Increased risk of cardiovascular events and mortality among non-diabetic chronic kidney disease patients with hypertensive nephropathy: the Gonryo study

Nakayama, Masaaki; Sato, Toshinobu; Miyazaki, Mariko; Matsushima, Masato; Sato, Hiroshi; Taguma, Yoshio; Ito, Sadayoshi

doi:10.1038/hr.2011.96

Cited by 52 publications

(38 citation statements)

References 35 publications

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“…12 In turn, coexistent hypertension is responsible for the progression of chronic kidney disease with accelerated segmental or global glomerulosclerosis that may be superimposed on the phenotype of the underlying kidney disease. 13,14 In this context, identification of genes and gene products that are linked to structural changes of the kidney remains one of the key questions in the analysis of renal impairment during hypertension.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of the Hypertension-Associated Gene NOSTRIN Alters Glomerular Barrier Function in Zebrafish ( Danio rerio )

Kirsch

Kaufeld²,

Korstanje³

et al. 2013

Hypertension

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Abstract-Hypertension is one of the major risk factors for chronic kidney disease. Using quantitative trait loci analysis, we identified the gene of the F-BAR protein NOSTRIN in the center of an overlapping region in rat and human quantitative trait loci that are associated with hypertension. Immunohistochemical analysis revealed a predominantly podocytic expression pattern of NOSTRIN in human and mouse glomeruli. Further, NOSTRIN colocalizes with cell-cell contactassociated proteins β-catenin and zonula occludens-1 and interacts with the slit-membrane-associated adaptor protein CD2AP. In zebrafish larvae, knockdown of nostrin alters the glomerular filtration barrier function, inducing proteinuria and leading to ultrastructural morphological changes on the endothelial and epithelial side and of the glomerular basement membrane of the glomerular capillary loop. We conclude that NOSTRIN expression is an important factor for the integrity of the glomerular filtration barrier. Disease-related alteration of NOSTRIN expression may not only affect the vascular endothelium and, therefore, contribute to endothelial cell dysfunction but might also contribute to the development of podocyte disease and proteinuria. Results NOSTRIN Is Expressed in Glomerular PodocytesImmunostainings with a polyclonal antibody directed against a peptide localized near the C terminus of rodent NOSTRIN revealed that NOSTRIN is expressed in peritubular capillaries and glomerular structures ( Figure 1A). Double stainings with podocytic and endothelial markers showed that glomerular NOSTRIN expression could be assigned to podocytic structures ( Figure 1B). A strong colocalization of NOSTRIN and the endothelial cell marker thrombomodulin could be observed in vascular structures outside the glomerulus (data not shown). Immunostainings of human kidney sections with an antibody directed against human NOSTRIN confirmed podocytic distribution pattern in the glomerulus ( Figure 1C). NOSTRIN Interacts With Cell Contact-Associated Proteins in Human PodocytesTo further characterize NOSTRIN expression in podocytes, we performed double stainings of NOSTRIN with the cell contact-associated proteins β-catenin and zonula occludens-1 in cultured human podocytes. As depicted in Figure 2A, NOSTRIN displayed a close colocalization with β-catenin and zonula occludens-1 in regions of cell-cell contacts ( Figure 2A). Coimmunoprecipitation experiments demonstrated that NOSTRIN interacts with cell-cell contact-specific proteins β-catenin, CD2AP, and caveolin-1 ( Figure 2B). Knockdown of NOSTRIN Induces a Renal Phenotype in ZebrafishTo prove that NOSTRIN is relevant for the integrity of the glomerular filtration barrier, we analyzed functional effects of NOSTRIN loss on the kidney in vivo in larval zebrafish. Although rat or human NOSTRIN is only 44% homologous to their zebrafish equivalent, the different functional domains remain conserved between the different species indicating that the zebrafish NOSTRIN orthologue might have similar functions ( Figure 3A). After inj...

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Section: Discussionmentioning

confidence: 99%

Knockdown of the Hypertension-Associated Gene NOSTRIN Alters Glomerular Barrier Function in Zebrafish ( Danio rerio )

Kirsch

Kaufeld²,

Korstanje³

et al. 2013

Hypertension

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“…We conducted a prospective observational cohort study, named the Gonryo CKD Project, in an outpatient basis in 11 hospitals that offer nephrology services, including one university hospital in Miyagi Prefecture, located in the northeast area of Japan [14,15]. The participating hospitals covered almost the entire medical network of the area.…”

Section: Participantsmentioning

confidence: 99%

Relationship between low blood pressure and renal/cardiovascular outcomes in Japanese patients with chronic kidney disease under nephrologist care: the Gonryo study

et al. 2015

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Background Previous studies established a J-shaped association between blood pressure (BP) and cardiovascular disease (CVD) in chronic kidney disease (CKD), and the different clinical profiles of CVD by ethnicity. However, the adequately lower BP target remains unclear in Asian patients with CKD. Methods This prospective observational study included 2,655 Japanese outpatients with CKD under nephrologist care who met the inclusion criteria, namely estimated glomerular filtration rate \60 mL/min and/or presenting proteinuria. The patients were divided by 10-mmHg BP increments by clinical data. The end points were death, cardiovascular events (CVEs), and end-stage kidney disease (ESKD) that requires renal replacement therapy. Results During a 3.02-year median follow-up, 64 patients died, 120 developed CVEs, and 225 progressed to ESKD. In the adjusted Cox models, the risks of CVEs and allcause mortality were higher in the patients with systolic BPs (SBPs) \ 110 mmHg than in those with SBPs of 130-139 mmHg. Moreover, the risk was higher in those with diastolic BPs (DBPs) \ 70 mmHg than in those with DBPs of 80-89 mmHg. Although SBPs C 140 mmHg were associated with higher incidence rates of ESKD, no significant increased risk was associated with BPs \ 130/ 80 mmHg. Conclusions SBPs \ 110 mmHg and DBPs \ 70 mmHg were independent risk factors of CVEs and all-cause mortality. No lower BPs were observed as significant risk factors of progression to ESKD. This study suggests that the lower BP target in Asian patients with CKD should be C110/70 mmHg.

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“…In the revision of the guidelines, the incidence of cardiovascular events and stroke was compared among the CHOIR and CREATE studies; the TREAT study, which was reported after the publication of the previous version of the guideline; the A21 study [42], which was an intervention study conducted in Japan; and the Gonryo study [48], which was an observational study conducted in Japan. As a result, the incidence of cardiovascular events was higher in Europe and the USA than in Japan.…”

Section: Statementmentioning

confidence: 99%

2015 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

Yamamoto¹,

et al. 2017

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Increased risk of cardiovascular events and mortality among non-diabetic chronic kidney disease patients with hypertensive nephropathy: the Gonryo study

Cited by 52 publications

References 35 publications

Knockdown of the Hypertension-Associated Gene NOSTRIN Alters Glomerular Barrier Function in Zebrafish ( Danio rerio )

Knockdown of the Hypertension-Associated Gene NOSTRIN Alters Glomerular Barrier Function in Zebrafish ( Danio rerio )

Relationship between low blood pressure and renal/cardiovascular outcomes in Japanese patients with chronic kidney disease under nephrologist care: the Gonryo study

2015 Japanese Society for Dialysis Therapy: Guidelines for Renal Anemia in Chronic Kidney Disease

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