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Xiaoyan Zhou

Publications and source records attributed to Xiaoyan Zhou.

At least 19 recordsLinked to original sources
PubMed2026

A bi-directional Mendelian randomization study of sarcopenia-related traits and renal function.

The association between sarcopenia and renal function has been reported in observational studies; however, the directionality and potential causal nature of these associations remain uncertain. We assessed whether genetically predicted sarcopenia-related traits are associated with renal function and vice versa using bidirectional Mendelian randomization (MR). We conducted a bidirectional two-sample MR analysis using publicly available European-ancestry GWAS summary statistics for appendicular lean mass (ALM), hand-grip strength (left and right), and walking pace, and for renal function (cystatin C-based estimated glomerular filtration rate [eGFRcystatin C] and urinary albumin excretion [UAE]). Causal estimates were primarily obtained using inverse-variance weighted (IVW) models, complemented by sensitivity analyses (MR-Egger intercept, weighted median/mode, MR-PRESSO, Radial MR, and leave-one-out). In forward MR, genetically predicted walking pace was positively associated with eGFRcystatin C. Genetically predicted ALM and grip strength (right and left) were inversely associated with UAE. In reverse MR, genetically predicted UAE was inversely associated with ALM and right-hand grip strength. Estimates were broadly consistent across sensitivity analyses, and outlier-robust analyses (MR-PRESSO/Radial MR) yielded similar results. These findings provide genetic evidence consistent with bidirectional relationships between sarcopenia-related traits and renal function (particularly UAE), under standard MR assumptions. Given potential limitations (e.g., heterogeneity, pleiotropy, and possible sample overlap), the results should be interpreted cautiously and complemented by other lines of evidence.

Humans↗
PubMed2026

Cancer of unknown primary: the evolution of tissue of origin identification in the artificial intelligence era.

Cancer of Unknown Primary (CUP) presents substantial diagnostic and therapeutic challenges owing to its heterogeneous nature and the absence of an identifiable primary tumor site. This review provides a structured search of the pathogenesis, epidemiological characteristics, and limitations of traditional diagnostic and therapeutic approaches for CUP, with an emphasis on the evolution of Tissue of Origin (TOO) identification techniques. Recent advances in precision medicine have accelerated the development of machine learning-based TOO identification tools, representing a paradigm shift in CUP diagnostics. Deep learning (DL) algorithms that integrate multi-omics data (such as genomics and transcriptomics) with clinical features have markedly enhanced the accuracy of tracing tumor origin, and artificial intelligence (AI) driven TOO models are increasingly being incorporated into clinical practice, offering new insights for pathological diagnosis, treatment selection, and prognostic evaluation. Nevertheless, several challenges remain, including issues of data standardization, model generalizability, and interpretability. Ethical considerations related to data privacy, algorithmic fairness, and clinical implementation also warrant careful attention. Future research should focus on establishing standardized multi-center databases, developing more interpretable AI models, and fostering multidisciplinary collaborative strategies for CUP management. Through continued refinement of technical solutions and regulatory guidelines, TOO identification is anticipated to progress from research to routine clinical application, ultimately supporting precise and personalized care for patients with CUP.

Artificial intelligence↗
PubMed2026

An Integrative Morphological and Genomic Analysis With a Refined Fluorescence In Situ Hybridization (FISH) Threshold and Novel Kinase Fusions in a Large Asian Cohort of Spitzoid Neoplasms.

