Reduction In Albumin Excretion Research Articles

Targeted stimulation of the vagus nerve reduces renal injury in female mice with systemic lupus erythematosus

Pharmacological stimulation of the vagus nerve has been shown to suppress inflammation and reduce blood pressure in a murine model of systemic lupus erythematosus (SLE) that is characterized by hypertension, inflammation, renal injury and dysautonomia. The present study aims to directly stimulate vagal nerves at the level of the dorsal motor nucleus of the vagus (DMV) using designer receptors exclusively activated by designer drugs (DREADDs) to determine if there is similar protection and confirm mechanism. Female NZBWF1/J (SLE) mice and NZW/LacJ mice (controls, labeled as NZW throughout) received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or control virus into the DMV at 31 weeks of age. After two weeks of recovery and viral transfection, the DREADD agonist clozapine-N-oxide (CNO; 3 mg/kg) was injected subcutaneously for an additional 14 days. At 35 weeks, mean arterial pressure (MAP; mmHg) was increased in SLE mice compared to NZW mice, but selective activation of DMV neurons did not significantly alter MAP in either group. SLE mice had higher indices of renal injury including albumin excretion rate (μg/day), glomerulosclerosis index, interstitial fibrosis, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) compared to NZW mice. Selective DMV neuronal activation reduced albumin excretion rate, glomerulosclerosis, interstitial fibrosis, and NGAL in SLE mice but not NZW mice. Together, these data indicate that selective activation of neurons within the DMV by DREADD protects the kidney suggesting an important role of vagus-mediated pathways in the progression of renal injury in SLE.

AW-APSH-2: “MINERALOCORTICOID RECEPTOR (MR)-ASSOCIATED HYPERTENSION” IN “GREEDY ORGAN HYPOTHESIS”

Spironolactone has been used for more than 60 years. Eplerenone is MR-specific MRB and esaxerenone possesses non-steroidal structure with high affinity and specificity to MR and exhibits long half-life. We conducted a double-blind phase III study of esaxerenone compared with eplerenone in patients with essential hypertension in 2020. Esaxerenone 2.5 mg elicited comparable hypotensive effect to eplerenone 50 mg and 5 mg exhibited significantly stronger effect than 2.5 mg. We also investigated the efficacy of dosage-escalation of esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes (DM) (HbA1c:6.8%) and albuminuria (212 mg/gCr). 5 mg esaxerenone induced 20/8mmHg blood pressure reduction and reduced albumin excretion significantly. Interestingly, in these studies, esaxerenone exerted similar hypotensive action in the patients with RAS inhibitors, compared to the groups without them. This observation indicates that MR can be activated being independent of renin-angiotensin-aldosterone system. In 2012, we proposed the concept of “MR-associated hypertension”, hypertension caused by over-activation of MR with wide range of plasma aldosterone level. Primary aldosteronism is the typical example of MR-associated hypertension, but even in low plasma aldosterone concentration state, such as obesity, DM, CKD, MR can be over-activated. There are several postulated mechanisms of over-activation of MR. Increased expression of MR, increased sensitivity of MR and MR protein stabilization. We are interested in the activation of MR by salt and sugar themselves. We focus on MR expressed in the intestine for sodium absorption. Administration of DOCA and high salt induced up-regulation of epithelial sodium channel, ENaC, the target molecule of MR. And intestine specific knock-out of MR mice exhibited blunted increase of blood pressure by DOCA and high salt loading. We also demonstrated that high sugar induces MR protein stabilization by PKC activation, O-GlcNac modification or EGFR-ERK activation. More recently, in relation to excessive salt and sugar intake and occurrence of non-communicable diseases (NCDs), including hypertension, we have proposed “Greedy Organ Hypothesis”. Excessive intake of salt and sugar are sensed by the kidney and the intestines, and these organs up-regulate SGLT, sodium-glucose co-transporters and come to absorb salt and sugar greedily. Excessive salt intake through SGLT2 makes the kidney greedy to induce hypertension/CKD. Excessive food intake through SGLT1 make the intestines greedy to induce obesity/DM. Furthermore, there is “crossing” relationships between “greedy organs” and NCDs. Greedy kidney and intestines over-activate MR and induce MR-associated hypertension. Therefore, MRB are effective to alleviate Greedy Organs and to suppress NCDs.

