Glomerular Hemodynamic Changes Research Articles

Evaluation of glomerular hemodynamic changes by sodium-glucose-transporter 2 inhibition in type 2 diabetic rats using in vivo imaging

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, or 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.

Possible renoprotective mechanisms of SGLT2 inhibitors.

Treatment with a sodium glucose cotransporter 2 (SGLT2) inhibitor in patients with chronic kidney disease reduces the renal risk independent of changes in blood glucose concentrations and blood pressure. However, the precise mechanism responsible for this SGLT2 inhibitor-induced renoprotective effect is unclear. We have previously shown that SGLT2 inhibitors induce antihypertensive effects with decreased sympathetic nerve activity, which is associated with transient natriuresis. Furthermore, treatment with an SGLT2 inhibitor improves renal ischemia by producing vascular endothelial growth factor-a in the renal tubules. Other studies have suggested that ketone body production, changes in glomerular hemodynamics, and intrarenal metabolic changes and a reduction in oxidative stress due to decreased tubulointerstitial glucose levels may also be involved in the renoprotective effects of SGLT2 inhibitors. In this review, we summarize the mechanism responsible for the SGLT2 inhibitor-induced renoprotective effects, including our recent hypothesis regarding an "aestivation-like response," which is a biological defense response to starvation.

How to interpret serum creatinine increases during decongestion.

During decongestion in acute decompensated heart failure (ADHF), it is common to observe elevations in serum creatinine (sCr) values due to vascular congestion, a mechanism that involves increased central venous pressure that has a negative impact on the nephron, promoting greater absorption of water and sodium, increased interstitial pressure in an encapsulated organ developing "renal tamponade" which is one of main physiopathological mechanism associated with impaired kidney function. For the treatment of this syndrome, it is recommended to use diuretics that generate a high urinary output and natriuresis to decongest the venous system, during this process the sCr values can rise, a phenomenon that may bother some cardiologist and nephrologist, since raise the suspicion of kidney damage that could worsen the prognosis of these patients. It is recommended that increases of up to 0.5 mg/dL from baseline are acceptable, but some patients have higher increases, and we believe that an arbitrary number would be impractical for everyone. These increases in sCr may be related to changes in glomerular hemodynamics and true hypovolemia associated with decongestion, but it is unlikely that they are due to structural injury or truly hypoperfusion and may even have a positive connotation if accompanied by an effective decongestion and be associated with a better prognosis in the medium to long term with fewer major cardiovascular and renal events. In this review, we give a comprehensive point of view on the interpretation of creatinine elevation during decongestion in patients with ADHF.

The Prevalence of Chronic Kidney Disease and Albuminuria in Patients With Type 1 and Type 2 Diabetes Attending a Single Centre.

Background Diabetes is the leading cause of chronic kidney disease worldwide. Diabetic kidney disease is one of the microvascular complications of diabetes and it involves changes in glomerular hemodynamics, interstitial fibrosis, and tubular atrophy. Early detection and management of Diabetic kidney disease (DKD) help to reduce morbidity and mortality. This study aims to assess the prevalence of nephropathy and albuminuria in the diabetic population attending an Irish tertiary care center. Methods Retrospective data collection and analysis of patients diagnosed with Type 1 diabetes mellitus(T1DM) and Type 2 diabetes mellitus (T2DM) through the Development and Integration of Accurate Mathematical Operations in Numerical Data-Processing (DIAMOND) database in a single Irish tertiary care center. An audit tool was used to collect patients' information including gender, age, type of diabetes, serum creatinine, urinary albumin excretion, albumin creatinine ratio (ACR), body mass index, and last available glycated hemoglobin (HbA1c). Results Out of 7394 subjects with T2DM, 3139 (42%) were identified with chronic kidney disease (CKD).There were 1866 subjects with positive ACR out of 3139 subjects with CKD in the T2DM cohort.This shows that 25% of subjects have diabetic kidney disease and 17% have CKD of undetermined etiology.In the T1DM cohort with 1166 subjects, 209 (18%) were identified with CKD.Out of these 209 subjects with CKD, 164 (14%) were ACR-positive.The prevalence of CKD and albuminuria were related to age in both T1DM and T2DM populations. Albuminuria showed a linear relationship with age in subjects with no known CKD, which shows that age causally relates to albuminuria independent of type and duration of diabetes. Conclusion CKD is more prevalent in patients with T2DM as compared to T1DM, whereas the prevalence of albuminuria is higher in the T1DM population.

