miR-125a-5p/miR-125b-5p contributes to pathological activation of angiotensin II-AT1R in mouse distal convoluted tubule cells by the suppression of Atrap.

The renin-angiotensin system plays a crucial role in the regulation of blood pressure. Activation of the angiotensin II (Ang II)-Ang II type 1 receptor (AT1R) signaling pathway contributes to the pathogenesis of hypertension and subsequent organ damage. AT1R-associated protein (ATRAP) has been identified as an endogenous inhibitory protein of the AT1R pathological activation. We have shown that mouse Atrap (Atrap) represses various Ang II-AT1R-mediated pathologies, including hypertension in mice. The expression of human ATRAP (ATRAP)/Atrap can be altered in various pathological states in humans and mice, such as Ang II stimulation and serum starvation. However, the regulatory mechanisms of ATRAP/Atrap are not yet fully elucidated. miRNAs are 21 to 23 nucleotides of small RNAs that post-transcriptionally repress gene expression. Single miRNA can act on hundreds of target mRNAs, and numerous miRNAs have been identified as the Ang II-AT1R signaling-associated disease phenotype modulator, but nothing is known about the regulation of ATRAP/Atrap. In the present study, we identified miR-125a-5p/miR-125b-5p as the evolutionarily conserved miRNAs that potentially act on ATRAP/Atrap mRNA. Further analysis revealed that miR-125a-5p/miR-125b-5p can directly repress both ATRAP and Atrap. In addition, the inhibition of miR-125a-5p/miR-125b-5p resulted in the suppression of the Ang II-AT1R signaling in mouse distal convoluted tubule cells. Taken together, miR-125a-5p/miR-125b-5p activates Ang II-AT1R signaling by the suppression of ATRAP/Atrap. Our results provide new insights into the potential approaches for achieving the organ-protective effects by the repression of the miR-125 family associated with the enhancement of ATRAP/Atrap expression.

SETD2 regulates SLC family transporter-mediated sodium and glucose reabsorptions in renal tubule.

A regulatory mechanism for SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule, is incompletely understood. Here, we report an important regulation of SLC family transporter by SETD2, a chromatin remodeling gene whose alterations have been found in a subset of kidney cancers. Kidney-specific inactivation of Setd2 resulted in hypovolemia with excessive urine excretion in mouse and interestingly, RNA-sequencing analysis of Setd2-deficient murine kidney exhibited decreased expressions of SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule. Importantly, inactivation of Setd2 in murine kidney displayed attenuated dapagliflozin-induced diuresis and glucose excretion, further supporting that SETD2 might regulate SLCfamily transporter-mediated sodium and glucose reabsorptions in renal tubule. These data uncover an important regulation of SLC family transporter by SETD2, which may illuminate a crosstalk between metabolism and epigenome in renal tubule.

Effect of tirzepatide on glycaemic control and weight loss compared with other glucagon-like peptide-1 receptor agonists in Japanese patients with type 2 diabetes mellitus.

AIM: To compare the therapeutic effects of glucose-dependent insulinotropic polypeptide (GIP)/ glucagon-like peptide-1 receptor agonists (GLP-1RAs) or GLP-1RAs in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library up to July 2023. Randomized controlled trials (RCTs) that compared GLP-1RAs or GIP/GLP-1RAs in Japanese patients with T2D were selected. A network meta-analysis was conducted to indirectly compare the treatments, focusing on efficacy in reducing glycated haemoglobin (HbA1c) levels and body weight (BW). RESULTS: A total of 18 RCTs were included in this analysis. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and BW compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference [95% confidence interval] -0.52 [-0.96; -0.08] and - 1.23 [-1.64; -0.81]; BW: -5.07 [-8.28; -1.86] and -6.84 [-8.97; -4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP-1RAs, such as dulaglutide, liraglutide and lixisenatide. CONCLUSIONS: Among Japanese patients with T2D, tirzepatide showed the greatest effectiveness in reducing HbA1c levels and inducing weight loss. The study provides evidence to guide GLP-1RA treatment strategies in Japanese patients with T2D.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

Effect of preceding drug therapy on the renal and cardiovascular outcomes of combined sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes and chronic kidney disease.