Corn Bedding Mediates Protection from the Dahl Salt‐Sensitive Hypertensive and Renal Damage Phenotype

The Dahl Salt‐Sensitive (SS) rat is a well‐established translational model of human salt sensitive hypertension. When challenged with a high salt (4.0% NaCl) diet, Dahl SS develop an increase in mean arterial pressure (MAP) and renal damage, as assessed by an increase in albumin excretion and infiltration of immune cells in the kidneys. Our colony of Dahl SS recently moved to a new animal facility, and we observed that the SS rats challenged on a high salt diet showed an attenuation of the high salt‐induced increase in MAP and albumin excretion. Upon further investigation, differences in the animal bedding were noted between the locations. In the present study, the salt‐sensitive disease phenotype was examined in age‐matched, genetically‐identical male Dahl SS rats fed the same diets (AIN‐76A with 0.4% or 4.0% NaCl) maintained on either an aspen‐based wood bedding or a corn‐cob based bedding. Based upon the known protective effects of a plant‐based diet and observations that the rats were eating the corn‐cob bedding, we hypothesized that the change in bedding from wood to corn was providing a protective phenotype to the SS rats. We tested this hypothesis by comparing the disease phenotypes in Dahl SS maintained on the corn‐cob or wood bedding from birth until the end of the study. SS rats were instrumented at 7 weeks of age with radiotelemeters for continuous blood pressure monitoring and were allowed about a week to recover. While the rats were maintained on a low salt (0.4% NaCl) diet, there were no significant differences in MAP (123.2±1.1 vs 126.8±0.8 mmHg, n=13, 16) or albumin excretion rate (7.5±1.8 vs 18.8±3.5 mg/day, n=10, 17) in Dahl SS maintained on the corn‐cob vs the wood bedding, respectively. While MAP and albumin excretion significantly increased in all Dahl SS following a 21‐day high salt challenge, there was significantly reduced albumin excretion in the corn‐cob bedding rats (128±27 mg/day, n=10) when compared to the wood bedding rats (332±50 mg/day, n=17, p˂0.005). The SS rats maintained on the corn‐cob bedding also had significantly attenuated MAP at the end of the 21 day challenge when compared to the rats on the wood bedding (corn‐cob bedding: 141.1±4.2 mmHg vs wood bedding: 159.5±3.6 mmHg, p˂0.0001, n=12, 16 respectively). This was further characterized with a significant reduction in CD45+ leukocytes infiltrating in the SS rat kidneys on corn‐cob bedding by ~48% (p<0.003). That occurred by a significant reduction observed in the CD11b/c+ macrophages/monocytes by ~49% (p<0.003) and in CD45R+ B‐cells by ~64% (p<0.004). There was no difference between the body weights of the rats between the different beddings (corn‐cob bedding: 336±6 g vs wood bedding: 339±5 g, n=13, 17) respectively but kidney weight was a significantly reduced by ~17% (p<0.0001) in corn‐cob bedding compared to the SS rats on the wood bedding. This attenuated phenotype was also mirrored in female Dahl SS rats when maintained on the corn‐cob bedding compared to age‐matched females on the wood bedding. These data suggest that the change in bedding from wood to corn had a significant protective effect in the Dahl SS rat. Further work will need to be performed to determine the exact cause in the reduction of the salt‐sensitive phenotype when on a corn‐cob bedding. These data highlight the importance of controlling all environmental parameters in experimental work, and to consider environmental effects that may influence other disease phenotypes.

Rosmarinic acid monotherapy is better than the combination of rosmarinic acid and telmisartan in preventing podocyte detachment and inhibiting the progression of diabetic nephropathy in rats.