Novel Insights in the Physiopathology and Management of Obesity-Related Kidney Disease

Obesity is recognized as an independent risk factor for the development of kidney disease, which has led to the designation of obesity-related glomerulopathy (ORG). Common renal features observed in this condition include glomerular hypertrophy, glomerulosclerosis, haemodynamic changes and glomerular filtration barrier defects. Additionally, and although less studied, obesity-related kidney disease also involves alterations in renal tubules, including tubule hypertrophy, lipid deposition and tubulointerstitial fibrosis. Although not completely understood, the harmful effects of obesity on the kidney may be mediated by different mechanisms, with alterations in adipose tissue probably playing an important role. An increase in visceral adipose tissue has classically been associated with the development of kidney damage, however, recent studies point to adipose tissue surrounding the kidney, and specifically to the fat within the renal sinus, as potentially involved in the development of ORG. In addition, new strategies for the treatment of patients with obesity-related kidney disease are focusing on the management of obesity. In this regard, some non-invasive options, such as glucagon-like peptide-1 (GLP-1) receptor agonists or sodium–glucose cotransporter-2 (SGLT2) inhibitors, are being considered for application in the clinic, not only for patients with diabetic kidney disease but as a novel pharmacological strategy for patients with ORG. In addition, bariatric surgery stands as one of the most effective options, not only for weight loss but also for the improvement of kidney outcomes in obese patients with chronic kidney disease.

Modified lipid metabolism and cytosolic phospholipase A2 activation in mesangial cells under pro-inflammatory conditions.

Diabetic kidney disease is a consequence of hyperglycemia and other complex events driven by early glomerular hemodynamic changes and a progressive expansion of the mesangium. The molecular mechanisms behind the pathophysiological alterations of the mesangium are yet to be elucidated. This study aimed at investigating whether lipid signaling might be the missing link. Stimulation of human mesangial cells with high glucose primed the inflammasome-driven interleukin 1 beta (IL-1β) secretion, which in turn stimulated platelet-derived growth factor (PDGF-BB) release. Finally, PDGF-BB increased IL-1β secretion synergistically. Both IL-1β and PDGF-BB stimulation triggered the formation of phosphorylated sphingoid bases, as shown by lipidomics, and activated cytosolic phospholipase cPLA2, sphingosine kinase 1, cyclooxygenase 2, and autotaxin. This led to the release of arachidonic acid and lysophosphatidylcholine, activating the secretion of vasodilatory prostaglandins and proliferative lysophosphatidic acids. Blocking cPLA2 release of arachidonic acid reduced mesangial cells proliferation and prostaglandin secretion. Validation was performed in silico using the Nephroseq database and a glomerular transcriptomic database. In conclusion, hyperglycemia primes glomerular inflammatory and proliferative stimuli triggering lipid metabolism modifications in human mesangial cells. The upregulation of cPLA2 was critical in this setting. Its inhibition reduced mesangial secretion of prostaglandins and proliferation, making it a potential therapeutical target.

MO614: Modified Lipid Metabolism and Cytosolic Phospholipase A2 Activation in Mesangial Cells Under Pro-Inflammatory Conditions

Abstract BACKGROUND AND AIMS Diabetic kidney disease (DKD) is thought to be a consequence of hyperglycemia and driven by early glomerular hemodynamic changes and progressive expansion of the mesangium. The molecular mechanism behind the pathophysiological alterations of the mesangium is yet to be elucidated. This study aimed at investigating whether lipid signaling might be the missing link. METHOD Human mesangial cells (HMCs) were stimulated with high glucose, IL-1β or PDGF-BB. Production of IL-1β and PDGF-BB, COX-2 induction and cPLA2 activation and prostaglandin secretion were investigated using a combination of ELISA, western blot, lipidomics, qPCR and activity assays. Inhibition of cPLA2 was evaluated using ELISA, migration and proliferation assays. Validation of data was performed in silico using the Nephroseq database [1] and a recently published glomerular transcriptomic DKD database. [2] RESULTS Stimulation of HMCs with high glucose primed IL-1β secretion through inflammasome NLRP3 signaling. In turn, IL-1β was able to stimulate PDGF-BB release. PDGF-BB increased IL-1β secretion synergistically. Both IL-1β and PDGF-BB stimuli caused lipid metabolism variations and in particular triggered the formation of phosphorylated sphingoid bases (PSBs) and the activation of the enzymes cPLA2 and COX-2. This led to the formation of prostanoids from arachidonic acid produced by cPLA2. As a result, prostaglandins were secreted. Another product of cPLA2 activation was lysophosphatidic acid (LPA), a proliferation effector. Blocking cPLA2-mediated release of arachidonic acid could in fact reduce HMCs’ proliferation and secretion of prostaglandins. CONCLUSION Hyperglycemia primes glomerular inflammatory and proliferative stimuli triggering lipid metabolism modifications in HMCs. The upregulation of cPLA2 was found to be critical in this setting. cPLA2 inhibition with AACOCF3 reduced mesangial secretion of prostaglandins and proliferation, making it a potential target for DKD therapy.