AIM: To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor agonist (GLP-1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP-1RA first. METHODS: We included 438 patients with CKD (GLP-1RA-first group, n = 223; SGLT2 inhibitor-first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)-matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only. RESULTS: Using the PS-matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP-1RA-first group, 10%; SGLT2 inhibitor-first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001). CONCLUSION: Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was significant. These results suggest that, in GLP-1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP-1RA treatment may lead to more favourable renal outcomes.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome presenting as recurrent aseptic peritonitis in a patient receiving peritoneal dialysis: a case report.

BACKGROUND: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by mutations in the ubiquitin-activating enzyme1 (UBA1) gene and characterised by an overlap between autoinflammatory and haematologic disorders. CASE PRESENTATION: We reported a case of a 67-year-Japanese man receiving peritoneal dialysis (PD) who had recurrent aseptic peritonitis caused by the VEXAS syndrome. He presented with unexplained fevers, headache, abdominal pain, conjunctival hyperaemia, ocular pain, auricular pain, arthralgia, and inflammatory skin lesions. Laboratory investigations showed high serum C-reactive protein concentration and increased cell count in PD effluent. He was treated with antibiotics for PD-related peritonitis, but this was unsuccessful. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography images demonstrated intense FDG uptake in his left superficial temporal artery, nasal septum, and bilateral auricles. The working diagnosis was giant cell arteritis, and he was treated with oral prednisolone (PSL) 15 mg daily with good response. However, he was unable to taper the dose to less than 10 mg daily because his symptoms flared up. Since Tocilizumab was initiated, he could taper PSL dose to 2 mg daily. Sanger sequencing of his peripheral blood sample showed a mutation of the UBA1 gene (c.122 T > C; p.Met41Thr). We made a final diagnosis of VEXAS syndrome. He suffered from flare of VEXAS syndrome at PSL of 1 mg daily with his cloudy PD effluent. PSL dose of 11 mg daily relieved the symptom within a few days. CONCLUSIONS: It is crucial to recognise aseptic peritonitis as one of the symptoms of VEXAS syndrome and pay attention to the systemic findings in the patients.

Effects of sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, and their combination on albuminuria in diabetic patients.

AIMS: Diabetes mellitus (DM) is the leading cause of chronic kidney disease. Albuminuria is associated with an increased risk of cardiovascular mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) and mineralocorticoid receptor antagonists (MRAs) protect against albuminuria; however, their combined effects on albuminuria are unclear. We performed a network meta-analysis to investigate the effects of SGLT2-Is, MRAs and their combination on albuminuria in type 2 DM. METHODS: We systematically searched PubMed, Medline, EMBASE and the Cochrane Library from inception up to 20 November 2022. We selected randomized control and crossover trials that compared MRAs, SGLT2-Is, MRAs + SGLT2-Is, or a placebo in patients with type 2 DM with a urinary albumin-creatinine ratio (UACR) ≥30 mg/g creatinine. The primary outcome was the change in the UACR. RESULTS: This meta-analysis analysed 17 studies with 34 412 patients. The use of combination treatment with SGLT2-Is and MRAs was associated with lower albuminuria compared with the use of SGLT2-Is, MRAs, or the placebo alone [mean difference (95% CI): -34.19 (-27.30; -41.08), -32.25 (-24.53; -39.97) and -65.22 (-57.97; -72.47), respectively]. Treatment with SGLT2-Is or MRAs alone caused a significant reduction in UACR compared with the placebo [mean difference (95% CI): -31.03 (-28.35; -33.72) and -32.97 (-29.68; -36.27), respectively]. The effects of MRAs on the UACR are comparable with those of SGLT2-Is. Sensitivity analyses showed similar results. CONCLUSION: Combination therapy with SGLT2-Is and MRAs was associated with lower albuminuria in patients with type 2 DM compared with monotherapy with SGLT2-Is or MRAs alone.

Clinical impact of left ventricular systolic dysfunction in patients undergoing dialysis access surgery.