Differentiating atypical Spitz tumors (ASTs) from true Spitz melanomas (SMs) and conventional melanomas with spitzoid features (MSFs) remains a formidable diagnostic challenge. Because current molecular epidemiological data are overwhelmingly derived from Caucasian cohorts, the genomic landscape of Asian populations remains largely unexplored. To elucidate the molecular progression landscape and refine the diagnostic criteria, we performed a comprehensive multimodal analysis-integrating histomorphology, immunohistochemistry, multiprobe fluorescence in situ hybridization (FISH), and targeted RNA/DNA-based next-generation sequencing (NGS)-on a cohort of 140 spitzoid neoplasms. This cohort, comprising 126 ASTs, 8 SMs, and 6 MSFs, represents the largest Asian cohort to date. Malignant phenotype strongly correlated with lesional asymmetry, deep atypical mitoses, a sheet-like growth pattern, diffuse preferentially expressed antigen of melanoma positivity, and significant loss of p16 expression (64.3% in SM/MSF vs 9.5% in ASTs; P < .0001). Building upon the established melanoma FISH criteria, we optimized a prognostic threshold of &#x2265;2 FISH abnormalities specifically tailored for spitzoid neoplasms. We demonstrated that isolated single chromosomal aberrations (particularly MYB loss) are relatively stable events that are frequent in indolent ASTs, whereas our refined &#x2265;2 threshold yielded 100% sensitivity and 92.5% specificity for predicting regional lymph node metastasis/local recurrence. Molecularly, NGS identified mutually exclusive initiating driver alterations (comprising kinase fusions and HRAS mutations) in 89.9% of true Spitz neoplasms, a remarkably high prevalence suggesting a distinct genetic background in Asian populations. We also characterized 5 entirely novel kinase fusions (ZNF24::ROS1, PCBP1::ROS1, NUMA1::RET, CBWD1::ALK, and TPR::NTRK1). Furthermore, NGS definitively segregated true Spitz neoplasms from morphological mimics (MSF), which lacked fusions and were driven by canonical genomic alterations of the conventional melanoma pathway. Integrating these genomic landscapes validated a stepwise progression model. Although isolated kinase fusions drove indolent ASTs, malignant SM invariably harbored concurrent pathogenic secondary alterations, demonstrating a profound reliance on CDKN2A/B, TP53, and CDK4 aberrations. Ultimately, we propose an integrated diagnostic algorithm combining morphological evaluation, the refined FISH threshold, and comprehensive NGS profiling, providing a precise, evidence-based framework for pathway classification and clinical management of spitzoid neoplasms.

fluorescence in situ hybridization↗
PubMed2006

Salt loading produces severe renal hemodynamic dysfunction independent of arterial pressure in spontaneously hypertensive rats.

We have previously shown that salt excess has adverse cardiac effects in spontaneously hypertensive rats (SHR), independent of its increased arterial pressure; however, the renal effects have not been reported. In the present study we evaluated the role of three levels of salt loading in SHR on renal function, systemic and renal hemodynamics, and glomerular dynamics. At 8 wk of age, rats were given a 4% (n = 11), 6% (n = 9), or 8% (n = 11) salt-load diet for the ensuing 8 wk; control rats (n = 11) received standard chow (0.6% NaCl). Rats had weekly 24-h proteinuria and albuminuria quantified. At the end of salt loading, all rats had systemic and renal hemodynamics measured; glomerular dynamics were specially studied by renal micropuncture in the control, 4% and 6% salt-loaded rats. Proteinuria and albuminuria progressively increased by the second week of salt loading in the 6% and 8% salt-loaded rats. Mean arterial pressure increased minimally, and glomerular filtration rate decreased in all salt-loaded rats. The 6% and 8% salt-loaded rats demonstrated decreased renal plasma flow and increased renal vascular resistance and serum creatinine concentration. Furthermore, 4% and 6% salt-loaded rats had diminished single-nephron plasma flow and increased afferent and efferent arteriolar resistances; glomerular hydrostatic pressure also increased in the 6% salt-loaded rats. In conclusion, dietary salt loading as low as 4% dramatically deteriorated renal function, renal hemodynamics, and glomerular dynamics in SHR independent of a minimal further increase in arterial pressure. These findings support the concept of a strong independent causal relationship between salt excess and cardiovascular and renal injury.

Albuminuria↗
PubMed2006

ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells.

ErbB2 overexpression in breast tumors results in increased metastasis and angiogenesis and reduced survival. To study ErbB2 signaling mechanisms in metastasis and angiogenesis, we did a spontaneous metastasis assay using MDA-MB-435 human breast cancer cells stably transfected with constitutively active ErbB2 kinase (V659E), a kinase-dead mutant of ErbB2 (K753M), or vector control (neo). Mice injected with V659E had increased metastasis incidence and tumor microvessel density than mice injected with K753M or control. Increased angiogenesis in vivo from the V659E transfectants paralleled increased angiogenic potential in vitro. V659E produced increased vascular endothelial growth factor (VEGF) through increased VEGF protein synthesis. This was mediated through signaling events involving extracellular signal-regulated kinase, phosphatidylinositol 3-kinase/Akt, mammalian target of rapamycin (mTOR), and p70S6K. The V659E xenografts also had significantly increased phosphorylated Akt, phosphorylated p70S6K, and VEGF compared with controls. To validate the clinical relevance of these findings, we examined 155 human breast tumor samples. Human tumors that overexpressed ErbB2, which have been previously shown to have higher VEGF expression, showed significantly higher p70S6K phosphorylation as well. Increased VEGF expression also significantly correlated with higher levels of Akt and mTOR phosphorylation. Additionally, patients with tumors having increased p70S6K phosphorylation showed a trend for worse disease-free survival and increased metastasis. Our findings show that ErbB2 increases VEGF protein production by activating p70S6K in cell lines, xenografts, and in human cancers and suggest that these signaling molecules may serve as targets for antiangiogenic and antimetastatic therapies.