Obesity-related glomerulopathy: Current approaches and future perspectives.

SummaryObesity‐related glomerulopathy (ORG) is a silent comorbidity which is increasing in incidence as the obesity epidemic escalates. ORG is associated with serious health consequences including chronic kidney disease, end‐stage renal disease (ESRD), and increased mortality. Although the pathogenic mechanisms involved in the development of ORG are not fully understood, glomerular hemodynamic changes, renin‐angiotensin‐aldosterone system (RAAS) overactivation, insulin‐resistance, inflammation and ectopic lipid accumulation seem to play a major role. Despite albuminuria being commonly used for the non‐invasive evaluation of ORG, promising biomarkers of early kidney injury that are emerging, as well as new approaches with proteomics and metabolomics, might permit an earlier diagnosis of this disease. In addition, the assessment of ectopic kidney fat by renal imaging could be a useful tool to detect and evaluate the progression of ORG. Weight loss interventions appear to be effective in ORG, although large‐scale trials are needed. RAAS blockade has a renoprotective effect in patients with ORG, but even so, a significant proportion of patients with ORG will eventually progress to ESRD despite therapeutic efforts. It is noteworthy that certain antidiabetic agents such as sodium‐glucose cotransporter 2 inhibitors (SGLT2i) or glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) could be useful in the treatment of ORG through different pleiotropic effects. In this article, we review current approaches and future perspectives in the care and treatment of ORG.

The Glomerular Filtration Rate and Proteinuria in Obese Children

Background: Obesity increases the risk of many pathologies, including cardiovascular and renal diseases. This study aimed to determine the association between obesity and proteinuria as well as glomerular hemodynamic changes (an early marker of kidney damage) in obese children and its relationship with metabolic syndrome. Methods: This case-control study included 112 overweight and obese male and female patients aged 7 - 16 years, and 35 age- and gender-matched healthy controls. The obese patients were divided into 4 subgroups according to BMI:normal weight (control group), overweight, obese, morbidly obese. The glomerular filtration rate was estimated using classical and adjusted formulas based on the various body size descriptors of Leger, Schwartz, Filler, and Zappitelli, and chronic kidney disease formulas in all patients and controls. Creatinine, cystatin C, 24-hour urine protein, and the estimated glomerular filtration were compared between groups. Results: Blood pressure, creatinine, and 24-hour urine protein values were significantly higher in the overweight and obese patient subgroups (P < 0.05). The estimated glomerular filtration rate, which was calculated using creatinine or cystatin C, was higher in the obese patients and subgroups than in the control group (P < 0.05). In contrast, the estimated glomerular filtration rate measured using both classical and adjusted formulas was significantly lower in the obese patients than in the controls (P < 0.05). Conclusions: Early indicators of renal damage are elevated urine protein and renal function test results compatible with impaired renal function. As such, obese pediatric patients should be routinely monitored for blood pressure, renal function, and proteinuria.

Biomarkers of kidney injury and indicators of renal inflammation in African American men with diabetes and diabetic nephropathy