BackgroundPodocyte injury and its subsequent detachment play a critical role in the development and progression of diabetic nephropathy (DN). The objective of this study was to investigate the effect of rosmarinic acid (RA) in preventing podocyte detachment and inhibiting the progression of DN in streptozotocin (STZ)-induced diabetic in rats.MethodsWe used 20 adult male Wistar rats as experimental animals, which were randomly divided into 5 groups (n=4 per group): nondiabetic rat group (negative control) and 4 groups of STZ-induced diabetic rats, namely, 1 group untreated diabetic rats (positive control) and 3 groups treated diabetic rats with RA 75 mg/kg, telmisartan (TMS) 1 mg/kg and combination of RA 75 mg/kg with TMS 1 mg/kg), respectively. After 8 weeks of therapy, urinary levels of podocin, nephrin and albumin and also serum cystatin C levels were examined by ELISA. The expression of p65 nuclear factor-kB by immunohistochemistry whereas expression of podocin and nephrin glomerulus were examined by immunofluorescence.ResultsIn the treated diabetic groups, we found that urinary level of podocin and nephrin, albumin urine excretion and serum cystatin C levels were significantly lower than the positive control group. Compared to negative controls, the group of treated diabetic rats did not differ significantly in preventing increased excretion of urinary nephrin and podocin. Meanwhile, treatment with RA monotherapy was significantly better than TMS or a combination of RA with TMS in reducing albumin excretion and preventing decreased kidney function.ConclusionIn STZ-induced diabetic rats, RA can prevent podocyte detachment. Treatment with RA and TMS either monotherapy or in combination can inhibit the development and progression of DN. However, the combination of both did not show a synergistic effect, even have higher urinary albumin excretion and worse kidney function compared to the RA monotherapy.

Metformin or Acarbose Treatment Significantly Reduced Albuminuria in Patients with Newly Diagnosed Type 2 Diabetes Mellitus and Low-Grade Albuminuria.

BackgroundA urine albumin to creatinine ratio (UACR) >30 mg/g is considered to represent albuminuria, but in type 2 diabetes mellitus, even low-grade albuminuria is associated with increased risk of cardiovascular disease. This study aimed to investigate the effects of metformin and acarbose treatment on urine albumin excretion in Chinese patients with newly diagnosed diabetes and low-grade albuminuria.Material/MethodsPatients with newly diagnosed diabetes (n=589) were divided into Group I (with a baseline UACR <10 mg/g) (n=331), and Group II (with a baseline UACR of 10–30 mg/g) (n=258). Following 48 weeks of treatment with metformin or acarbose, the UACR, blood pressure, body mass index (BMI), blood glucose, lipid profiles, and homeostasis model assessment of insulin resistance (HOMA-IR) were compared.ResultsBaseline diastolic blood pressure, levels of blood glucose and low-density lipoprotein cholesterol (LDL-C), and HOMA-IR were significantly increased in Group II compared with Group I (all P<0.05). In Group II, both metformin and acarbose treatment significantly reduced the UACR (P<0.001); the effect was significantly greater following acarbose treatment compared with metformin treatment (P<0.05). In Group I, neither metformin nor acarbose treatment significantly changed the UACR, but both Group I and Group II showed a significant and comparable reduction in BMI, blood glucose, blood pressure, and HOMA-IR.ConclusionsIn a group of Chinese patients with newly diagnosed type 2 diabetes mellitus, low-grade albuminuria (baseline UACR of 10–30 mg/g) was associated with metabolic factors before treatment. Treatment with either metformin or acarbose significantly reduced albumin excretion.

KORELASI KADAR KREATININ SERUM DENGAN HASIL TES ALBUMIN URINE PADA PASIEN DENGAN PENYAKIT GINJAL DI RSUD dr. SOEGIRI LAMONGAN

Abstract: Examination of blood creatinine levels is one of the parameters used to assess renalfunction, since serum and urinary excretion concentrations within 24 hours are relatively constant.However, in another clinical guideline, there is a type of examination that is more recommended inmost patients with the risk of kidney failure, urine albumin test. In the event of renal dysfunction,the ability of creatinine filtration will decrease and serum creatinine will increase as well as somesubstances that should not exist in the urine, such as albumin, to appear. Reduced albumin excretion in the urine may be able to slow the rate of renal failure and help to delay the body’s need forkidney or dialysis transplantation. This cross-sectional study aims to analyze the relationship between serum creatinine and albuminuria in patients with kidney disease. Serum creatinine levelexamination by Jaffe method and urine albumin examination were qualitatively performed on therespondents who met the inclusion criteria. A total of 92 data were then analyzed by Chi-squarewith α&lt;0,05. The results of this study indicate that there is a significant relationship betweenserum creatinine and albuminuria levels in patients with general kidney disease (p = 0.000, r =0.728), and in male patients (p = 0.000, r = 0.736) and females (p = 0,000; r = 0.686) with theage level 41-50 years. There is no relationship between serum creatinine and albuminuria in maleand female patients at the age of 20-30 years and 31–40 years.