Animals↗
PubMed2006

Uric acid: its relationship to renal hemodynamics and the renal renin-angiotensin system.

Reports relating hyperuricemia and hypertension have been filed for many decades. Nevertheless, controversy remains concerning serum uric acid concentration as an independent risk factor underlying coronary heart disease (CHD) and essential hypertension or as an indirect marker of renovascular involvement. Earlier studies in normotensive subjects and hypertensive patients demonstrated that serum uric acid concentration was closely related to intrarenal hemodynamic alterations, suggesting that it is an excellent marker of vascular involvement. Our data from clinical studies and in an animal model of severe hypertensive nephrosclerosis have strengthened this concept. Conversely, other reports have suggested that uric acid may be a pathogenetic factor. Supporting arguments for this theory maintain that experimental hyperuricemia induces hypertension and renal damage. Epidemiologically, hyperuricemia is associated with hypertension, CHD, renal disease, toxemia of pregnancy, and other outcomes, although mechanisms remain unclear. Additionally, there are no available data on the effects of lowering uric acid on pressure control and organ protection.

Humans↗
PubMed2006

Hypertensive renal vascular disease and cardiovascular endpoints.

PURPOSE OF REVIEW: Hypertension involves the entire cardiovascular system, and hypertensive vascular disease may promote and exacerbate cardiac and renal dysfunction. We discuss the coexistence of cardiorenal disease as a manifestation of vascular involvement in hypertension, and the relationship of biomarkers of renal vascular involvement in hypertension with cardiovascular endpoints. RECENT FINDINGS: Markers of renal dysfunction, especially microalbuminuria, have been considered recently as potent predictors of cardiovascular morbidity and mortality in all explored populations, including hypertensive individuals. Microalbuminuria, per se, is related to vascular injury and to the increased glomerular permeability of albumin as a direct manifestation of renal vascular involvement in hypertension, a systemic vascular disease. Left ventricular hypertrophy in hypertension develops even before proteinuria or impairment of renal function. Factors including anemia, inflammation and hyperuricemia are either induced or exacerbated by renal vascular disease, and each of these may exert additional influence in determining the increased incidence of cardiovascular events with progressive renal dysfunction. SUMMARY: The development and progression of vascular disease is the primary determinant in the progressive cardiac and renal dysfunction observed in hypertension and, therefore, is the underlying mechanism of the overall clinical manifestations of cardiorenal disease. Commonly used biomarkers of renal and vascular function are important tools for determination of the progression and, hence, management of hypertensive disease and its complications.

Albuminuria↗
PubMed2006

Facial expression recognition using kernel canonical correlation analysis (KCCA).

In this correspondence, we address the facial expression recognition problem using kernel canonical correlation analysis (KCCA). Following the method proposed by Lyons et al. and Zhang et al., we manually locate 34 landmark points from each facial image and then convert these geometric points into a labeled graph (LG) vector using the Gabor wavelet transformation method to represent the facial features. On the other hand, for each training facial image, the semantic ratings describing the basic expressions are combined into a six-dimensional semantic expression vector. Learning the correlation between the LG vector and the semantic expression vector is performed by KCCA. According to this correlation, we estimate the associated semantic expression vector of a given test image and then perform the expression classification according to this estimated semantic expression vector. Moreover, we also propose an improved KCCA algorithm to tackle the singularity problem of the Gram matrix. The experimental results on the Japanese female facial expression database and the Ekman's "Pictures of Facial Affect" database illustrate the effectiveness of the proposed method.

Algorithms↗
PubMed2005

Superiority of combination of thiazide with angiotensin-converting enzyme inhibitor or AT1-receptor blocker over thiazide alone on renoprotection in L-NAME/SHR.

