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The glomerular filtration rate (GFR) is the outcome of glomerular hemodynamics, influenced by a series of parameters: renal plasma flow, resistances of afferent arterioles and efferent arterioles (EAs), hydrostatic pressures in the glomerular capillary and Bowman’s capsule, and plasma colloid osmotic pressure in the glomerular capillary. Although mathematical models have been proposed to predict the GFR at both the single-nephron level and the two-kidney system level using these parameters, mathematical equations governing glomerular filtration have not been well-established because of two major problems. First, the two-kidney system-level models are simply extended from the equations at the single-nephron level, which is inappropriate in epistemology and methodology. Second, the role of EAs in maintaining the normal GFR is underappreciated. In this article, these two problems are concretely elaborated, which collectively shows the need for a shift in epistemology toward a more holistic and evolving way of thinking, as reflected in the concept of the complex adaptive system (CAS). Then, we illustrate eight fundamental mathematical equations and four hypotheses governing glomerular hemodynamics at both the single-nephron and two-kidney levels as the theoretical foundation of glomerular hemodynamics. This illustration takes two steps. The first step is to modify the existing equations in the literature and establish a new equation within the conventional paradigm of epistemology. The second step is to formulate four hypotheses through logical reasoning from the perspective of the CAS (beyond the conventional paradigm). Finally, we apply the new equation and hypotheses to comprehensively analyze glomerular hemodynamics under different conditions and predict the GFR. By doing so, some concrete issues are eliminated. Unresolved issues are discussed from the perspective of the CAS and a desinger’s view. In summary, this article advances the theoretical study of glomerular dynamics by 1) clarifying the necessity of shifting to the CAS paradigm; 2) adding new knowledge/insights into the significant role of EAs in maintaining the normal GFR; 3) bridging the significant gap between research findings and physiology education; and 4) establishing a new and advanced foundation for physiology education.

Increased fluid‐flow shear stress (FFSS) contributes to hyperfiltration‐induced podocyte and glomerular injury resulting in progression of chronic kidney disease (CKD). We reported that increased FFSS in vitro and in vivo upregulates PGE2 receptor EP2 (but not EP4 expression), COX2‐PGE2‐EP2 axis, and EP2‐linked Akt‐GSK3β‐β‐catenin signaling pathway in podocytes. To understand and use the disparities between PGE2 receptors, specific agonists, and antagonists of EP2 and EP4 were used to assess phosphorylation of Akt, GSK3β and β‐catenin in podocytes using Western blotting, glomerular filtration barrier function using in vitro albumin permeability (Palb) assay, and mitigation of hyperfiltration‐induced injury in unilaterally nephrectomized (UNX) mice at 1 and 6 months. Results show an increase in Palb by PGE2, EP2 agonist (EP2AGO) and EP4 antagonist (EP4ANT), but not by EP2 antagonist (EP2ANT) or EP4 agonist (EP4AGO). Pretreatment with EP2ANT blocked the effect of PGE2 or EP2AGO on Palb. Modulation of EP2 and EP4 also induced opposite effects on phosphorylation of Akt and β‐Catenin. Individual agonists or antagonists of EP2 or EP4 did not induce significant improvement in albuminuria in UNX mice. However, treatment with a combination EP2ANT + EP4AGO for 1 or 6 months caused a robust decrease in albuminuria. EP2ANT + EP4AGO combination did not impact adaptive hypertrophy or increased serum creatinine. Observed differences between expression of EP2 and EP4 on the glomerular barrier highlight these receptors as potential targets for intervention. Safe and effective mitigating effect of EP2ANT + EP4AGO presents a novel opportunity to delay the progression of hyperfiltration‐associated CKD as seen in transplant donors. [ABSTRACT FROM AUTHOR]

The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, and 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The glomerular filtration rate (GFR) is the outcome of glomerular hemodynamics, influenced by a series of parameters: renal plasma flow, resistances of afferent arterioles and efferent arterioles (EAs), hydrostatic pressures in the glomerular capillary and Bowman's capsule, and plasma colloid osmotic pressure in the glomerular capillary. Although mathematical models have been proposed to predict the GFR at both the single-nephron level and the two-kidney system level using these parameters, mathematical equations governing glomerular filtration have not been well-established because of two major problems. First, the two-kidney system-level models are simply extended from the equations at the single-nephron level, which is inappropriate in epistemology and methodology. Second, the role of EAs in maintaining the normal GFR is underappreciated. In this article, these two problems are concretely elaborated, which collectively shows the need for a shift in epistemology toward a more holistic and evolving way of thinking, as reflected in the concept of the complex adaptive system (CAS). Then, we illustrate eight fundamental mathematical equations and four hypotheses governing glomerular hemodynamics at both the single-nephron and two-kidney levels as the theoretical foundation of glomerular hemodynamics. This illustration takes two steps. The first step is to modify the existing equations in the literature and establish a new equation within the conventional paradigm of epistemology. The second step is to formulate four hypotheses through logical reasoning from the perspective of the CAS (beyond the conventional paradigm). Finally, we apply the new equation and hypotheses to comprehensively analyze glomerular hemodynamics under different conditions and predict the GFR. By doing so, some concrete issues are eliminated. Unresolved issues are discussed from the perspective of the CAS and a desinger's view. In summary, this article advances the theoretical study of glomerular dynamics by 1) clarifying the necessity of shifting to the CAS paradigm; 2) adding new knowledge/insights into the significant role of EAs in maintaining the normal GFR; 3) bridging the significant gap between research findings and physiology education; and 4) establishing a new and advanced foundation for physiology education., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kuang, Ahmetaj and Qu.)

Dysregulation in glomerular hemodynamics favors hyperfiltration in diabetic kidney disease (DKD). Although carnosine supplementation ameliorates features of DKD, its effect on glomerular vasoregulation is not known. We assessed the influence of carnosine and carnosinase-1 (CN1) on afferent glomerular arteriole vasodilation and its association with glomerular size, hypertrophy, and nephrin expression in diabetic BTBRob/ob mice. Two cohorts of mice including appropriate controls were studied: i.e., diabetic mice that received oral carnosine supplementation (cohort 1) and human (h)CN1 transgenic (TG) diabetic mice (cohort 2). The lumen area ratio (LAR) of the afferent arterioles and glomerular parameters were measured by conventional histology. Three-dimensional analysis using a tissue clearing strategy was also used. In both cohorts, LAR was significantly larger in diabetic BTBRob/ob versus nondiabetic BTBRwt/ob mice (0.41 ± 0.05 vs. 0.26 ± 0.07, P < 0.0001 and 0.42 ± 0.06 vs. 0.29 ± 0.04, P < 0.0001) and associated with glomerular size (cohort 1: r = 0.55, P = 0.001 and cohort 2: r = 0.89, P < 0.0001). LAR was partially normalized by oral carnosine supplementation (0.34 ± 0.05 vs. 0.41 ± 0.05, P = 0.004) but did not differ between hCN1 TG and wild-type BTBRob/ob mice. In hCN1 TG mice, serum CN1 concentrations correlated with LAR (r = 0.90, P = 0.006). Diabetic mice displayed decreased nephrin expression and increased glomerular hypertrophy. This was not significantly different in hCN1 TG BTBRob/ob mice (P = 0.06 and P = 0.08, respectively). In conclusion, carnosine and CN1 may affect intraglomerular pressure in an opposing manner through the regulation of afferent arteriolar tone. This study corroborates previous findings on the role of carnosine in the progression of DKD. [ABSTRACT FROM AUTHOR]