Diabetic nephropathy (DN) is a progressive kidney disease caused by damage to the capillaries in the kidneys' glomeruli due to changes in glomerular hemodynamics, causing renal lesions and fibrosis. Oxidative stress and inflammatory responses represent underlying causes for developing chronic kidney damage. Treatment outcomes for DN are poor because many patients with DN are diagnosed late due to lack of clinical tests based on sensitive biomarkers. Monocyte chemoattractant protein‐1 (MCP‐1) is a major promoter of inflammation, renal injury, and fibrosis in diabetic nephropathy. In the United States, minority ethnic communities bear a disproportionate burden of complications of diabetes and are at a higher risk of developing end stage renal disease. Participation in biomedical research by African American men is especially low due to historical mistrust with the research institutions. The objective of this study is to assess correlations between biomarkers of kidney injury and indicators of inflammation among three groups of African American men: 1) diabetic patients without DN, 2) diabetic patients with diagnosed DN, and 3) non‐diabetic controls. Fasting blood and urine samples were collected from patients recruited through a community health clinic. Surveys were administered to establish patient profiles and family history. Enzyme‐linked immunosorbent assays (ELISA) were used to determine the levels of plasma MCP‐1 and the levels of three biomarkers of kidney injury, namely, cystatin C, neutrophil gelatinase‐associated lipocalin (NGAL), and kidney injury molecule 1 (KIM‐1). The data were analyzed by 2‐way ANOVA. The data showed that the levels of serum cystatin C were significantly higher in patients with diagnosed DN compared to non‐diabetic controls (p&lt;0.01). Additionally, diabetic patients showed a significant increase in serum cystatin C levels relative to the non‐diabetic controls (p&lt;0.05). In contrast, urine cystatin C levels were significantly lower in patients with DN compared to the other two groups. Plasma NGAL levels were significantly higher in patients with DN compared to both non‐diabetic and diabetic patients (p&lt;0.01). However, there was no significant difference in the levels of urine KIM‐1 among the three groups. In conclusion, serum MCP‐1 exhibited higher levels in patients with DN compared to both diabetic patients and non‐diabetic controls (p&lt;0.0001). The significant increase in serum MCP‐1 levels suggests that inflammation is an underlying cause of kidney injury in African American men who have DN. Furthermore, the data suggest that a significant number of diabetic African American men may have undiagnosed kidney injury as shown by elevated cystatin C levels.Support or Funding InformationThis study was supported by the Minority Men's Health Initiative (MMHI) through NIH/NIMHD Center Award # U54MD008621 (CFDA 93.307), Sub‐Award # HU140004 and sub‐award #HU150006.

Superoxide dismutase mimetic, tempol, aggravates renal injury in advanced-stage stroke-prone spontaneously hypertensive rats

The aim of this study was to determine whether antioxidant therapy could relieve hypertension and retard the progression of renal damage in advanced-stage hypertensive rats. Twenty-four-week-old spontaneously hypertensive stroke-prone rats were treated for 8 weeks with the superoxide dismutase mimetic tempol, low-dose or high-dose candesartan (an angiotensin receptor blocker), or hydralazine, and blood pressure and renal damage were compared. Elevated blood pressure and renal damage with heterogeneity were present after 8 weeks, with greater glomerulosclerosis in the juxtamedullary glomeruli than in the superficial glomeruli. Although both tempol and candesartan effectively reduced reactive oxygen species production in the kidney, tempol did not decrease blood pressure and exacerbated urine protein and histological damage, such as glomerulosclerosis and interstitial fibrosis, particularly in juxtamedullary nephrons (tempol vs. untreated: glomerulosclerosis index, 2.0 vs. 1.5, P<0.01; fibrosis, 15 vs. 10%, P<0.001). In contrast, high-dose candesartan and hydralazine prevented these forms of renal damage with lowering blood pressure. Low-dose candesartan also prevented this renal damage without lowering blood pressure. Moreover, there were increased numbers of larger and smaller glomeruli in the juxtamedullary cortex of tempol-treated rats, suggesting that changes in glomerular hemodynamics may be responsible for the exacerbation of glomerulosclerosis. Both candesartan- and hydralazine-treated rats had glomeruli that were slightly decreased in size. These results suggest that single-antioxidant therapy starting at an advanced-stage may be ineffective for hypertension and rather exacerbate renal damage in nonsalt loaded SHRSP. Furthermore, lowering blood pressure and inhibiting the renin-angiotensin system could be critical for slowing the progression of hypertensive renal damage at an advanced stage.