Inhibition of Mammalian Target of Rapamycin Complex 1 Attenuates Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats.

The goal of the present study was to explore the protective effects of mTORC1 (mammalian target of rapamycin complex 1) inhibition by rapamycin on salt-induced hypertension and kidney injury in Dahl salt-sensitive (SS) rats. We have previously demonstrated that H2O2 is elevated in the kidneys of SS rats. The present study showed a significant upregulation of renal mTORC1 activity in the SS rats fed a 4.0% NaCl for 3 days. In addition, renal interstitial infusion of H2O2 into salt-resistant Sprague Dawley rats for 3 days was also found to stimulate mTORC1 activity independent of a rise of arterial blood pressure. Together, these data indicate that the salt-induced increases of renal H2O2 in SS rats activated the mTORC1 pathway. Daily administration of rapamycin (IP, 1.5 mg/kg per day) for 21 days reduced salt-induced hypertension from 176.0±9.0 to 153.0±12.0 mm Hg in SS rats but had no effect on blood pressure salt sensitivity in Sprague Dawley treated rats. Compared with vehicle, rapamycin reduced albumin excretion rate in SS rats from 190.0±35.0 to 37.0±5.0 mg/d and reduced the renal infiltration of T lymphocytes (CD3+) and macrophages (ED1+) in the cortex and medulla. Renal hypertrophy and cell proliferation were also reduced in rapamycin-treated SS rats. We conclude that enhancement of intrarenal H2O2 with a 4.0% NaCl diet stimulates the mTORC1 pathway that is necessary for the full development of the salt-induced hypertension and kidney injury in the SS rat.

Factors associated with the reduction of albumin excretion in diabetic hypertensive patients: differential effect of manidipine versus amlodipine.

In AMANDHA trial, the addition of manidipine, but not amlodipine, in diabetic patients with uncontrolled hypertension, microalbuminuria and preserved renal function resulted in a large decrease of urinary albumin excretion (UAE) despite similar blood pressure (BP) reductions. Factors associated with the reduction of UAE were analyzed. For this purpose, a multivariable analysis was performed. Although after 6 months of treatment, manidipine and amlodipine decreased BP to a similar extent, reductions of UAE were higher with manidipine. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were associated with changes in UAE. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were independently associated with changes in UAE. Compared with amlodipine, manidipine reduced UAE to a higher extent, independently of BP reduction.

In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway.

We investigated whether 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) could improve early diabetic nephropathy through the DNA-damage-inducible transcript 4/tuberous sclerosis 2/mammalian target of rapamycin pathway. Rat mesangial cells were cultured in media containing normal glucose or high glucose and were treated with or without 1,25(OH)2D3. Mesangial cells proliferation was measured. Streptozotocin-induced diabetic rats were injected intravenously with a recombinant lentivirus against the rat vitamin D receptor gene. Urinary and serum albumin, fasting plasma glucose, serum triglyceride, total cholesterol, calcium, parathyroid hormone and serum 25-dihydroxy-vitamin D (25(OH)D) levels, mean glomerular volume, glomerular basement membrane thickness and total kidney volume were determined. The expressions of vitamin D receptor, DNA-damage-inducible transcript 4, and mammalian target of rapamycin were measured. 1,25(OH)2D3 inhibited the proliferation of mesangial cells induced by hyperglycemia. 1,25(OH)2D3 also significantly reduced albumin excretion, mean glomerular volume, glomerular basement membrane, and total kidney volume in rats with diabetic nephropathy. The expression of DNA-damage-inducible transcript 4 was elevated by 1,25(OH)2D3 treatment. The phosphorylation of mammalian target of rapamycin was reduced by 1,25(OH)2D3 treatment. Vitamin D receptor gene silencing blocked all of the above results. The current study demonstrates that 1,25(OH)2D3 can effectively inhibit mesangial cells proliferation induced by hyperglycemia, thus suppressing the development of diabetic nephropathy. This study also shows that the nephron-protective effect of 1,25(OH)2D3 occurs partly through the DDIT4/TSC2/mTOR pathway.