Background Glomerular hyperfiltration (GHF) is paradoxically associated with increased cardiovascular events in healthy individuals, but the pathogenesis remains unclear. We aim to investigate whether GHF is associated with mortality and whether decreased heart rate variability (HRV) is associated with GHF. Methods and Results We retrospectively analyzed 1615 participants (aged 66.1±17.3 years, 61.9% men) without prior cardiovascular events. The glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. GHF was defined as glomerular filtration rate >the 95th percentile after stratification for age and sex, whereas normal filtration was defined as the 25th to 75th percentiles. HRV indexes, including time domain, frequency domain, and sample entropy, were measured using 24‐hour ambulatory electrocardiography. Clinical outcomes were defined as all‐cause mortality at 2 years. During a mean follow‐up of 16.5±8.2 months, there were 117 deaths (7.2%). GHF was associated with a higher risk of death (hazard ratio and 95% CIs, 1.97 [1.15–3.37]). Reduced HRV indexes, including time domain, frequency domain, and sample entropy (odds ratio and 95% CIs, 0.79 [0.70–0.89]) were all independently associated with the presence of GHF after accounting for age, sex, mean heart rate, morbidities, and medications. In subgroup analysis, reduced HRV was more predictive of GHF in the young than the elderly. Mediation analysis revealed a significant mediation effect between HRV and GHF in addition to their respective detrimental effects on survival. Conclusions Reduced HRV was independently associated with the presence of GHF. Autonomic dysfunction may be involved in the pathogenesis of adverse outcomes of GHF in individuals without prior cardiovascular events.

Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte function in vivo. FFSS-treated cultured podocytes show upregulated AKT-GSK3β-β-catenin signaling. The present study was undertaken to confirm (i) the activation of β-catenin signaling in podocytes in vivo using unilaterally nephrectomized (UNX) TOPGAL mice with the β-galactosidase reporter gene for β-catenin activation, (ii) β-catenin translocation in FFSS-treated mouse podocytes, and (iii) β-catenin signaling using publicly available data from UNX mice. The UNX of TOPGAL mice resulted in glomerular hypertrophy and increased the mesangial matrix consistent with hemodynamic adaptation. Uninephrectomized TOPGAL mice showed an increased β-galactosidase expression at 4 weeks but not at 12 weeks, as assessed using immunofluorescence microscopy (p < 0.001 at 4 weeks; p = 0.16 at 12 weeks) and X-gal staining (p = 0.008 at 4 weeks; p = 0.65 at 12 weeks). Immunofluorescence microscopy showed a significant increase in phospho-β-catenin (Ser552, p = 0.005) at 4 weeks but not at 12 weeks (p = 0.935) following UNX, and the levels of phospho-β-catenin (Ser675) did not change. In vitro FFSS caused a sustained increase in the nuclear translocation of phospho-β-catenin (Ser552) but not phospho-β-catenin (Ser675) in podocytes. The bioinformatic analysis of the GEO dataset, #GSE53996, also identified β-catenin as a key upstream regulator. We conclude that transcription factor β-catenin mediates FFSS-induced podocyte (glomerular) injury in solitary kidney.

Background: Increased renal sodium avidity is a hallmark feature of the heart failure syndrome., Summary: Increased renal sodium avidity refers to the inability of the kidneys to elicit potent natriuresis in response to sodium loading. This eventually causes congestion, which is a major contributor to hospital admissions and mortality in heart failure., Key Messages: Important novel concepts such as the renal tamponade hypothesis, accelerated nephron loss, and the role of hypochloremia, the sympathetic nervous system, inflammation, the lymphatic system, and interstitial sodium buffers are involved in the pathophysiology of renal sodium avidity. A good understanding of these concepts is crucially important with respect to treatment recommendations regarding dietary sodium restriction, fluid restriction, rapid up-titration of guideline-directed medical therapies, combination diuretic therapy, natriuresis-guided diuretic therapy, use of hypertonic saline, and ultrafiltration., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Angiotensin I-converting enzyme (ACE) levels in humans are under strong genetic influence. Genetic variation in ACE has been linked to risk for and progression of cardiovascular and renal diseases. Causality has been documented in genetically modified mice, but the mechanisms underlying causality are not completely elucidated. To further document the vascular and renal consequences of a moderate genetic increase in ACE synthesis, we studied genetically modified mice carrying three copies of the ACE gene (three-copy mice) and littermate wild-type animals (two-copy mice). We investigated peripheral and renal vascular reactivity to angiotensin II and bradykinin in vivo by measuring blood pressure and renal blood flow after intravenous administration and also reactivity of isolated glomerular arterioles by following intracellular Ca2+ mobilization. Carrying three copies of the ACE gene potentiated the systemic and renal vascular responses to angiotensin II over the whole range of peptide concentration tested. Consistently, the response of isolated glomerular afferent arterioles to angiotensin II was enhanced in three-copy mice. In these mice, signaling pathways triggered by endothelial activation by bradykinin or carbachol in glomerular arterioles were also altered. Although the nitric oxide (NO) synthase (NOS)/NO pathway was not functional in arterioles of two-copy mice, in muscular efferent arterioles of threecopy mice NOS3 gene expression was induced and NO mediated the effect of bradykinin or carbachol. These data document new and unexpected vascular consequences of a genetic increase in ACE synthesis. Enhanced vasoconstrictor effect of angiotensin II may contribute to the risk for cardiovascular and renal diseases linked to genetically high ACE levels. [ABSTRACT FROM AUTHOR]

Deleterious effects of purinergic P2X1 and P2X7 receptors (P2XRs) in ANG II-dependent hypertension include increased renal vascular resistance, and impaired autoregulation and pressure natriuresis. However, their specific effects on the determinants of glomerular hemodynamics remain incompletely delineated. To investigate the P2XR contributions to altered glomerular hemodynamics in hypertension, the effects of acute blockade of P2X1R, P2X7R, and P2X4R with NF449, A438079, and PSB12054, respectively, were evaluated in ANG II infused rats (435 ng·kg-1·min-1). P2X1R or P2X7R blockade reduced afferent (6.85 ± 1.05 vs. 2.37 ± 0.20 dyn·s-1·cm-5) and efferent (2.85 ± 0.38 vs. 0.99 ± 0.07 dyn·s-1·cm-5) arteriolar resistances, leading to increases in glomerular plasma flow (75.82 ± 5.58 vs. 206.7 ± 16.38 nl/min), ultrafiltration coefficient (0.0198 ± 0.0024 vs. 0.0512 ± 0.0046 nl·min-1·mmHg-1), and single-nephron glomerular filtration rate (22.73 ± 2.02 vs. 51.56 ± 3.87 nl/min) to near normal values. Blockade of P2X4R did not elicit effects in hypertensive rats. In normotensive sham-operated rats, only the P2X1R antagonist caused an increase plasma flow and single-nephron glomerular filtration rate, whereas the P2X4R antagonist induced glomerular vasoconstriction that was consistent with evidence that P2X4R stimulation increases release of nitric oxide from endothelial cells. Mean arterial pressure remained unchanged in both hypertensive and normotensive groups. Western blot analysis showed overexpression of P2X1R, P2X7R, and P2X4R proteins in hypertensive rats. Whereas it has been generally assumed that the altered glomerular vascular resistances in ANG II hypertension are due to AT1 receptor-mediated vasoconstriction, these data indicate a predominant P2X1R and P2X7R control of glomerular hemodynamics in ANG II hypertension. [ABSTRACT FROM AUTHOR]