The renal and glomerular dynamic effects of combining thiazide and angiotensin antagonists have not been reported. The present study was designed to examine the effects of hydrochlorothiazide (HCTZ) alone or in combination with an angiotensin-converting enzyme inhibitor or ANG II type 1-receptor blocker on renal hemodynamics, glomerular dynamics, renal function, and renal histopathology in the N(omega)-nitro-l-arginine methyl ester-treated spontaneously hypertensive rat (l-NAME/SHR) model. HCTZ (80 mg x kg(-1) x day(-1)) alone or in combination with enalapril (30 mg x kg(-1) x day(-1)) or losartan (30 mg x kg(-1) x day(-1)) or enalapril (15 mg.kg(-1).day(-1)) plus losartan (15 mg x kg(-1) x day(-1)) was administered to l-NAME/SHR (5.0 +/- 0.10 mg x kg(-1) x day(-1)) for 3 wk. Mean arterial pressure, total peripheral resistance, renal plasma flow, glomerular filtration rate, glomerular hydrostatic pressure, afferent and efferent glomerular arteriolar resistances, single nephron plasma flow, single nephron glomerular filtration rate, serum creatinine concentration, 24-h urinary protein excretion, and glomerular and arteriolar injury scores were determined. HCTZ reduced mean arterial pressure, total peripheral resistance, glomerular hydrostatic pressure, and afferent and efferent glomerular arteriolar resistances (P < 0.05, at least) but slightly increased renal plasma flow and single nephron plasma flow associated with reduced serum creatinine concentration, urinary protein excretion, and arteriolar injury score compared with l-NAME/SHR control. However, the combination of enalapril and/or losartan with HCTZ markedly improved each of these functions. These results demonstrated minor benefits of HCTZ monotherapy and a marked superiority of its combination with enalapril and/or losartan over HCTZ monotherapy on renoprotection in l-NAME/SHR, thereby providing strong evidence of their clinical benefits for hypertensive patients with renal functional impairment.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Differential effects of antihypertensive drugs on renal and glomerular hemodynamics and injury in the chronic nitric-oxide-suppressed rat.

BACKGROUND/AIMS: Prolonged nitric oxide synthase (NOS) inhibition with N(omega)-nitro-L-arginine methylester in normotensive and hypertensive rats has been demonstrated to produce severe systemic and glomerular hypertension with glomerular sclerosis, and these changes have become a useful experimental model of hypertensive nephrosclerosis. This review summarizes data from our serial studies as well as work of others who are also investigating the effects of the commonly used antihypertensive drugs (including calcium antagonist, angiotensin-converting enzyme inhibitor, angiotensin II type 1 receptor blocker, aldosterone antagonist and thiazide diuretic) on renal and glomerular hemodynamics, renal function and glomerular histopathology using this model. METHODS: A Medline search was performed to identify the relevant literature describing renal effects of antihypertensive drugs in models of hypertension and nephrosclerosis produced or exacerbated by NOS inhibition. RESULTS: Existing data have indicated that most of these drug classes have produced dramatic renoprotective effects, structurally or functionally, on nephrosclerosis induced by prolonged NOS inhibition. CONCLUSION: This review of experimental studies has provided strong evidence supporting the clinical benefits of antihypertensive drugs for hypertensive patients with renal impairment particularly those with endothelial dysfunction associated with NOS deficiency.

Animals↗
PubMed2005

Expression of cyclooxygenase-2 mRNA and identification of its splice variant in human myometrium obtained from women in labor.

In order to investigate the expression of cyclooxygenase-2 (COX-2) in human lower segments of myometrium obtained from women in labor and those not in labor and identify the splicing variant of COX-2, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the expression of COX-2. The primers were designed and synthesized according to the sequence of rat COX-2 splice variant which was discovered firstly by us. Then the splicing variant of COX-2 in human myometrium from woman in labor was identified, cloned into vector and sequenced. The results showed that the expression of COX-2 mRNA was lower in human myometrium obtained from women who were not in labor than that in labor women and a new band of COX-2 was obtained in myometrium from labor woman. The fragment included an unspliced intron, which pitched between exons 7 and 8. It was suggested that COX-2 gene was not only expressed highly in human myometrium from woman in labor, but also produced splicing variant by alternative splicing.

Adult↗
PubMed2005

Physiologic evidence of renoprotection by antihypertensive therapy.