Abstract P048: Effects of Aerobic Exercise on Oxidative Stress in the Kidneys of Type2 Diabetic Rats

Objective: Aerobic exercise is known to have multiple beneficial effects including renal protection in type 2 diabetes mellitus and obesity. However, the mechanisms regulating these actions of aerobic exercise remain unclear. The present study evaluated the effects of chronic aerobic exercise on early stage of diabetic nephropathy focusing on renal oxidative stress and nitric oxide (NO), using Zucker diabetic fatty (ZDF) rats as an animal model of obese type 2 diabetes. Methods: Male ZDF rats (6 weeks old) underwent forced treadmill exercise for 8 weeks (Ex-ZDF). Sedentary ZDF (Sed-ZDF) and Zucker lean (Sed-ZL) rats served as controls. After the last exercise session, all rats were subjected to an intra-peritoneal glucose tolerance test. Result: Exercise ameliorated hyperglycemia with increased insulin secretion, and raised the values of homeostasis model assessment for β-cell function (HOMA-β) in ZDF rats. Exercise also reduced albumin excretion and normalized creatinine clearance in ZDF rats. Endothelial (e) and neuronal (n) NO synthase (NOS) protein expression, and NOS activity in the kidneys of Sed-ZDF rats were lower compared with Sed-ZL rats, while both NOS expression and NOS activity were upregulated by exercise in ZDF rats. Although there was no significant difference in plasma levels of adiponectin between the groups, plasma levels of leptin were significantly higher in the Ex-ZDF group compared with the Sed-ZL and Sed-ZDF groups. Exercise decreased plasma and urinary thiobarbituric acid-reactive substances (TBARS) as an index of lipid peroxidation in ZDF rats. Additionally, renal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and expression of p47phox protein were significantly higher in the kidneys of the Sed-ZDF group compared with the Sed-ZL group, and there was no significant difference between the Ex-ZDF and Sed-ZL groups. Immunoblots for Nox4, Nox2, namely gp91phox and p22phox protein were undetected in the kidneys of the Sed-ZDF and Ex-ZDF group as well as the Sed-ZL group. In addition, expression of nitrotyrosine as an index of peroxynitrite (ONOO–) formation was significantly lower in the kidneys of the Sed-ZDF group compared with the Sed-ZL group, and was significantly higher in the Ex-ZDF group compared with the Sed-ZDF group. Further, morphometric evidence of renal damage was alleviated in response to exercise. Conclusion: Upregulated NOS activity and NOS protein, and ameliorated NADPH oxidase activity and p47phox protein in the kidneys may be potential mechanisms by which chronic aerobic exercise can reduced early diabetic nephropathy in ZDF rats. Chronic aerobic exercise does have beneficial effects and may be a novel therapeutic approach for preventing the development of renal dysfunction in patients with type 2 diabetes mellitus and obesity.

Chronic Running Exercise Alleviates Early Progression of Nephropathy with Upregulation of Nitric Oxide Synthases and Suppression of Glycation in Zucker Diabetic Rats.

Exercise training is known to exert multiple beneficial effects including renal protection in type 2 diabetes mellitus and obesity. However, the mechanisms regulating these actions remain unclear. The present study evaluated the effects of chronic running exercise on the early stage of diabetic nephropathy, focusing on nitric oxide synthase (NOS), oxidative stress and glycation in the kidneys of Zucker diabetic fatty (ZDF) rats. Male ZDF rats (6 weeks old) underwent forced treadmill exercise for 8 weeks (Ex-ZDF). Sedentary ZDF (Sed-ZDF) and Zucker lean (Sed-ZL) rats served as controls. Exercise attenuated hyperglycemia (plasma glucose; 242 ± 43 mg/dL in Sed-ZDF and 115 ± 5 mg/dL in Ex-ZDF) with increased insulin secretion (plasma insulin; 2.3 ± 0.7 and 5.3 ± 0.9 ng/mL), reduced albumin excretion (urine albumin; 492 ± 70 and 176 ± 11 mg/g creatinine) and normalized creatinine clearance (9.7 ± 1.4 and 4.5 ± 0.8 mL/min per body weight) in ZDF rats. Endothelial (e) and neuronal (n) NOS expression in kidneys of Sed-ZDF rats were lower compared with Sed-ZL rats (p<0.01), while both eNOS and nNOS expression were upregulated by exercise (p<0.01). Furthermore, exercise decreased NADPH oxidase activity, p47phox expression (p<0.01) and α-oxoaldehydes (the precursors for advanced glycation end products) (p<0.01) in the kidneys of ZDF rats. Additionally, morphometric evidence indicated renal damage was reduced in response to exercise. These data suggest that upregulation of NOS expression, suppression of NADPH oxidase and α-oxoaldehydes in the kidneys may, at least in part, contribute to the renal protective effects of exercise in the early progression of diabetic nephropathy in ZDF rats. Moreover, this study supports the theory that chronic aerobic exercise could be recommended as an effective non-pharmacological therapy for renoprotection in the early stages of type 2 diabetes mellitus and obesity.