The aim of this analysis was to examine sex-based differences in renal segmental resistances in healthy controls (HCs) and patients with type 1 diabetes (T1D). We hypothesized that hyperfiltration-an early hemodynamic abnormality associated with diabetic nephropathy-would disproportionately affect women with T1D, thereby attenuating protection against the development of renal complications. Glomerular hemodynamic parameters were evaluated in HC (n = 30) and in normotensive, normoalbuminuric patients with T1D and either baseline normofiltration [n = 36, T1D-N, glomerular filtration rate (GFR) 90-134 ml·min-1·1.73 m2] or hyperfiltration (n = 32, T1D-H, GFR ⩾ 135 ml·min-1·1.73 m2) during euglycemic conditions (4 - 6 mmol/l). Gomez's equations were used to derive efferent (RE) and afferent (RA) arteriolar resistances, glomerular hydrostatic pressure (PGLO) from inulin (GFR) and paraaminohippurate [effective renal plasma flow (ERPF)] clearances, plasma protein and estimated ultrafiltration coefficients (KFG). Female patients with T1D with hyperfiltration (T1D-H) had higher RE (1,985 ± 487 vs. 1,381 ± 296 dyne·sec-1·cm-5, P < 0.001) and filtration fraction (FF, 0.20 ± 0.047 vs. 0.16 ± 0.03 P < 0.05) and lower ERPF (876 ± 245 vs. 1,111 ± 298 134 ml·min-1·1.73 m2 P < 0.05) compared with male T1D-H patients. Overall, T1D-H patients had higher PGLO and lower RA vs. HC subjects, although there were no sex-based differences. In conclusion, female T1D-H patients had higher RE and FF and lower ERPF than their male counterparts with no associated sex differences in RA. Prospective intervention studies should consider sex as a modifier of renal hemodynamic responses to renal protective therapies. [ABSTRACT FROM AUTHOR]

Hyperfiltration subjects podocytes to increased tensile stress and fluid flow shear stress (FFSS). We showed a 1.5- to 2.0-fold increase in FFSS in uninephrectomized animals and altered podocyte actin cytoskeleton and increased synthesis of prostaglandin E2 (PGE2) following in vitro application of FFSS. We hypothesized that increased FFSS mediates cellular changes through specific receptors of PGE2. Presently, we studied the effect of FFSS on cultured podocytes and decapsulated isolated glomeruli in vitro, and on solitary kidney in uninephrectomized sv129 mice. In cultured podocytes, FFSS resulted in increased gene and protein expression of cyclooxygenase (COX)-2 but not COX-1, prostanoid receptor EP2 but not EP4, and increased synthesis and secretion of PGE2, which were effectively blocked by indomethacin. Next, we developed a special flow chamber for applying FFSS to isolated glomeruli to determine its effect on an intact glomerular filtration barrier by measuring change in Palbumin permeability (PPalb) in vitro. FFSS caused an increase in PPalb that was blocked by indomethacin (P < 0.001). Finally, we show that unilateral nephrectomy in sv129 mice resulted in glomerular hypertrophy (P = 0.006), increased glomerular expression of COX-2 (P < 0.001) and EP2 (P = 0.039), and increased urinary Palbumin excretion (P = 0.001). Activation of the COX-2-PGE2-EP2 axis appears to be a specific response to FFSS in podocytes and provides a mechanistic basis for alteration in podocyte structure and the glomerular filtration barrier, leading to Palbuminuria in hyperfiltration-mediated kidney injury. The COX-2-PGE2-EP2 axis is a potential target for developing specific interventions to ameliorate the effects of hyperfiltration-mediated kidney injury in the progression of chronic kidney disease. [ABSTRACT FROM AUTHOR]

Abstract: The administration of curcumin before and throughout the study attenuates oxidant stress and glomerular hemodynamic alterations induced by 5/6 nephrectomy (5/6NX). The purpose of this work was to study if curcumin is able to reverse established glomerular hemodynamic alterations (e.g. hyperfiltration and glomerular hypertension) and oxidant stress in rats with 5/6NX. Curcumin (120mg/kg) was given to rats with established renal injury (30 days after surgery) and continued for 30 days (days 31–60 of the study). All rats were studied on day 60 after surgery. Curcumin was able (a) to reverse 5/6NX-induced glomerular hypertension and hyperfiltration, (b) to induce cell proliferation and nuclear translocation of Nrf2 and (c) to reverse 5/6NX-induced oxidant stress and decrease in antioxidant enzymes. These beneficial effects of curcumin were associated with the ability of this antioxidant to reverse renal structural alterations, proteinuria, hypertension, interstitial fibrosis, fibrotic glomeruli, tubular atrophy and mesangial expansion. It has been shown for the first time that curcumin is able to reverse established oxidants stress glomerular hypertension and hyperfiltration in rats with 5/6NX. These novel findings may play a key role in the attenuation of proteinuria and progression of renal damage in rats with 5/6NX. These data suggest that curcumin may be useful to reverse established hemodynamic alterations and renal injury in patients with chronic renal failure. [Copyright &y& Elsevier]

