed by a hydrodynamic-based gene delivery approach, as described previously.…”

Section: Animal Modelsmentioning

confidence: 99%

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

Zhou

Miao

et al. 2015

The American Journal of Pathology

131

117

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Loss of Klotho and activation of the renin-angiotensin system (RAS) are common pathological findings in chronic kidney diseases. However, whether these two events are intricately connected is poorly understood. We hypothesized that Klotho might protect kidneys by targeted inhibition of RAS activation in diseased kidneys. To test this hypothesis, mouse models of remnant kidney, as well as adriamycin nephropathy and unilateral ureteral obstruction, were utilized. At 6 weeks after 5/6 nephrectomy, kidney injury was evident, characterized by elevated albuminuria and serum creatinine levels, and excessive deposition of interstitial matrix proteins. These lesions were accompanied by loss of renal Klotho expression, up-regulation of RAS components, and development of hypertension. In vivo expression of exogenous Klotho through hydrodynamic-based gene delivery abolished the induction of multiple RAS proteins, including angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor, and normalized blood pressure. Klotho also inhibited b-catenin activation and ameliorated renal fibrotic lesions. Similar results were obtained in mouse models of adriamycin and obstructive nephropathy. In cultured kidney tubular epithelial cells, Klotho dose-dependently blocked Wnt1-triggered RAS activation. Taken together, these results demonstrate that Klotho exerts its renal protection by targeted inhibition of RAS, a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders. Chronic kidney disease (CKD) is increasingly recognized as a major public health problem, because it affects about 10% to 13% of the adult population worldwide.1e3 Among many risk factors for developing CKD, aging is an independent and strong predictor for progressive renal insufficiency. 4 The elderly population also tends to develop hypertension and cardiovascular disease, characteristic features consistent with the activation of the renin-angiotensin system (RAS). 5,6 These observations suggest that aging, CKD, and RAS activation might be intimately linked. However, the molecular details behind these connections are not fully understood.RAS consists of several key components, including angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), and angiotensin II type I and type II receptors (AT1 and AT2, respectively).7e9 Two main enzymes in this system, renin and ACE, lead to the formation of angiotensin II, the principal active peptide of RAS, which mediates both blood pressureedependent and eindependent kidney damage in CKD. Several factors can induce RAS activation, such as reactive oxygen species, hyperglycemia, and albumin. 10,11 We recently found that all RAS genes contain T cell factor/ lymphoid enhancer-binding factor binding sites in their promoter regions and are directly regulated by canonical Wnt/ b-catenin signaling.12 These results have established that bcatenin is a master regulator controlling the expression of all RAS components in the kidneys.

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Angiotensin II overcomes strain-dependent resistance of rapid CKD progression in a new remnant kidney mouse model

Cited by 137 publications

References 81 publications

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

Hibiscus SabdariffaLinnaeus Aqueous Extracts Attenuate the Progression of Renal Injury in 5/6 Nephrectomy Rats

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

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