Combination Irbesartan/Amlodipine versus Irbesartan/Cilnidipine for Attenuation of Albuminuria in Rats with Streptozotocin-Induced Diabetic Nephropathy

Background: Excessive urinary albumin excretion is associated with hypertension and diabetic nephropathy. Calcium channel blockers (CCBs) used as antihypertensives suppress such albuminuria with variable efficacy. While hypertension benefits from the addition of angiotensin receptor blockers (ARBs), it is unknown if ARBs alter the effects of CCBs on albuminuria. Objective: This study compared the efficacy of combined ARB irbesartan with either CCB amlodipine or CCB cilnidipine on albuminuria associated with experimental diabetic nephropathy. Methods: Male Sprague-Dawley rats with streptozotocin-induced diabetes were treated with a CCB alone (amlodipine 2.0 mg/kg/d or cilnidipine 2.0 mg/kg/d), an ARB alone (irbesartan 20.0 mg/kg/d), or combinations. In the acute protocol, changes in glomerular afferent and efferent arteriole diameters were examined by a charge-coupled device video microscope following single doses. In the chronic protocol, urinary albumin excretion, glomerular reactive oxygen species, and endothelial surface layer (ESL) condition were evaluated after 2 weeks of daily treatment. Results: In the acute protocol, cilnidipine mono therapy caused a greater dilation in glomerular efferent arterioles than amlodipine monotherapy, while combination therapy with irbesartan induced comparable efferent arteriole dilation. In the chronic protocol, cilnidipine mono therapy suppressed albuminuria, reduced glomerular oxidative stress, and protected the glomerular ESL against degeneration to a much greater extent that amlodipine monotherapy. However, addition of irbesartan reduced albumin excretion, oxidative stress, and ESL degeneration to the same extent in both groups. Conclusions: While cilnidipine is more effective alone, the combinations of irbesartan with cilnidipine or amlodipine are equally effective for reducing albuminuria and other pathological sequela of experimental diabetic nephropathy.

Beyond Glycosuria: Exploring the intrarenal effects of SGLT-2 inhibition in diabetes

For millennia, the syndrome that has become known as diabetes was considered to be primarily a disease of the urinary system and, by association, of dysfunction in the kidneys (recognized as the source of urine). In the last decade, there has been renewed interest in the role of the kidneys in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodiumglucose cotransporter 2 (SGLT-2) as a means to control glucose levels and augment calorie-wasting leading to weight loss. However, beyond actions on glycaemic control, inhibition of proximal glucose absorption via SGLT-2 has significant direct effects to attenuate hyperfiltration and reduce renal hypertrophy. Increased distal sodium delivery may also act to suppress the intrarenal renin-angiotensin-aldosterone system, although systemic activity may be modestly increased due to osmotic diuresis. Reducing proximal glucose reabsorption may also protect the tubular cells from exposure to excess glucose and glucose-induced reactive oxygen species. On the other hand, distal glucose delivery following inhibition of SGLT-2 may increase glycogen deposition, the significance of which is unclear. However, subjects with familial glycosuria appear to have a benign renal prognosis. Some studies have demonstrated significant reductions in albumin excretion in various experimental models and as post-hoc observations in clinical trials. Whether these reflect renoprotection or are simply the result of intraglomerular haemodynamic changes remains unclear. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress.