Background: Sildenafil treatment ameliorates progressive renal injury resulting from extensive renal ablation; however, modifications induced by sildenafil in the glomerular hemodynamic pathophysiology of the remnant kidney have not been investigated. Aim: To determine the effects of sildenafil in the glomerular microcirculation and their relation to histological damage in the renal ablation model. Methods: Micropuncture studies were performed 60 days after 5/6 nephrectomy in rats that received no treatment, sildenafil (5 mg/kg/day) and reserpine, hydralazine and hydrochlorothiazide to maintain the blood pressure within normal levels. Sham-operated rats untreated and treated with sildenafil served as controls. Results: As expected, renal ablation induced systemic and glomerular hypertension, hyperfiltration, proteinuria, glomerulosclerosis and tubulointerstitial inflammatory damage in the remnant kidney. Sildenafil treatment prevented single-nephron hyperfiltration and hypertension, suppressed renal arteriolar remodeling, ameliorated systemic hypertension and proteinuria, increased urinary excretion of cGMP and NO2-/NO3-, decreased oxidative stress and improved histological damage in the remnant kidney. Normalization blood pressure with reserpine, hydralazine and hydrochlorothiazide did not modify glomerular hemodynamics, proteinuria or histological changes induced by renal ablation. Conclusions: Beneficial effects of sildenafil in the remnant kidney are associated with a reduction in the arteriolar remodeling, renal inflammatory changes and prevention of changes in the glomerular microcirculation. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Adenosine triphosphate (ATP) is liberated from macula densa cells in response to increased tubular NaCl delivery. However, it is not known whether ATP from the macula densa is broken down to adenosine, or whether this adenosine mediates efferent arteriole (Ef-Art) tubuloglomerular feedback (TGF). We hypothesized that increased macula densa Ca2+, release of ATP and degradation of ATP to adenosine are necessary for Ef-Art TGF. Rabbit Ef-Arts and adherent tubular segments (with the macula densa) were simultaneously microperfused in vitro while changing the NaCl concentration at the macula densa. The Ef-Art was perfused orthograde through the end of the afferent arteriole (Af-Art). In Ef-Arts preconstricted with norepinephrine (NE), increasing NaCl concentration from 10 to 80 mM at the macula densa dilated Ef-Arts from 7.5±0.7 to 11.1±0.3 μm. Buffering increases in macula densa Ca2+ with the cell-permeant Ca2+ chelator BAPTA-AM diminished Ef-Art TGF from 3.1±0.3 to 0.1±0.2 μm. Blocking adenosine formation by adding α-β-methyleneadenosine 5′-diphosphate (MADP) blocked Ef-Art TGF from 2.9±0.5 to 0.1±0.2 μm. Increasing luminal NaCl at the macula densa from 10 to 45 mM caused a moderate Ef-Art TGF response, 1.3±0.1 μm. It was potentiated to 4.0±0.3 μm by adding hexokinase, which enhances conversion of ATP into adenosine. Our data show that in vitro changes in macula densa Ca2+ and ATP release are necessary for Ef-Art TGF. ATP is broken down to form adenosine, which mediates signal transmission of Ef-Art TGF.Kidney International (2007) 71, 861–866. doi:10.1038/sj.ki.5002161; published online 7 March 2007 [ABSTRACT FROM AUTHOR]

Intrarenally synthesized angiotensin II (Ang II) may be involved in the progression of glomerulonephritis, leading to irreversible glomerulosclerosis. There is increasing evidence that systemic angiotensin receptor blocker (ARB) treatment has beneficial effect on the prognosis of progressive glomerulonephritis and diabetic nephropathy. However, the cellular and molecular mechanisms behind this therapeutic effect of ARB remain unclear. In this study, we used a novel strategy of local ARB delivery via type-1 collagen sponge, to treat progressive glomerulonephritis that would result in irreversible glomerulosclerosis in our previously established rat model. At days 9 and 14 after disease induction, mild proteinuria, 20.7±4.7 and 10±1.3 mg/day, was found. Local ARB treatment reduced proteinuria significantly to 3.19±3.2 and 5.25±0.95 mg/day (P<0.01), respectively. Scoring of glomerular matrix expansion and sclerotic index revealed that local ARB treatment significantly ameliorated glomerular pathology. Ang II type 1 receptor mRNA expression was remarkably enhanced in the Ang II group and ARB treatment reversed this effect at 14 days. Local delivery of ARB significantly improved glomerular blood flow levels, compared to the untreated disease control group, from 710±18.25 to 859.44±22.86 μm/s, respectively. Local delivery of ARB into the kidney affected local RAS and thus improved the renal injury and function in the potentially progressive glomerulosclerosis of rat model.Kidney International (2006) 70, 1591–1598. doi:10.1038/sj.ki.5001872; published online 20 September 2006 [ABSTRACT FROM AUTHOR]

There is increasing evidence that changes of glomerular hemodynamics or glomerular growth responses may promote the development of glomerulosclerosis. Major problems retarding research progress include lack of suitable experimental animal models, with the exception of the ablation model, and the need for in vivo real-time analysis of glomerular hemodynamics. This study examined the sequence of pathological changes from the viewpoints of microcirculation and histopathology, from the acute stage to the chronic course and the final stage of glomerulosclerosis, using the confocal laser scanning microscope system. There is a marked difference in prognosis between sham-operated (two-kidney) and nephrectomized (one-kidney) rats after injection with anti-Thy-1 antibody. The former reversibly returns to normal and the latter irreversibly go to progressive sclerosis, respectively. The turning point determining the progression of glomerulosclerosis in both groups seemed to be the period from 7 to 14 days after disease induction, when disturbance of local intraglomerular blood flow continued in the one-kidney groups. In conclusion, this study provides the first hemodynamic-based evidence showing that disturbance of intraglomerular microcirculation is a critical marker for progressive glomerulosclerosis.Kidney International (2006) 69, 1792–1798. doi:10.1038/sj.ki.5000350; published online 5 April 2006 [ABSTRACT FROM AUTHOR]

In clinical nephrology, the glomerular filtration rate (GFR) has been recognized as the golden standard to assess renal function. However, a normal GFR does not necessarily mean normal filtration capability of the kidneys, because impaired filtration capability can be compensated for by elevating glomerular hydraulic pressure. Therefore, an early phase of glomerular dysfunction cannot be detected by the baseline GFR alone. On the other hand, glomerular capillary hypertension is widely recognized as one of the strong risk factors for the progression of nephropathies. Now, it is very important to imagine glomerular hemodynamics in each patient with nephropathy for detecting early dysfunction, as well as for evaluating risk factors. Here, I would like to summarize the current status of how an early phase of renal dysfunction can be detected in clinical practice. I truly anticipate that new methods to assess glomerular hemodynamics in humans will be developed in the near future. [ABSTRACT FROM AUTHOR]

Real-time observation of glomerular hemodynamic changes in diabetic rats: Effects of insulin and ARB.Background.The progression of diabetic nephropathy is closely related to disturbances in glomerular hemodynamics, such as glomerular hypertension and/or hyperperfusion. The aim of this study was to observe and to analyze glomerular hemodynamics in rats with diabetes mellitus (DM) in vivo using confocal laser scan microscopy (CLSM). We also examined the effects of candesartan cilexetil (TCV-116), a selective angiotensin II type 1 receptor blocker (ARB), on glomerular hemodynamics in DM.Methods.Munich-Wistar rats were divided into six groups: (1) four-day control; (2) four-day DM; (3) 28-day control; (4) 28-day DM; (5) DM treated with insulin; (6) DM treated with TCV-116. The kidney-to-body weight ratio, glomerular volume, and proteinuria were estimated. Glomerular hemodynamic changes were observed using CLSM and renal expression of endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) was evaluated by immunofluorescence.Results.The kidney-to-body weight ratio, glomerular volume, the diameters of afferent arterioles (AA) and efferent arterioles (EA), erythrocyte velocities within glomeruli, and volume flow in glomerular capillary loops in four-day DM were significantly higher than in control rats, and increases were even more pronounced in the 28-day DM. TCV-116 treatment ameliorated all these findings and significantly decreased proteinuria, but there was no effect on the blood glucose level. On the other hand, insulin treatment was followed by normalization of all these changes induced in DM. Enhanced renal expression of eNOS in DM was suppressed when treated with either TCV-116 or insulin, while expression of nNOS was unaltered among the four groups.Conclusion.This imaging procedure allowed us to evaluate glomerular microcirculation in vivo, including the diameters of AA and EA, erythrocyte velocity, and volume flow. DM significantly induced glomerular hemodynamic alteration and renal hypertrophy. DM treated with either insulin or ARB ameliorated these changes. This study shows that progress in imaging technology promises to make major contributions to revealing the involvement of hemodynamic changes in glomerular diseases, aiding prognosis and the monitoring of therapeutic effects, as well. [ABSTRACT FROM AUTHOR]