Hypertension increases urinary excretion of immunoglobulin G, ceruloplasmin and transferrin in normoalbuminuric patients with type 2 diabetes mellitus

Increased urinary excretion of certain plasma proteins, such as immunoglobulin G (IgG), ceruloplasmin and transferrin, with different molecular radii of 55 Å or less and different isoelectric points have been reported to precede development of microalbuminuria in patients who have diabetes mellitus with hypertension. We examined how hypertension affects these urinary proteins in a diabetic state. Excretion of IgG, ceruloplasmin, transferrin, albumin, α2-macroglobulin with a large molecular radius of 88 Å and N-acetylglucosaminidase in first-morning urine samples were measured in normoalbuminuric patients (urinary albumin-to-creatinine ratio < 15 mg/g) with hypertension and nondiabetes mellitus (group hypertension, n = 32), type 2 diabetes mellitus and normotension (group diabetes mellitus, n = 52) and type 2 diabetes mellitus and hypertension (group Both, n =45), and in age-matched controls (n = 72). Urinary IgG, ceruloplasmin, transferrin, albumin and N-acetylglucosaminidase and estimated glomerular filtration rate (eGFR) were significantly elevated in groups diabetes mellitus and Both compared with controls. Furthermore, urinary IgG, ceruloplasmin and transferrin in group Both were significantly higher than those in group diabetes mellitus. These exhibited a positive and relatively strong association with eGFR compared with controls. No significant difference in urinary albumin or N-acetylglucosaminidase was found between the two diabetic groups. In contrast, group hypertension had elevated urinary transferrin without any changes in the other compounds. Urinary α2-macroglobulin did not differ among the four groups. These findings suggest that normoalbuminuric diabetic patients without hypertension have both glomerular hemodynamic changes such as increased intraglomerular hydraulic pressure and altered proximal tubules, and that hypertension increases intraglomerular hydraulic pressure. Increased urinary IgG, ceruloplasmin and transferrin may reflect an increase in intraglomerular hydraulic pressure.

Anti-neutral endopeptidase, natriuretic peptides disarrangement, and proteinuria onset in membranous nephropathy

Neutral endopeptidase (NEP) is the first podocytic antigen responsible for human membranous nephropathy (MN). Besides the prevailing pathogenetic mechanism of immune complex, NEP is also involved in the metabolism of natriuretic peptides (NP). The identification of anti-NEP antibodies in human MN suggests that the decreased circulating NEP may down-regulate the NP catabolism. In this context, we hypothesize that NP disarrangement secondary to anti-NEP antibodies may account, in part, for the onset of proteinuria in MN. Whereas the pathways for the onset of proteinuria caused by elevated NP level are still obscure. The data presented in this review focus on those which support this hypothesis with regards to evidence from the glomerular haemodynamic changes, endothelial permeability, glomerular basement membrane disruption, and podocyte detachment.

Drug-Induced Nephrotoxicity and Its Biomarkers

Nephrotoxicity occurs when kidney-specific detoxification and excretion do not work properly due to the damage or destruction of kidney function by exogenous or endogenous toxicants. Exposure to drugs often results in toxicity in kidney which represents the major control system maintaining homeostasis of body and thus is especially susceptible to xenobiotics. Understanding the toxic mechanisms for nephrotoxicity provides useful information on the development of drugs with therapeutic benefi ts with reduced side effects. Mechanisms for drug-induced nephrotoxicity include changes in glomerular hemodynamics, tubular cell toxicity, inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy. Biomarkers have been identifi ed for the assessment of nephrotoxicity. The discovery and development of novel biomarkers that can diagnose kidney damage earlier and more accurately are needed for effective prevention of drug-induced nephrotoxicity. Although some of them fail to confer specificity and sensitivity, several promising candidates of biomarkers were recently proved for assessment of nephrotoxicity. In this review, we summarize mechanisms of drug-induced nephrotoxicity and present the list of drugs that cause nephrotoxicity and biomarkers that can be used for early assessment of nephrotoxicity.

N-terminal-pro-brain natriuretic peptide is decreased in insulin dependent gestational diabetes mellitus: a prospective cohort trial

BackgroundN-terminal-pro-brain natriuretic peptide (NT-proBNP) is elevated in gestational hypertension and preeclampsia. This trial aimed to generate data for gestational diabetes mellitus patients, who are at risk to develop these complications.MethodsWe have measured NT-proBNP in 223 otherwise healthy women between gestational week 24 and 32 referred to the outpatient diabetes unit in a cross-sectional study.Results88 control subjects, 45 patients with indication for medical nutrition therapy (MNT) alone and 90 patients who required insulin therapy were included. Groups of women were comparable regarding gestational week. Body mass index before pregnancy and at blood draw was significantly higher in subjects with insulin dependent gestational diabetes mellitus compared to MNT controlled gestational diabetes mellitus. NT-proBNP was significantly lower in patients with insulin dependent gestational diabetes mellitus (35 ± 25 pg/ml) compared to controls (53 ± 43 pg/ml, p = 0.012).ConclusionsNT-proBNP is within the reference range of normal subjects in women with gestational diabetes mellitus. Differences in body mass index, changes in glomerular filtration rate and haemodynamics may explain lower NT-proBNP concentrations in insulin dependent gestational diabetes mellitus. A false negative interpretation needs to be considered in these women.

