Role of neuronal nitric oxide synthase in the macula densa

Role of neuronal nitric oxide synthase in the macula densa.BackgroundThere 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).MethodsAf-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.ResultsTGF 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 μm; P < 0.001). This effect was not observed in JGAs from rabbits fed a normal- (19.0 ± 0.5 vs. 19.3 ± 0.8 μm after 7-NI) or high-NaCl diet (18.6 ± 0.7 vs. 18.4 ± 0.7 μm).ConclusionsFirst, 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

半月体性腎炎におけるbeta2 integrin 関与の病型間の相違について

An immunohistochemical study was performed to investigate the involvement of beta2 integrins in the glomerular infiltration of leukocytes in different types of human crescentic glomerulonephritis (CrGN). On 51 ethanol-fixed paraffin embedded renal biopsy specimens (34 cases of pauci-immune type and 17 cases of immune-mediated type), the following antigens were evaluated by immunoperoxidase method ; the glomerular (intra-capillary and extra-capillary) expression of ICAM-1, deposition of FRA and infiltration of leukocytes bearing beta2 integrins (LFA-1, CR3 and CR4). ICAM-1 was expressed both in extra-capillary and intra-capillary areas in very early stage of crescent formation and was rapidly decreased with the progression of the stage of crescent. Similarly, infiltration of leukocytes bearing beta2 integrins were observed both in extra-capillary and intra-capillary areas in early stage of crescent formation and were rapidly decreased with the progression of the stage of crescent. In pauci-immune type, the extra-capillary expression of ICAM-1 was significantly correlated with extra-capillary infiltration of LFA-1+cells (γ=0.800, p<0.0001) and CR3+cells (γ=0.791, p<0.0001). The extra-capillary deposition of FRA was also significantly correlated with extra-capillary infiltration of CR3+cells (γ=0.685, p<0.001) and CR4+cells (γ=0. 741, p<0.0001). In both types, the intra-capillary expression of ICAM-1 was significantly correlated with intra-capillary infiltration of LFA-1+cells (γ=0.618, p<0.01 and γ=0.754, p<0.05 respectively). These results suggested that ICAM-1/LFA-1 and ICAM-1/CR3 interaction might be involved in both the extra- and intra-capillary infiltration of leukocytes in pauci-immune CrGN. CR3 and CR4 might also function as fibrin/fibrinogen receptors in extra-capillary lesions in this type. On the other hand, only ICAM-1/LFA-1 interaction might be involved only in the intra-capillary infiltration of leukocytes in immune mediated CrGN

Reduction in the magnitude of serum potassium elevation in combination therapy with esaxerenone (CS‐3150) and sodium–glucose cotransporter 2 inhibitor in patients with diabetic kidney disease: Subanalysis of two phase III studies

Aims/Introduction: We evaluated the effect of co-administration of esaxerenone and a sodium–glucose cotransporter 2 (SGLT2) inhibitor on the magnitude of serum potassium elevation in Japanese patients with diabetic kidney disease. Materials and Methods: We carried out a prespecified subanalysis of data from two phase III studies: a multicenter, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes and microalbuminuria (J308); and a multicenter, single-arm, open-label trial in patients with type 2 diabetes and macroalbuminuria (J309). Changes in serum potassium levels during the studies and other measures were evaluated according to SGLT2 inhibitor use. Results: In both studies, time-course changes in serum potassium levels, and incidence rates of serum potassium elevation were lower in patients with co-administration of SGLT2 inhibitor in both the placebo and esaxerenone groups than those without the inhibitor. In contrast, time-course changes and mean percentage changes from baseline in urinary albumin-to-creatinine ratio, the proportion of patients with albuminuria remission and time-course changes in blood pressure did not change with or without SGLT2 inhibitor, whereas the albumin-to-creatinine ratio and blood pressure were reduced with esaxerenone. The blood glucose-lowering effect of SGLT2 inhibitor was not affected by esaxerenone. Conclusions: In Japanese patients with type 2 diabetes and albuminuria treated with esaxerenone, concomitant use of SGLT2 inhibitor reduced the magnitude of serum potassium elevation without any change of its antihypertensive and albuminuria-suppressing effects. Co-administration of esaxerenone and SGLT2 inhibitor might be a beneficial treatment option for patients with diabetic kidney disease

Body Weight Control by a High-Carbohydrate/Low-Fat Diet Slows the Progression of Diabetic Kidney Damage in an Obese, Hypertensive, Type 2 Diabetic Rat Model

Obesity is one of several factors implicated in the genesis of diabetic nephropathy (DN). Obese, hypertensive, type 2 diabetic rats SHR/NDmcr-cp were given, for 12 weeks, either a normal, middle-carbohydrate/middle-fat diet (MC/MF group) or a high-carbohydrate/low-fat diet (HC/LF group). Daily caloric intake was the same in both groups. Nevertheless, the HC/LF group gained less weight. Despite equivalent degrees of hypertension, hyperglycemia, hyperlipidemia, hyperinsulinemia, and even a poorer glycemic control, the HC/LF group had less severe renal histological abnormalities and a reduced intrarenal advanced glycation and oxidative stress. Mediators of the renoprotection, specifically linked to obesity and body weight control, include a reduced renal inflammation and TGF-beta expression, together with an enhanced level of adiponectin. Altogether, these data identify a specific role of body weight control by a high-carbohydrate/low-fat diet in the progression of DN. Body weight control thus impacts on local intrarenal advanced glycation and oxidative stress through inflammation and adiponectin levels

Angiotensin II Type 1 Receptor Blockers Reduce Urinary Angiotensinogen Excretion and the Levels of Urinary Markers of Oxidative Stress and Inflammation in Patients with Type 2 Diabetic Nephropathy

Objective To demonstrate that the administration of an angiotensin (Ang) II type 1 receptor (AT1R) blocker (ARB) inhibits the vicious cycle of high glucose (HG)-reactive oxygen species (ROS)-angiotensinogen (AGT)-Ang II-AT1R-ROS by suppressing ROSs and inflammation, thus ameliorating diabetic nephropathy (DN). Research Design and Methods Thirteen hypertensive DN patients were administered ARBs, and the following parameters were evaluated before and 16 weeks after the treatment: urinary AGT (UAGT), albumin (albumin-creatinine ratio: ACR), 8-hydroxydeoxyguanosine (8-OHdG), 8-epi-prostaglandin F2α (8-epi-PGF2α), monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6, and IL-10. Results ARB treatment reduced the blood pressure and urinary levels of AGT, ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 but increased the urinary levels of IL-10. The reduction rate of UAGT correlated with the reduction rate of blood pressure; the reduction rates of the urinary ACR, 8-OHdG, 8-epi-PGF2α, MCP-1, and IL-6 levels; and the increase rate of the urinary IL-10 levels. Moreover, subjects who had high UAGT values at baseline exhibited higher reduction rates of urinary albumin excretion. Conclusions ARB-induced blockade of the abovementioned vicious cycle contributes to the renoprotective effects of ARBs in DN. The urinary levels of AGT could represent a predictive factor for reduced ACR in patients receiving ARB treatment