AT1 receptors mediate angiotensin II–induced release of nitric oxide in afferent arterioles.Background.Recent studies have indicated that angiotensin II (Ang II) possibly activates the nitric oxide (NO) system. We investigated the role of AT receptor subtypes (AT-R) in mediating the Ang II–induced NO release in afferent arterioles (Af) of mice.Methods.Isolated Af of mice were perfused, and the isotonic contraction measured. Further, NO release was determined using DAF-FM, a fluorescence indicator for NO. Moreover, we qualitatively assessed the expression of AT-R at the mRNA level using reverse transcription-polymerase chain reaction (RT-PCR).Results.Ang II reduced luminal diameters dose dependently (67.3± 6.3% at 10−6 mol/L). Inhibition of AT2-R with PD123.319 did not change the Ang II contractile response. AT1-R blockade with ZD7155 inhibited contraction. Stimulation of AT2-R during AT1-R inhibition with ZD7155, and preconstriction with norepinephrine (NE) had no influence on the diameter. Drug application via the perfusion pipette changed flow and pressure, and enhanced NO fluorescence byΔF= 4.0± 0.4% (N= 14, background). Luminal application of Ang II (10−7 mol/L) increased the NO fluorescence byΔF= 9.9± 1.2% (N= 8). AT1-R blockade blunted the increase to background levels (ΔF to 4.0± 0.3%,N= 6,P<0.05), but AT2-R blockade did not (8.1± 0.9%,N= 9). L-NAME nearly abolished the Ang II effect on the NO fluorescence (ΔF= 1.6± 0.5% (N= 8). NE did not increase NO release beyond the background levels. RT-PCR showed expression of both AT1-R and AT2-R.Conclusion.The results indicate an Ang II–induced NO release in Af of mice, which is mediated by AT1-R. Thus, Ang II balances its own constrictor action in Af. This control mechanism is very important in view of high renin and angiotensin II concentration in the juxtaglomerular apparatus. [ABSTRACT FROM AUTHOR]

We evaluated the glomerular filtration rate (GFR) during the second postpartum week in 22 healthy women who had completed an uncomplicated pregnancy. We used physiological techniques to measure GFR, renal plasma flow, and oncotic pressure and computed a value for the two-kidney ultrafiltration coefficient (Kf). We compared these findings with those in pregnant women previously studied on the first postpartum day as well as nongravid women of reproductive age. Healthy female transplant donors of reproductive age permitted the morphometric analysis of glomeruli and computation of the single-nephron Kf. The aforementioned physiological and morphometric measurements were utilized to estimate transcapillary hydraulic pressure (Δp) from a mathematical model of glomerular ultrafiltration. We conclude that postpartum day 1 is associated with marked glomerular hyperfiltration (+41%). A theoretical analysis of GFR determinants suggests that depression of glomerular capillary oncotic pressure, the force opposing the formation of filtrate, is the predominant determinant of early elevation of postpartum GFR. A reversal of the gestational hypervolemia and hemodilution, still evident on postpartum day 1, eventuates by postpartum week 2. An elevation of oncotic pressure in the plasma that flows axially along the glomerular capillaries to supernormal levels ensues; however, GFR remains modestly elevated (+20%) above nongravid levels. An analysis of filtration dynamics at this time suggests that a significant increase in Δp by up to 16%, an ∼50% increase in Kf, or a combination of smaller increments in both must be invoked to account for the persistent hyperfiltration. [ABSTRACT FROM AUTHOR]

Glomerular hemodynamics are controlled by a variety of physical, nervous and hormonal factors including the potent vasoconstrictors, angiotensin (ANG) II and endothelin- 1 (ET-1), and the vasodilator prostanoids (prostaglandin = PG) and nitric oxide (NO). Since no micropuncture data on the canine kidney exist with respect to the relative roles of the endogenous vasoactive hormones/ autacoids NO, PG and ANG II in modulating glomerular hemodynamics, in the present study using the micropuncture technique in anesthetized dogs on a normal salt intake, we investigated the relative effects of these hormones/autacoids by means of the L-arginine analog, Nω-nitro-L-arginine methyl ester hydrochloride (LNAME), a competitive NO synthase (NOS) inhibitor, the cyclooxygenase inhibitor indomethacin (INDO), and the AT1 receptor blocker EXP 3174. An intrarenal arterial (i.r.a.) bolus (within 5 min) of 2.5 mg of L-NAME led to a significant decrease in total renal blood flow (RBF) and single nephron glomerular blood flow (SNGBF) from 4.46 ± 0.51 to 3.52 ± 0.41 ml/min/g kidney weight and from 0.393 ± 0.041 to 0.341 ± 0.037 µl/min (p < 0.01), respectively, without a change in glomerular filtration rate (GFR). The increase in arteriolar resistance was more pronounced at the efferent (+31%) than at the afferent (+13%) arteriole, and Kf decreased from 4.5 ± 0.5 to 3.7 ± 0.4 nl/min/mm Hg (p < 0.01). INDO (5 mg/kg i.v. bolus followed by 0.17 mg/kg/min i.v.) had no effect on glomerular hemodynamics. EXP 3174 (30 µg/kg/min i.r.a.) increased RBF and SNGBF from 4.35 ± 0.45 to 4.99 ± 0.50 ml/min/g kidney weight and from 0.403 ± 0.028 to 0.478 ± 0.039 µl/min (p < 0.01), respectively, without an effect on GFR. It reduced the efferent arteriolar resistance by 25% as compared to 13% at the afferent arteriolar level. EXP 3174 increased Kf from 5.1 ± 0.4 to 8.1 ± 0.6 mm Hg (p < 0.01) in the presence of a decrease in effective filtration pressure from 13.2 ± 1.7 to 8.3 ± 1.0 mm Hg (p < 0.01). The glomerular hemodynamic effects of L-NAME were unaltered by pretreatment with INDO or EXP 3174, whereas its tubular effects were restored in the presence of EXP 3174. Thus, from these first micropuncture data in the anesthetized dog on a normal sodium intake we conclude that (1) acute intrarenal inhibition of NOS by L-NAME decreases RBF and SNGBF due to vasoconstriction of the afferent and, more pronounced, efferent arterioles. Since L-NAME simultaneously decreases Kf, GFR remains unaltered. (2) These renal hemodynamic effects of NOS inhibition were not mediated by prostanoids or intrarenal ANG II. Thus, the tonic activity of intrarenal NOS plays an important role in maintaining glomerular hemodynamics in the canine kidney. [ABSTRACT FROM AUTHOR]