A Special Focus on the Role of α&lt;sub&gt;1D&lt;/sub&gt;-Adrenoreceptors in the Assessment of Renal Tubular Sodium Re-absorptive Responses in Spontaneously Hypertensive Rats Subjected to High Sodium Diet

α(1D)-adrenoceptors are involved in the genesis/maintenance of hypertension in spontaneously hypertensive rats (SHR). This study aims to investigate the role of α(1D)-adrenoceptors in the antinatriuretic and antidiuretic responses in SHR subjected to high sodium (SHRHNa) and normal sodium (SHRNNa) intake for six weeks. Renal inulin clearance study was performed in which the antinatriuretic and antidiuretic responses to phenylephrine were examined in the presence and absence of α(₁D)-adrenoceptors blocker BMY7378. Data, mean±S.E.M. were subjected to ANOVA with significance at p<0.05. Results show that feeding SHR for six weeks with high salt did not cause any change in blood pressure. SHRHNa had higher (all p<0.05) urine flow rate (UFR), fractional and absolute excretion of sodium (FE(Na) and U(Na)V) compared to SHRNNa. Phenylephrine infusion produced significant reduction in UFR, FE(Na) and U(Na)V in both SHRHNa and SHRNNa. The antidiuretic and antinatriuretic responses to phenylephrine in both groups were attenuated in the presence of BMY7378. Moreover, the antidiuretic and antinatriuretic responses to phenylephrine and BMY7378 were independent on any significant changes in renal and glomerular hemodynamics in both groups. Thus we conclude that high sodium intake did not bring any further increase in blood pressure of SHR, however, it results in exaggerated natriuresis and diuresis in SHRHNa. Irrespective of dietary sodium changes, α₁-adrenoceptors are involved in mediating the antinatriuretic and antidiuretic responses to phenylephrine in SHR. Further, high sodium intake did not significantly influence the functionality of α(₁D)-adrenoceptors in mediating the adrenergically induced antinatriuresis and antidiuresis.

In VivoVisualization of Glomerular Microcirculation and Hyperfiltration in Streptozotocin-Induced Diabetic Rats

Knowledge of glomerular structural and hemodynamic changes in vivo is still limited under diabetic conditions. In this study, we examined the alterations in glomerular structure and permeability of macromolecules and the effects of telmisartan using a confocal laser microscope. Diabetes was induced by injecting streptozotocin. After 4 and 8 weeks, the filtration and permeability of differently sized compounds across the glomerular capillaries were visualized using a confocal laser microscope by injecting 500-kilodalton and 40-kilodalton dextran. At 7 weeks, some diabetic rats were treated with telmisartan for 1 week. The permeation of the 40-kilodalton dextran across the glomerular capillaries into Bowman's space was quantified. Glomerular volume, diameters of the afferent and efferent arterioles, and glomerular permeability were compared. Glomerular volume was significantly increased in the diabetic rats, and there was heterogeneity in the glomerular volumes. The diameter ratio of the afferent to efferent arterioles significantly increased, and there was increased glomerular permeability in the diabetic rats compared with the control rats. Telmisartan treatment reduced glomerular permeability without affecting glomerular volume. These data showed that glomerular hyperfiltration started from the early phase of diabetes, accompanied by dilatation of afferent arterioles and glomerular hypertrophy.

Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia

Endothelial dysfunction is a characteristic feature during the renal damage induced by mild hyperuricemia. The mechanism by which uric acid reduces the bioavailability of intrarenal nitric oxide is not known. We tested the hypothesis that oxidative stress might contribute to the endothelial dysfunction and glomerular hemodynamic changes that occur with hyperuricemia. Hyperuricemia was induced in Sprague-Dawley rats by administration of the uricase inhibitor, oxonic acid (750 mg/kg per day). The superoxide scavenger, tempol (15 mg/kg per day), or placebo was administered simultaneously with the oxonic acid. All groups were evaluated throughout a 5-wk period. Kidneys were fixed by perfusion and afferent arteriole morphology, and tubulointerstitial 3-nitrotyrosine, 4-hydroxynonenal, NOX-4 subunit of renal NADPH-oxidase, and angiotensin II were quantified. Hyperuricemia induced intrarenal oxidative stress, increased expression of NOX-4 and angiotensin II, and decreased nitric oxide bioavailability, systemic hypertension, renal vasoconstriction, and afferent arteriolopathy. Tempol treatment reversed the systemic and renal alterations induced by hyperuricemia despite equivalent hyperuricemia. Moreover, because tempol prevented the development of preglomerular damage and decreased blood pressure, glomerular pressure was maintained at normal values as well. Mild hyperuricemia induced by uricase inhibition causes intrarenal oxidative stress, which contributes to the development of the systemic hypertension and the renal abnormalities induced by increased uric acid. Scavenging of the superoxide anion in this setting attenuates the adverse effects induced by hyperuricemia.

Cyclooxygenases, Prostanoids, and Glomerular Injury

The association of prostanoid production with glomerular injury has been appreciated for more than 20 yr, well in advance of more recent studies that have characterized pathways that are associated with phospholipid hydrolysis and metabolism of free arachidonic acid to prostanoids. Release of arachidonic acid from phospholipids by phospholipase A2 generally is the rate-limiting step in the synthesis of prostanoids (1). Free arachidonic acid is metabolized by cyclooxygenases (COX), followed by prostaglandin or thromboxane synthases. There are two COX genes, which result in transcription of COX-1 and COX-2 proteins, as well as COX-3, a splice variant of COX-1 (2). In many tissues, COX-1 is expressed constitutively, whereas COX-2 is induced in disease states, but in certain cells within the kidney, COX-2 also is expressed constitutively (3). Therefore, the view that COX-1 produces prostanoids that are necessary for normal physiologic functions whereas COX-2–derived prostanoids play a pathologic role does not necessarily apply to kidney physiology. Effects of prostanoids are mediated via specific receptors, and many of these have been identified in renal cells (4). In experimental animal models, administration of nephritogenic toxins or deposition of antibody and complement within glomeruli may induce changes in prostanoid generation by intrinsic glomerular cells. Alternatively, production of glomerular prostanoids may be altered after recruitment of leukocytes. A functional role for prostanoids in glomerular injury first was suggested by studies that showed that nonsteroidal anti-inflammatory drugs can alter glomerular hemodynamics and urinary protein excretion in various proteinuric states. Studies in the 1980s and early 1990s used pharmacologic manipulation of prostanoid synthesis to study changes in glomerular permselectivity, and some but not all of these studies showed that administration of inhibitors of COX or thromboxane synthase can reduce proteinuria (reviewed in reference [5]). For example, these drugs lowered proteinuria in Adriamycin nephropathy in rats (a model of minimal-change disease/focal glomerulosclerosis), nephrotoxic nephritis in rats and mice (anti–glomerular basement membrane disease), passive Heymann nephritis (PHN) in rats (membranous nephropathy), and rat anti–Thy-1 nephritis (mesangioproliferative nephritis). When studied, reduction of proteinuria occurred independent of changes in glomerular hemodynamics. Another approach to modulating prostanoid effects has been to shift production of dienoic prostanoids to inactive trienoic metabolites with diets that are rich in omega-3 fatty acids (e.g., fish oils). These diets have shown beneficial effects on renal function and/or proteinuria in animals with lupus nephritis, nephrotoxic nephritis, PHN, and focal glomerulosclerosis. Fish oil may alter humoral or cell-mediated immune responses or may affect glomerular cell function and permselectivity directly. Together, a number of studies that used distinct experimental approaches support a role for prostanoids in exacerbating proteinuria in various glomerulopathies. It also should be noted that indomethacin was shown to reduce proteinuria in human nephrotic syndrome (6), and a beneficial effect of fish oil diet on the progression of renal failure was reported in IgA nephropathy in humans (7). Since the late 1990s, a newer generation of studies has addressed the role of COX and prostanoids in glomerular injury. These studies followed the discovery of COX-2, characterization of prostanoid receptors, and the advent of selective inhibitors. For example, glomeruli from rats with PHN express significantly more COX-1 and COX-2 and produce more prostanoids than normal rat glomeruli (8). The increase in prostanoids was attenuated with a COX-2 selective inhib

Real-time observation of glomerular hemodynamic changes in diabetic rats: Effects of insulin ARB

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. 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. 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. 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.