Carnosine treatment in combination with ACE inhibition in diabetic rats

In humans, we reported an association of a certain allele of carnosinase gene with reduced carnosinase activity and absence of nephropathy in diabetic patients. CN1 degrades histidine dipeptides such as carnosine and anserine. Further, we and others showed that treatment with carnosine improves renal function and wound healing in diabetic mice and rats. We now investigated the effects of carnosine treatment alone and in combination with ACE inhibition, a clinically established nephroprotective drug in diabetic nephropathy.Male Sprague–Dawley rats were injected i.v. with streptozotocin (STZ) to induce diabetes. After 4weeks, rats were unilaterally nephrectomized and randomized for 24weeks of treatment with carnosine, lisinopril or both.Renal CN1 protein concentrations were increased under diabetic conditions which correlated with decreased anserine levels. Carnosine treatment normalized CN1 abundance and reduced glucosuria, blood concentrations of glycosylated hemoglobin (HbA1c), carboxyl-methyl lysine (CML), N-acetylglucosamine (GlcNac; all p<0.05 vs. non-treated STZ rats), reduced cataract formation (p<0.05) and urinary albumin excretion (p<0.05), preserved podocyte number (p<0.05) and normalized the increased renal tissue CN1 protein concentration. Treatment with lisinopril had no effect on HbA1C, glucosuria, cataract formation and CN1 concentration, but reduced albumin excretion rate more effectively than carnosine treatment (p<0.05). Treatment with both carnosine and lisinopril combined the effects of single treatment, albeit without additive effect on podocyte number or albuminuria.Increased CN1 amount resulted in decreased anserine levels in the kidney. Both carnosine and lisinopril exert distinct beneficial effects in a standard model of diabetic nephropathy. Both drugs administered together combine the respective effects of single treatment, albeit without exerting additive nephroprotection.

Efficiency assessment for antihypertensive, hemodynamic, renal effects of adenosine-converting enzyme (ACE) inhibitors and irbesartan and impact on endothelial disfunction in patients with stage II hypertension

Aim. To provide a comparative assessment of the impact of enalapril maleate and Irbesartanum on renal function, endothelium, hemodynamic and blood pressure in patients with essential hypertension stage II. Methods and results. The results of the most part of meta-analyses demonstrate absolutely comparable efficiency of iACE [inhibitors of adenosine-converting enzyme] and angiotensin II-renin-blockers (ARBs) in respect of reduction in frequency of different cardiovascular diseases. However, attention should be drawn towards the fact that ARBs show substantially higher efficiency as compared to other classes of antihypertensive drugs by strength of nephroprotective effects. Especially when diabetic or hypertensive neuropathy progression is inhibited. The objective of this study was to investigate the microalbuminuria level and the endothelial function in patients with stage II hypertension and to compare the impact of ACE inhibitors and Irbesartan. 60 patients with stage II hypertension (HTN) before treatment and after 12 weeks therapy were examined. The key factor for selection was the presence of microalbuminuria (MAU). The group of patients with stage II HTN with MAU was divided into two groups: 30 patients were treated with ACE inhibitor, namely Enalaprili maleates “Enalapril” (I group) and 30 patients were treated with Irbesartan, namely “Aprovel” (II group) accordingly. It was established that the Irbesartan group showed significant reduction in albuminuria level from 127.1±26.3 μg/mL to 56.2±21.8 μg/mL (by 44%, Р<0.05), while the ACE-inhibitor group showed reduction from 125.3±21.5 μg/mL to 101.3±19.6 (Р<0.05). Thus, at the end of the treatment period the albuminuria level in the Irbesartan group was 44.8% lower than in the other group (Р<0.05). 60% of patients of this group and only about 30% of patients of the ACE-inhibitor group reached normal level of albuminuria. On comparing Е-1 level between the patients with stage II HTN of both groups it was revealed that reduction level of endothelin-I in the group treated with Irbesartan was 12% lower than in the group of patients treated with Enalapril. NО2 level as compared with the data before treatment and after administered therapy increased by 35% in case of treatment with Enalapril and by 42.5% in case of treatment with Aprovel. NО3 level increased by 21% and accordingly 29%, and NОх level – by 28% and 33% accordingly.This fact indicates that Irbesartan treatment results in improvement in renal functional state in patients with HTN what is revealed by highly significant reduction in albumin excretion in urine and is due to increase of functional renal reserve and so positively effects endothelial function. Conclusion. This suggests that treatment with Irbesartanum increases renal functional reserve and has a positive effect on endothelial function.