Background: Although renal protective effect of interrupting the inflammatory process is well established, it is still controversial if it also prevents the glomerular hemodynamic disturbances that initiate renal injury. We investigated the effects of suppressing inflammation with mycophenolate mofetil (MMF) on glomerular hemodynamics, arteriolar structural changes, and renal histologic injury in rats with subtotal renal ablationMethods: Micropuncture studies were performed 30 days after 5/6 nephrectomy in rats untreated and treated with MMF (30 mg/kg/day). Renal histology, immunohistochemistry for lymphocytes, macrophages and inducible nitric oxide synthase (iNOS) expression, as well as afferent arteriolar (AA) morphometry was evaluated.Results: Renal ablation significantly increased proteinuria (6.8 to 82.7 mg/day), mean arterial pressure (MAP) (120 to 166 mm Hg), single-nephron glomerular filtration rate (SNGFR) (34.8 to 56.3 nL/min), glomerular plasma flow (QA) (117.7 to 246.9 nL/min), and glomerular capillary pressure (PGC) (48.9 to 61.0 mm Hg). Afferent resistance (AR), efferent resistance, and ultrafiltration coefficient remained unchanged. Despite persisting arterial hypertension (152 mm Hg), MMF prevented proteinuria (13.3 mg/day), and significantly reduced SNGFR (44.4 nL/min), PGC (49.1 mm Hg), and QA (163.2 nL/min) due to a rise in AR (3.13 vs. 2.18 1010 dyn/sec/cm-5). Glomerular sclerosis, tubulointerstitial damage, lymphocyte and macrophage infiltration, and iNOS expression were significantly reduced by MMF, in addition hypertrophy of AA resistance evaluated by the media/lumen ratio was prevented (P < 0.001).Conclusions: Reduction in proteinuria, SNGFR, QA, and PGC, despite elevated MAP, indicate preservation of AA function. These results suggest that inflammation associated arteriolopathy of AA contributes to glomerular hemodynamic disturbances that participate in the progression of renal disease. [ABSTRACT FROM AUTHOR]

Background. We induced pathological changes in the glomerular capillary walls by causing damage to endothelial cells produced by lipopolysaccharide (LPS) injection in pregnant rats and compared the induced lesions with those of human preeclamptic nephropathy, known as glomerular endothelial damage. Methods. Forty-three uninephrectomized and salt-loaded Wistar rats were divided into three groups. Twenty-six pregnant rats (Group I) and 9 nonpregnant rats (Group II) were injected intravenously with LPS ( E. coli 055:B5, 130 μg/kg) on day 15 of gestation, and 8 pregnant rats (Group III) were injected with vehicle. The kidneys of the rats were pathologically and physiologically examined on day 20. Glomerular hemodynamic changes were evaluated under a real-time confocal laser-scanning microscope (CLSM) with a high-speed CCD video camera. Results. Twenty-one (81%) rats in Group I showed glomerular microangiopathic lesions detected as endothelial swelling, a double contour of the basement membrane, and intracapillary fibrin deposits by light and electron microscopy. Immunofluorescent analysis showed that fibrinogen deposition colocalized with the endothelial cell markers. The lesions were observed in only one rat (11%) in Group II. The glomerular blood flow decreased significantly in Group I compared with Group III ( P < 0.05, 218.7 ± 122.0 vs 883.2 ± 122.0 μm/s). Conclusion. The glomerular lesions induced by injecting LPS in pregnant rats showed endothelial cell abnormalities and secondary intracapillary coagulation. We consider that these glomerular lesions were “specified” during gestation, and they had many histopathological and physiological findings in common with human preeclamptic nephropathy. [ABSTRACT FROM AUTHOR]

Effect of acute iNOS inhibition on glomerular function in tubulointerstitial nephritis. Background. Tubulointerstitial nephritis (TIN) is characterized by progressive inflammatory infiltrate of the renal interstitium, induction of cortical tubular inducible nitric oxide synthase (iNOS) and reductions in glomerular filtration rate (GFR). These studies were designed to examine the changes in glomerular hemodynamics 7 and 21 days after induction of TIN and to evaluate the effect of acute iNOS blockade on glomerular function in the early stages of this model. Methods. TIN was induced by immunizing Brown Norway rats with renal tubular antigen in complete Freund's adjuvant (RTA/CFA). Control rats were immunized with CFA alone. Micropuncture and morphologic studies were performed 7 and 21 days after immunization. Results. Histology revealed minimal peritubular and interstitial inflammation in the RTA/CFA group one week after immunization while extensive interstitial inflammation with few preserved superficial nephron was observed three weeks after RTA/CFA immunization. Micropuncture studies on day 7 in the RTA/CFA group revealed a significant reduction in single nephron GFR due to a profound reduction in nephron plasma flow and in the ultrafiltration coefficient. Studies performed on day 21 revealed that single nephron GFR (SNGFR), nephron plasma flow (SNPF) and the ultrafiltration coefficient had returned to the normal baseline value despite the severe reduction in GFR. To assess the role of increased nitric oxide production secondary to iNOS induction on the glomerular hemodynamic changes observed in the early stages of the disease, the iNOS blocker (l-N6 -iminoethyl lysine, L-NIL) was administered IV (1 mg/h) in RTA/CFA rats and CFA rats. L-NIL had no effect in CFA rats but produced significant increases in GFR, SNGFR and SNPF in RTA/CFA rats. Conclusions. These results demonstrate that TIN is associated with a progressive reduction in GFR, which is... [ABSTRACT FROM AUTHOR]

Background: There is evidence that macula densa nitric oxide (NO) inhibits tubuloglomerular feedback (TGF). However, TGF response is not altered in mice deficient in neuronal nitric oxide synthase (nNOS) (-/-). Furthermore, nNOS expression in the macula densa is inversely related to salt intake, yet micropuncture studies have shown that NOS inhibition potentiates TGF in rats on high sodium intake but not in rats on a low-salt diet. These inconsistencies may be due to confounding systemic factors, such as changes in circulating renin. To further clarify the role of macula densa nNOS in TGF response, independent of systemic factors, we tested the hypothesis that (1) TGF response is inversely related to sodium intake, and (2) during low sodium intake, NO produced by macula densa nNOS tonically controls the basal diameter of the afferent arteriole (Af-Art).Methods: Af-Arts and attached macula densas were simultaneously microperfused in vitro. TGF response was determined by measuring Af-Art diameter before and after increasing NaCl in the macula densa perfusate. TGF response was studied in wild-type (+/+) and nNOS knockout mice (-/-), as well as in juxtaglomerular apparatuses (JGAs) from rabbits fed a low-, normal-, or high-NaCl diet.Results: TGF responses were similar in nNOS +/+ and -/- mice. However, in nNOS +/+ mice, 7-nitroindazole (7-NI) perfused into the macula densa significantly potentiated the TGF response (P = 0.001), while in nNOS -/- mice, this potentiation was absent. In rabbits on three different sodium diets, TGF responses were similar and were potentiated equally by 7-NI. However, in JGAs from rabbits on a low-NaCl diet, adding 7-NI to the macula densa while perfusing it with low-NaCl fluid caused Af-Art vasoconstriction, decreasing the diameter by 14% (from 21.7 +/- 1.3 to 18.6 +/- 1.5 microm; P < 0.001). This effect was not observed in JGAs from rabbits fed a normal- (19.0 +/- 0.5 vs. 19.3 +/- 0.8 microm after 7-NI) or high-NaCl diet (18.6 +/- 0.7 vs. 18.4 +/- 0.7 microm).Conclusions: First, in this in vitro preparation, chronic changes in macula densa nNOS do not play a major role in the regulation of TGF. Compensatory mechanisms may develop during chronic alteration of nNOS that keep TGF relatively constant. Second, nNOS regulates TGF response acutely. Third, the results obtained in the +/+ and -/- mice also confirm that the effect of 7-NI is due to inhibition of macula densa nNOS. Finally, during low sodium intake (without induction of TGF), the regulation of basal Af-Art resistance by macula densa nNOS suggests that NO in the macula densa helps maintain renal blood flow during the high renin secretion caused by low sodium intake. [ABSTRACT FROM AUTHOR]

