Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nephroangiosclerosis (NAS) is increasingly diagnosed in adult and elderly patients with slowly progressive chronic renal insufficiency. Since these patients usually present with arterial hypertension, this is considered the main cause of NAS (sometimes called, in fact, hypertensive NAS or hypertensive nephropathy). However, there is evidence that other factors such as aging, black race, smoking, and metabolic disturbances contribute to the development and progression of the disease. In some patients, these factors may be prominent while hypertension may be mild or even absent: this form has been denominated ischemic nephropathy (IN). Are NAS and IN really two different diseases or just different presentations of cardiovascular disease involving the kidney? The latter hypothesis is supported by evidence that (a) NAS and IN share a relative aspecificity in their clinical symptoms (low proteinuria, microhematuria, high blood pressure, dyslipidemia) and histopathological features (as determined in the few cases that undergo a kidney biopsy), and (b) there is a high likelihood that atheromatous and hypertensive lesions coexist in the same patient. In this ''Controversy in Nephrology'', Rosario Cianci and Alessandro Zuccala' analyze this issue and try to answer the following questions: 1 - Are NAS and IN two different diseases or two different expressions of the same disease? Rosario Cianci, ''They are two different diseases''. Alessandro Zuccala', ''They represent two different expressions of the same disease''. 2 - Is the pathogenesis different in nephroangiosclerosis and IN? Rosario Cianci, ''The pathogenesis is high blood pressure in NAS and renal ischemia in IN''. Alessandro Zuccala', ''NAS and IN share the same multifactorial pathogenesis: vascular metabolic alterations can cause chronic renal ischemia with or without hypertension''. 3 - Is a biopsy necessary for the diagnosis? Rosario Cianci, ''Yes, it is''. Alessandro Zuccala', ''No, it is not''. 4 - Is it possible to prevent or to slow the progression of the renal damage in this (these) disease(s)? Rosario Cianci, ''Yes it is, by reducing blood pressure''. Alessandro Zuccala', ''Normalization of blood pressure is not enough but all the other risk factors of vascular damage must be addressed, when possible''.
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PMID:[Nephroangiosclerosis and ischemic nephropathy: two different entities or two renal manifestations of the same systemic cardiovascular disease?]. 1955 27

FSGS is the most common primary glomerular disease underlying ESRD in the United States and is increasing in incidence globally. FSGS results from podocyte injury, yet the mechanistic details of disease pathogenesis remain unclear. This has resulted in an unmet clinical need for cell-specific therapy in the treatment of FSGS and other proteinuric kidney diseases. We previously identified Yes-associated protein (YAP) as a prosurvival signaling molecule, the in vitro silencing of which increases podocyte susceptibility to apoptotic stimulus. YAP is a potent oncogene that is a prominent target for chemotherapeutic drug development. In this study, we tested the hypothesis that podocyte-specific deletion of Yap leads to proteinuric kidney disease through increased podocyte apoptosis. Yap was selectively silenced in podocytes using Cre-mediated recombination controlled by the podocin promoter. Yap silencing in podocytes resulted in podocyte apoptosis, podocyte depletion, proteinuria, and an increase in serum creatinine. Histologically, features characteristic of FSGS, including mesangial sclerosis, podocyte foot process effacement, tubular atrophy, interstitial fibrosis, and casts, were observed. In human primary FSGS, we noted reduced glomerular expression of YAP. Taken together, these results suggest a role for YAP as a physiologic antagonist of podocyte apoptosis, the signaling of which is essential for maintaining the integrity of the glomerular filtration barrier. These data suggest potential nephrotoxicity with strategies directed toward inhibition of YAP function. Further studies should evaluate the role of YAP in proteinuric glomerular disease pathogenesis and its potential utility as a therapeutic target.
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PMID:Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure. 2601 53