PURPOSE OF REVIEW: Hypertension is vastly prevalent worldwide and constitutes the second leading cause of end-stage renal disease. Therefore, treating hypertension and protecting the kidney from deterioration are exceedingly important. Although previous studies have explored the renal effects of various antihypertensive drugs in animal models and humans, recent clinical trials are all the more convincing. This review summarizes the latest data demonstrating the physiologic evidence of renoprotection by antihypertensive therapy. RECENT FINDINGS: Experimental studies in various models of hypertension with renal injury have demonstrated clearly that angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, or aldosterone antagonists promote beneficial renal actions, through hemodynamic and nonhemodynamic mechanisms. Of particular significance, recent clinical trials have demonstrated renoprotection by angiotensin II inhibition in patients with hypertension and chronic kidney disease. Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade have provided equivalent renal benefits, and their dual action seems to confer greater renoprotection. The available data on the renal outcomes of other antihypertensive drugs such as calcium antagonists have been inconsistent. SUMMARY: The results of the numerous experimental and clinical studies have established the renoprotective properties of renin-angiotensin-aldosterone inhibitors, which confer greater benefit by virtue of their effects over and beyond blood pressure reduction. These findings provide the convincing basis for the recommendation of angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, or both as first-line therapy in hypertension with chronic kidney disease.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Diagnosis and follow-up study of carotid cavernous fistulas with color Doppler ultrasonography: analysis of 33 cases.

OBJECTIVE: The purpose of this study was to observe image characteristics and hemodynamic changes of carotid-cavernous sinus fistulas (CCFs) and to evaluate the efficacy of interventional treatment for CCFs by color Doppler ultrasonography (CDUS). METHODS: Thirty-three patients with suspected CCFs were studied with CDUS. Forty-six volunteers took part in this study as controls. Scanning was performed through temporal, orbital, and occipital windows to measure the blood flow parameters of the internal carotid artery (ICA) and related vessels. All results were confirmed by cerebral angiography. Nineteen patients were followed after interventional treatment. RESULTS: Thirty-two patients (97%) were found to have CCFs by CDUS. Irregular mosaic flashes were observed in the cavernous sinus region, the cross-section areas of which were significantly larger than those of the normal intracranial ICA (1.7-5.2 versus 0.2-0.5 cm(2); P < .01). A lower resistive index of the ICA in the affected side was revealed with spectral analysis of relevant vessels. The peak velocity of vessels distal to the fistula was significantly lower than that of the healthy side and control group (P < .05). Superior ophthalmic veins had a reversed arterialized flow pattern with a mean velocity of 34.5 cm/s and an average resistive index +/- SD of 0.31 +/- 0.08. In follow-up study, the mosaic flashes and turbulence flow disappeared in 14 patients and remained in 5 after the interventional operation. CONCLUSIONS: Combined with the direct sign of an irregular mosaic flash in the cavernous sinus region, hemodynamic changes in relevant branch vessels, and a reversed arterialized flow pattern in superior ophthalmic veins, CDUS has great value in confirming diagnosis and follow-up study of CCFs.

Adult↗
PubMed2004

Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers.

The Akt/mammalian target of rapamycin (mTOR)/4E-BP1 pathway is considered to be a central regulator of protein synthesis, involving the regulation of cell proliferation, differentiation, and survival. The inhibitors of mTOR as anticancer reagents are undergoing active evaluation in various malignancies including breast cancer. However, the activation status of the Akt/mTOR/4E-BP1 pathway and its potential roles in breast cancers remain unknown. Thus, we examined 165 invasive breast cancers with specific antibodies for the phosphorylation of Akt, mTOR, and 4E-BP1 by immunohistochemistry and compared them with normal breast epithelium, fibroadenoma, intraductal hyperplasia, and ductal carcinoma in situ. We discovered that the phosphorylation of Akt, mTOR, and 4E-BP1 increased progressively from normal breast epithelium to hyperplasia and abnormal hyperplasia to tumor invasion. Phosphorylated Akt, mTOR, and 4E-BP1 were positively associated with ErbB2 overexpression. Survival analysis showed that phosphorylation of each of these three markers was associated with poor disease-free survival independently. In vitro, we further confirmed the causal relationship between ErbB2 overexpression and mTOR activation, which was associated with enhanced invasive ability and sensitivity to a mTOR inhibitor, rapamycin. Our results, for the first time, demonstrate the following: (a) high levels of phosphorylation of Akt, mTOR, and 4E-BP1 in breast cancers, indicating activation of the Akt/mTOR/4E-BP1 pathway in breast cancer development and progression; (b) a link between ErbB2 and the Akt/mTOR/4E-BP1 pathway in breast cancers in vitro and in vivo, indicating the possible role of Akt/mTOR activation in ErbB2-mediated breast cancer progression; and (c) a potential role for this pathway in predicting the prognosis of patients with breast cancer, especially those treated with mTOR inhibitors.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Evaluation of left ventricular ejection fraction by tissue locus imaging.