Angiotensin II enhances tubuloglomerular feedback via luminal AT1 receptors on the macula densa. Background. Recent studies have revealed angiotensin II subtype 1 (AT1) receptors on macula densa cells, raising the possibility that angiotensin II (Ang II) could enhance tubuloglomerular feedback (TGF) by affecting macula densa cell function. We hypothesized that Ang II enhances TGF via activation of AT1 receptors on the luminal membrane of the macula densa. Methods. Rabbit afferent arterioles and the attached macula densa were simultaneously microperfused in vitro, keeping pressure in the afferent arteriole at 60 mm Hg. Results. The afferent arteriole diameter was measured while the macula densa was perfused with low NaCl (Na+, 5 mmol/L; Cl-, 3 mmol/L) and then with high NaCl (Na+, 79 mmol/L; Cl-, 77 mmol/L) to induce a TGF response. When TGF was induced in the absence of Ang II, the afferent arteriole diameter decreased by 2.4 ± 0.5 μm (from 17.3 ± 1.0 to 14.9 ± 1.2 μm). With Ang II (0.1 nmol/L) present in the lumen of the macula densa, the diameter decreased by 3.8 ± 0.7 μm (from 17.3 ± 1.0 to 13.5 ± 1.2 μm, P < 0.05 vs. TGF with no Ang II, N = 8). To test whether Ang II enhances TGF via activation of AT1 receptors on the luminal membrane of the macula densa, Ang II plus losartan (1 μmol/L) was added to the lumen. Losartan itself did not alter TGF. When TGF was induced in the absence of Ang II and losartan, the afferent arteriole diameter decreased by 2.3 ± 0.3 μm (from 15.9 ± 1.0 to 13.6 ± 1.2 μm). When Ang II and losartan were both present in the macula densa perfusate, the diameter decreased by 2.4 ± 0.4 μm (from 15.8 ± 0.9 to 13.4 ± 0.7 μm, P> 0.8 vs. TGF with no Ang II and losartan, N = 7). We then examined whether AT2 receptors on the macula densa... [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is considered a putative factor predisposing to acute renal failure (ARF). Since outer medullary hypoxic injury may play an important role in the pathogenesis of acute tubular necrosis, we explored the impact of experimental HF on the propensity to develop ARF with hypoxic medullary injury following the inhibition of prostaglandin and nitric oxide synthesis. Methods: Compensated, high-output HF was induced in Sprague-Dawley rats by aorto-caval fistula. At the eighth to ninth postoperative day, the rats were injected with indomethacin and N(omega) nitro-L-arginine methyl ester (L-NAME; ARF protocol) and were sacrificed 24 hours later for morphologic evaluation. Results: Kidney function comparably declined in HF-ARF rats and in control sham operated animals (CTR-ARF). Nevertheless, outer medullary hypoxic damage with medullary thick ascending limb (mTAL) necrosis occurred almost exclusively in the HF-ARF group (11 +/- 4% vs. 0.2 +/- 0.2% of tubules in CTR-ARF, P < 0.03). In a third group of HF animals subjected to vehicles only (HF-Nil), kidney function was preserved and renal morphology remained intact. Papillary-tip necrosis was consistently found in all animals subjected to indomethacin and L-NAME, irrespective of preconditioning. Morphometric evaluation disclosed that HF was not associated with mTAL hypertrophy. Conclusions: Incipient HF predisposes to hypoxic outer medullary injury, probably reflecting the impact of regional vasoconstrictive stimuli rather than tubular hypertrophy when protective local vasodilating mechanisms are hampered. The presence and extent of outer medullary hypoxic damage cannot be predicted from the functional derangement, which in the experimental settings may also represent prerenal azotemia or papillary damage. [ABSTRACT FROM AUTHOR]

Cyclooxygenase-2 (COX-2) is a recently discovered isoform of cyclooxygenase that is inducible by various types of inflammatory stimuli. Although this enzyme is considered to play a major role in inflammation processes by catalyzing the production of prostaglandins, the precise location, distribution, and regulation of prostaglandin synthesis remains unclear in several tissues. Using in situ hybridization histochemistry, we investigated the induction of COX-1 and COX-2 mRNA expression after systemic administration of a pyrogen, lipopolysaccharide (LPS), in kidney and adrenal gland in the rat. The COX-2 mRNA signals dramatically increased 1 h after LPS treatment in the kidney outer medulla and adrenal cortex, where almost no or little expression was observed in nontreated animals, and returned to control levels within 24 h. COX-2 mRNA levels increased in the kidney inner medulla 6 h after treatment. There was also a significant increase in mRNA levels in the kidney cortex and adrenal medulla. On the other hand, COX-1 mRNA levels did not show any detectable changes except in the kidney inner medulla, where a significant downregulation of mRNA expression was observed after LPS treatment. Light and electron immunocytochemistry using COX-2 antibodies showed that strong COX-2 immunoreactivity was localized to certain cortical cells of the thick ascending limb of Henle. In addition, based on double-staining with antiserum to nitric oxide synthase (NOS) four further cell populations could be identified in kidney cortex, including weakly COX-2-positive, NOS-positive macula densa cells. After LPS treatment, changes in COX-2 immunoreactivity could be observed in interstitial cells in the kidney medulla and in inner cortical cells in the adrenal gland. These results show that COX-2 is a highly induced enzyme that can be upregulated in specific cell populations in kidney and adrenal gland in response to inflammation, leading to the elevated levels of prostaglandins seen during fever. In contrast COX-1 mRNA levels remained unchanged in this experimental situation, except for a decrease in kidney inner medulla. [ABSTRACT FROM AUTHOR]