Renal effects of dapagliflozin in patients with type 2 diabetes.

Diabetes mellitus was originally conceived as a renal disorder. In the last decade, however, there has been renewed interest in role of the kidney in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodium glucose transporter-2 (SGLT2) as a means to better control glucose levels and at the same time augment calorie wasting and lower insulin, blood pressure and uric acid levels. Such actions, indirectly, may also have benefits for the prevention of diabetic complications including renal disease. However, there are also data to support the potential for direct renoprotective actions arising from inhibition of SGLT2, including actions to attenuate diabetes-associated hyperfiltration and tubular hypertrophy, as well as reduce the tubular toxicity of glucose. Some studies have demonstrated significant reductions in albumin excretion in various experimental models, independent of its effects on blood pressure or glucose control. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress. This article reviews the clinical and experimental data pertaining to the renal effects of SGLT2 inhibition with a particular focus on dapaglifozin.

Fabry Disease

Fabry disease is an X-linked disorder resulting from mutations of the gene that encodes the lysosomal hydrolase α -galactosidase A, and leads to progressive lysosomal accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids.[1][1] In classically affected male patients, clinical

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Aliskiren Reduces Morning Blood Pressure in Hypertensive Patients with Diabetic Nephropathy

Diabetic nephropathy (DN) is a leading disease that requires renal replacement therapy. The progression of renal dysfunction in DN is faster than the other renal diseases. While antihypertensive therapy reduces albuminuria, a good indicator for the progression, hypertension in DN is treatment resistant. Among patients with DN who took angiotensin receptor blockers (ARBs), 27 patients who exhibited poor control of albuminuria were enrolled into the study. Angiotensin receptor blocker was exchanged to aliskiren (150–300 mg/d) and clinical parameters were followed for 6 months. Exchange to aliskiren decreased albuminuria (1.57 ± 0.68 to 0.89 ± 0.45 g/gCr, P < .01) without changes in estimated glomerular filtration rate and office blood pressure (BP). Body weight and hemoglobin A1c were not altered. Aliskiren also reduced plasma renin activity (2.0 ± 0.9 to 1.2 ± 0.6 ng/mL/h, P < .01). While evening BP was unchanged, morning systolic BP (139 ± 8 to 132 ± 7 mm Hg, P < .01) and diastolic BP (81 ± 7 to 76 ± 6 mm Hg, P < .05) were decreased significantly after 6 months. Our results indicated that aliskiren decreased BP, especially morning BP in hypertensive patients with DN. The present data suggest that aliskiren exerts renoprotective actions including reduction in albumin excretion for patients with DN.

Renoprotective effects of (+)-catechin in streptozotocin-induced diabetic rat model

Diabetic nephropathy is a complication of diabetes mellitus leading to end-stage renal disease. Oxidative stress and inflammation play a major role in the pathogenesis of diabetic nephropathy. Green tea, known for its antioxidant and anti-inflammatory properties, has been shown to be renoprotective. We hypothesized that (+)-catechin (CTN), a component of green tea, is responsible for the renoprotection. Our investigation of the therapeutic potential of CTN in streptozotocin-induced diabetic rats demonstrated for the first time that the effects of CTN treatment were comparable with the effects of an angiotensin-converting enzyme inhibitor (ACEi) enalapril for the treatment of albumin excretion. After 12 weeks of CTN treatment with 35 mg/d in the drinking water, urinary albumin excretion and plasma creatinine concentrations in all the diabetic treatment groups were reduced, compared with the diabetic group with no treatment. Urine creatinine and creatinine clearance were higher in diabetic groups treated with CTN and ACEi compared with the diabetic group with no treatment. Endothelin 1, lipid peroxidation, concentration of alanine transferase enzyme, and expression of fibronectin were lower in all the treatment groups compared with the diabetic group with no treatment. Concentrations of free thiols were higher in the CTN-treated group compared with the diabetic rats with no treatment. Our findings suggest that CTN has renoprotective properties comparable with ACEi, and coadministration of CTN and enalapril might be useful in reducing albumin excretion as well as improving endothelial function. (+)-Catechin might be successfully used in the future for clinical situations where ACEi is poorly tolerated or contraindicated.