The newly developed echocardiographic technique called "tissue locus imaging" (TLI) can visualize temporal series of images in a single picture by maintaining the display of previous images with a shading function; therefore, it can display the whole systolic shift of the mitral leaflets toward the apex in a single picture and can potentially offer useful information on left ventricular (LV) function. In 36 consecutive patients with varying degrees of LV dysfunction (15 with coronary artery disease, 9 with cardiomyopathy, 3 with hypertension, 2 with aortic stenosis, 1 with aortic regurgitation, and 6 controls), the systolic shift of the mitral leaflets (X) by TLI showed a significant correlation with the LV ejection fraction (Y) by 2-dimensional echocardiography (Y = 7.2 x+13, r(2) = 0.83, p <0.01). TLI enables the evaluation and visualization of LV systolic function by displaying the whole systolic shift of the mitral leaflets toward the apex.

Adult↗
PubMed2004

Lineage infidelity of MDA-MB-435 cells: expression of melanocyte proteins in a breast cancer cell line.

The origin of cell lines is critical in defining cell type-specific biological functions. Several reports suggested that the MDA-MB-435 cell line, a cell line extensively used for studying breast cancer biology, has a gene expression pattern most compatible with melanocyte origin. However, we demonstrate that MDA-MB-435 cells express breast-specific or epithelial-specific markers. Also, MDA-MB-435 cells were induced to express breast differentiation-specific proteins and secrete milk lipids as observed in other well-established breast cancer cell lines. Notably, MDA-MB-435 cells also expressed melanocyte-specific proteins as did another highly aggressive breast cancer cell line. MDA-MB-435 xenograft tissue sections stained entirely positive for epithelium-specific markers but only partially positive for melanocyte-specific markers. Thus, MDA-MB-435 is most likely a breast epithelial cell line that has undergone lineage infidelity.

Animals↗
PubMed2004

Aldosterone antagonism ameliorates proteinuria and nephrosclerosis independent of glomerular dynamics in L-NAME/SHR model.

BACKGROUND: The renin-angiotensin-aldosterone system participates importantly in the progression of hypertensive renal disease. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists have been demonstrated to afford renoprotection in L-NAME-exacerbated nephrosclerosis in SHR rats. This study was designed to examine the effects of the aldosterone antagonist eplerenone on systemic and renal hemodynamics, glomerular dynamics, renal function and histopathology in L-NAME/SHR, and determine whether aldosterone antagonism would enhance the effectiveness of ACE inhibition. METHODS: Six groups of 20-week-old SHR were studied using renal micropuncture and histopathological techniques after 3 weeks of treatment: SHR control (tapwater, n = 10); SHR + eplerenone (101 +/- 8.3 mg/kg/day, n = 10); SHR + L-NAME (5.0 +/- 0.12 mg/kg/day, n = 9); SHR + L-NAME + eplerenone (n = 8); SHR + L-NAME + lisinopril (3 mg/kg/day, n = 9), and SHR + L-NAME + eplerenone + lisinopril (n = 9). RESULTS: L-NAME-treated SHR developed massive proteinuria, severe hypertensive nephrosclerosis, and tubulointerstitial damage. Eplerenone significantly reduced proteinuria (127.4 +/- 26.5 vs. 51.9 +/- 16.7 mg/24 h, p < 0.01), improved glomerular and arteriolar injuries (65 +/- 9 vs. 29 +/- 9 score/100 glomeruli, p < 0.01; 116 +/- 18 vs. 41 +/- 13 score/100 arterioles, p < 0.01, respectively), and decreased tubulointerstitial damage index (1.43 +/- 0.07 vs. 0.39 +/- 0.07, p < 0.01) without altering mean arterial pressure or glomerular dynamics. Combined therapy of eplerenone with lisinopril produced no further benefits than lisinopril alone. CONCLUSION: The aldosterone antagonist eplerenone significantly ameliorated proteinuria and nephrosclerosis in the L-NAME/SHR model, independent of hemodynamic effects.

Animals↗