In order to evaluate the progression of renal disease, Munich-Wistar rats were submitted to 5/6 nephrectomy and given whole-body x- or γ-irradiation with or without remnant kidney protection or were submitted only to remnant kidney irradiation. All groups received a single 6-Gy dose immediately after surgery. Whole-kidney function, glomerular hemodynamics, 24-hour proteinuria and histopathology were assessed 60 days after surgery and irradiation. The irradiated nephrectomized animals presented whole-kidney function parameters comparable to those of normal rats. In addition, they were less hypertensive and had higher hematocrit. They showed glomerular hyperfiltration and hypertension even greater than their respective nephrectomized controls. However, the interrelations among the glomerular filtration determinants were somewhat different in irradiated animals. Their 24-hour proteinuria was significantly lower and the sclerosis index and tubulointerstitial injury score were markedly smaller. Among irradiated animals, the worst sclerosis index was observed in those with a shielded remnant kidney and the best in those without protection of the remnant kidney. This led us to speculate about a possible influence of resident mesangial cells on the early events following renal mass ablation and on the maintenance of subsequent physiopathologic changes. Therefore, radiation undoubtedly provoked a beneficial change in the course of renal disease when the renal mass ablation model was employed. Many factors could have contributed to this favorable feature including lower levels of systemic arterial pressure, less increment in ΔP, diminished proteinuria, and maintenance of tubulointerstitial space integrity. Our data also suggest that development of glomerulosclerosis seems to be determined by events occurring immediately after injury.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Integrin expression and IgA nephropathy: In vitro modulation by IgA with altered glycosylation and macromolecular IgA. Background. Signal transduction by mesangial cell (MC) integrins regulates cell growth and survival, extracellular matrix production, and organization. The aim of the study was to investigate human MC integrin modulation by differently glycosylated IgA and macromolecular IgA, which are thought to play a pathogenetic role in IgA nephropathy (IgAN). Methods. MCs were incubated with purified human polymeric IgA, heat-aggregated IgA, IgA glycoforms generated by enzymatic hydrolysis of saccharide residues and serum fractions from IgAN patients, and controls isolated by lectin affinity and containing IgA with peculiar glycan patterns. Integrins were quantitated by flow cytometry. Results. Cultured MCs highly expressed αv β3 and some α3 β1 ; αv β3 was up-regulated by matrix components (P < 0.02). In vitro desialylated and degalactosylated polymeric human IgA enhanced αv β3 expression on cultured MCs (P < 0.001). Serum IgA glycoforms isolated from IgAN patients with high exposure of internal sugars, GalNAc, Neu5Ac2,6GalNAc, and Man enhanced αv expression on cultured MCs more than healthy controls. Conclusions. These data support the hypothesis that IgA glycation plays a role in modulating the cell–matrix interaction, and that this mechanism can be operating in IgAN. [ABSTRACT FROM AUTHOR]

Background Glomerular hyperfiltration (GHF) is paradoxically associated with increased cardiovascular events in healthy individuals, but the pathogenesis remains unclear. We aim to investigate whether GHF is associated with mortality and whether decreased heart rate variability (HRV) is associated with GHF. Methods and Results We retrospectively analyzed 1615 participants (aged 66.1±17.3 years, 61.9% men) without prior cardiovascular events. The glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. GHF was defined as glomerular filtration rate >the 95th percentile after stratification for age and sex, whereas normal filtration was defined as the 25th to 75th percentiles. HRV indexes, including time domain, frequency domain, and sample entropy, were measured using 24-hour ambulatory electrocardiography. Clinical outcomes were defined as all-cause mortality at 2 years. During a mean follow-up of 16.5±8.2 months, there were 117 deaths (7.2%). GHF was associated with a higher risk of death (hazard ratio and 95% CIs, 1.97 [1.15-3.37]). Reduced HRV indexes, including time domain, frequency domain, and sample entropy (odds ratio and 95% CIs, 0.79 [0.70-0.89]) were all independently associated with the presence of GHF after accounting for age, sex, mean heart rate, morbidities, and medications. In subgroup analysis, reduced HRV was more predictive of GHF in the young than the elderly. Mediation analysis revealed a significant mediation effect between HRV and GHF in addition to their respective detrimental effects on survival. Conclusions Reduced HRV was independently associated with the presence of GHF. Autonomic dysfunction may be involved in the pathogenesis of adverse outcomes of GHF in individuals without prior cardiovascular events.

Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte function in vivo. FFSS-treated cultured podocytes show upregulated AKT-GSK3β-β-catenin signaling. The present study was undertaken to confirm (i) the activation of β-catenin signaling in podocytes in vivo using unilaterally nephrectomized (UNX) TOPGAL mice with the β-galactosidase reporter gene for β-catenin activation, (ii) β-catenin translocation in FFSS-treated mouse podocytes, and (iii) β-catenin signaling using publicly available data from UNX mice. The UNX of TOPGAL mice resulted in glomerular hypertrophy and increased the mesangial matrix consistent with hemodynamic adaptation. Uninephrectomized TOPGAL mice showed an increased β-galactosidase expression at 4 weeks but not at 12 weeks, as assessed using immunofluorescence microscopy (p < 0.001 at 4 weeks; p = 0.16 at 12 weeks) and X-gal staining (p = 0.008 at 4 weeks; p = 0.65 at 12 weeks). Immunofluorescence microscopy showed a significant increase in phospho-β-catenin (Ser552, p = 0.005) at 4 weeks but not at 12 weeks (p = 0.935) following UNX, and the levels of phospho-β-catenin (Ser675) did not change. In vitro FFSS caused a sustained increase in the nuclear translocation of phospho-β-catenin (Ser552) but not phospho-β-catenin (Ser675) in podocytes. The bioinformatic analysis of the GEO dataset, #GSE53996, also identified β-catenin as a key upstream regulator. We conclude that transcription factor β-catenin mediates FFSS-induced podocyte (glomerular) injury in solitary kidney. [ABSTRACT FROM AUTHOR]

Loss of renal functional reserve, that is, absence of the glomerular vasodilatory response to amino-acid infusion, has been interpreted as equivalent to glomerular hyperperfusion/hypertension, and there fore proposed as a marker of high risk for progressive glomerular sclerosis. To substantiate the validity of this hypothesis we evaluated the renal response to glycine and the extent of glomerular damage 10–12 weeks after induction of anti-glomerular basement membrane glomerulonephritis with or without superimposed clip hypertension. Untreated rats and rats chronically treated with quinapril, a converting-enzyme inhibitor, were studied. In untreated groups, loss of renal functional reserve was demonstrated since GFR, single-nephron GFR (SNGFR) and plasma flow (SNPF) did not increase during glycine infusion. The absence of renal reserve was associated with glomerular hyperfusion/hypertension, and development of proteinuria and glomerulosclerosis. Quinapril reduced proteinuria and diffuse sclerosis in anti-glomerular basement membrane GN, and decreased blood pressure and segmental glomeruloscierosis in anti glomerular basement membrane GN with superimposed clip hypertension. Both treated groups demonstrated a restoration of renal functional reserve, as depicted by increases in GFR, SNGFR, and SNPF after glycine, despite persistence of glomerular hyperperfusion/hypertension. These data demonstr that renal functional reserve testing, although it does not detect glomerular hyperperfusion/hypertension, can provide information on the progression of glomerular damage. [ABSTRACT FROM PUBLISHER]

Autoregulation of glomerular capillary pressure via regulation of the resistances at the afferent and efferent arterioles plays a critical role in maintaining the glomerular filtration rate over a wide range of mean arterial pressure. Angiotensin II and prostaglandins are among the agents which contribute to autoregulation and drugs which interfere with these agents may have a substantial impact on afferent and efferent arteriolar resistance. We describe a patient who suffered an episode of anuric acute kidney injury following exposure to a nonsteroidal anti-inflammatory agent while on two diuretics, an angiotensin-converting enzyme inhibitor, and an angiotensin receptor blocker. The episode completely resolved and we review some of the mechanisms by which these events may have taken place and suggest the term 'acute renal autoregulatory dysfunction' to describe this syndrome. [ABSTRACT FROM AUTHOR]