Podocyte apoptosis is a major mechanism that leads to proteinuria in many chronic kidney diseases. However, the concert mechanisms that cause podocyte apoptosis in these kidney diseases are not fully understood. The Rho family of small GTPases has been shown to be required in maintaining podocyte structure and function. Recent studies have indicated that podocyte-specific deletion of Cdc42 in vivo, but not of RhoA or Rac1, leads to congenital nephrotic syndrome and glomerulosclerosis. However, the underlying cellular events in podocyte controlled by Cdc42 remain unclear. Here, we assessed the cellular mechanisms by which Cdc42 regulates podocyte apoptosis. We found that the expression of Cdc42 and its activity were significantly decreased in high glucose-, lipopolysaccharide- or adriamycin-injured podocytes. Reduced Cdc42 expression in vitro and in vivo by small interfering RNA and selective Cdc42 inhibitor ML-141, respectively, caused podocyte apoptosis and proteinuria. Our results further demonstrated that insufficient Cdc42 or Nwasp, its downstream effector, could decrease the mRNA and protein expression of YAP, which had been regarded as an anti-apoptosis protein in podocyte. Moreover, our data indicated that the loss of stress fibers caused by Cdc42/Nwasp deficiency also decreased Yes-associated protein (YAP) mRNA and protein expression, and induced podocyte apoptosis. Podocyte apoptosis induced by Cdc42/Nwasp/stress fiber deficiency was significantly inhibited by overexpressing-active YAP. Thus, the Cdc42/Nwasp/stress fibers/YAP signal pathway may potentially play an important role in regulating podocyte apoptosis. Maintaining necessary Cdc42 would be one potent way to prevent proteinuria kidney diseases.
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PMID:Cdc42 deficiency induces podocyte apoptosis by inhibiting the Nwasp/stress fibers/YAP pathway. 2698 10

Preeclampsia (PE) is a gestational disorder with hypertension and proteinuria leading to maternal and fetal morbidity and mortality. Yes-associated protein (YAP), a transcription coactivator of Hippo pathway, was identified as an oncoprotein participated in tumorigenesis. However, the effect of YAP on trophoblast has not been investigated. In our study, YAP expression levels in first-trimester, full-term, and PE placentas were detected using quantitative real-time polymerase chain reaction (PCR), Western blot assays, and immunohistochemistry. Yes-associated protein expression was also detected in BeWo and HTR-8/SVneo. Overexpression plasmid and YAP small interfering RNA were introduced into trophoblast cells. Furthermore, we utilized a Transwell invasion assay, flow cytometry, and Cell Counting Kit-8 analysis to examine the role of YAP in the invasion, apoptosis, and proliferation of HTR-8/SVneo trophoblast cells. The result showed that both YAP messenger RNA (mRNA) and protein expression levels were less in preeclamptic placentas. Yes-associated protein mRNA and protein expression levels were more highly expressed in BeWo. Yes-associated protein enhanced cell invasion, reduced the cellular apoptotic response, and had no effect on proliferation. In addition, the overexpression of YAP activated the expression of caudal-related homeobox transcription factor 2 (CDX2), whereas reduced expression of YAP inhibited the expression of CDX2. Our results demonstrate that decreased YAP levels may contribute to the development of PE by regulating trophoblast invasion and apoptosis involving regulation of CDX2. Collectively, we proposed decreased YAP may contribute to trophoblast dysfunction, which suggests it might represent a prognostic biomarker and therapeutic target for PE.
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PMID:YAP Is Decreased in Preeclampsia and Regulates Invasion and Apoptosis of HTR-8/SVneo. 2930 55

Podocytes are crucial for the establishment of the blood-urine filtration barrier in the glomeruli of the kidney. These cells are mainly affected during glomerulopathies causing proteinuria and kidney function impairment. Ongoing podocyte injury leads to podocyte loss, finally followed by end-stage kidney disease. Podocytes display a predominant nuclear localization of YAP (Yes-associated protein), one effector protein of the Hippo pathway, which regulates the balance between proliferation, differentiation, and apoptosis in cells. Nuclear active YAP seems to be critical for podocyte survival in vivo and in vitro. We can show here that different treatments leading to sequestration of YAP into the cytoplasm in podocytes, like decreased rigidity of the substrate, incubation with dasatinib, or overexpression of Hippo pathway members result in the induction of apoptosis. A RNA sequencing analysis of large tumor suppressor kinase 2 (LATS2) overexpressing podocytes confirmed a significant upregulation of apoptotic genes. The downregulation of Hippo pathway components suggests a feedback mechanism in podocytes. Noteworthy was the regulation of genes involved in cell-cell junction, the composition of the extracellular space, and cell migration. This suggests an influence of Hippo pathway activity on podocyte integrity. As focal segmental glomerulopathy (FSGS) goes along with an activation of the Hippo pathway in podocytes, a comparison of our data with two independent studies of transcriptional regulation in human FSGS glomeruli obtained from the Nephroseq database was performed. This comparison affirmed a multitude of consistent transcriptional changes concerning the regulation of genes influencing apoptosis and the Hippo signaling pathway as well as cell junction formation and cell migration. The link between Hippo pathway activation in podocytes and the regulation of junction and migration processes in vivo might be a fundamental mechanism of glomerular sclerosis and loss of renal function.
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PMID:Nuclear YAP localization as a key regulator of podocyte function. 3015 11