BACKGROUND: An arteriovenous fistula (AVF) is the most frequently used dialysis access for haemodialysis. However, it can cause volume loading for the heart and may induce circulatory failure when performed in patients with low cardiac function. This study aimed to characterise patients with low cardiac function when initiating dialysis and determine how cardiac function changes after the dialysis access surgery. METHODS: We conducted a retrospective observational study at two centres incorporating 356 patients with end-stage kidney disease who underwent echocardiography before the dialysis access surgery. RESULTS: An AVF and a subcutaneously fixed superficial artery were selected in 70.4% and 23.5% of 81 patients with reduced/mildly reduced (< 50%) left ventricular ejection fraction (LVEF), respectively, and in 94.2% and 1.1% of 275 patients with preserved (≥ 50%) LVEF (p < 0.001), respectively. Follow-up echocardiography was performed in 70.4% and 38.2% of patients with reduced/mildly reduced and preserved LVEF, respectively, which showed a significant increase in LVEF (41 ± 9-44 ± 12%, p = 0.038) in patients with reduced/mildly reduced LVEF. LVEF remained unchanged in 12 patients with reduced/mildly reduced LVEF who underwent subcutaneously fixed superficial artery (30 ± 10-32 ± 15%, p = 0.527). Patients with reduced/mildly reduced LVEF had lower survival rates after surgery than those with preserved LVEF (p = 0.021 for log-rank). CONCLUSION: The LVEF subcategory was associated with dialysis access selection. After the dialysis access surgery, LVEF was increased in patients with reduced/mildly reduced LVEF. These results may help select dialysis access for patients initiating dialysis.

Blunted humoral immune response to the fourth dose of BNT162b2 COVID-19 vaccine in patients undergoing hemodialysis.

BACKGROUND: We aimed to investigate the impact of a fourth dose of BNT162b2 vaccine (Comirnaty®, Pfizer-BioNTech) on anti-SARS-CoV-2 (anti-S IgG) antibody titers in patients receiving hemodialysis (HD) and healthcare workers (HCWs). METHODS: A multi-institutional retrospective study at five dialysis clinics in Japan was conducted using 238 HD patients and 58 HCW controls who received four doses of the BNT162b2 mRNA vaccine. Anti-S IgG titers were measured at 1, 3, and 6 months after the second dose, at 1 and 5/6 months after the third dose, and at 1 month after the fourth dose of vaccine. RESULTS: The log anti-S IgG titers of the HD patients after the second vaccination were significantly lower than those of the control group, but equalized 1 month after the third vaccination: 9.94 (95% CI 9.82-10.10) vs. 9.81 (95% CI 9.66-9.96), (P = 0.32). In both groups, the fold-increase in anti-S IgG titers was significantly lower after the fourth dose than after the third dose of vaccine. In addition, there was a strong negative correlation between antibody titers 1 month after the fourth vaccination and antibody titers immediately before the vaccination. In both groups, the waning rate of anti-S IgG titers from the post-vaccination peak level after the third vaccine dose was significantly slower than that after the second dose. CONCLUSIONS: These findings suggest that the humoral immune response was blunted after the fourth dose of the conventional BNT162b2 vaccine. However, multiple vaccinations could extend the window of humoral immune protection.

Effects of a High-Protein Diet on Kidney Injury under Conditions of Non-CKD or CKD in Mice.

Considering the prevalence of obesity and global aging, the consumption of a high-protein diet (HPD) may be advantageous. However, an HPD aggravates kidney dysfunction in patients with chronic kidney disease (CKD). Moreover, the effects of an HPD on kidney function in healthy individuals are controversial. In this study, we employed a remnant kidney mouse model as a CKD model and aimed to evaluate the effects of an HPD on kidney injury under conditions of non-CKD and CKD. Mice were divided into four groups: a sham surgery (sham) + normal diet (ND) group, a sham + HPD group, a 5/6 nephrectomy (Nx) + ND group and a 5/6 Nx + HPD group. Blood pressure, kidney function and kidney tissue injury were compared after 12 weeks of diet loading among the four groups. The 5/6 Nx groups displayed blood pressure elevation, kidney function decline, glomerular injury and tubular injury compared with the sham groups. Furthermore, an HPD exacerbated glomerular injury only in the 5/6 Nx group; however, an HPD did not cause kidney injury in the sham group. Clinical application of these results suggests that patients with CKD should follow a protein-restricted diet to prevent the exacerbation of kidney injury, while healthy individuals can maintain an HPD without worrying about the adverse effects.

Deficiency of the kidney tubular angiotensin II type1 receptor-associated protein ATRAP exacerbates streptozotocin-induced diabetic glomerular injury via reducing protective macrophage polarization.

Although activation of the renin-angiotensin system and of its glomerular components is implicated in the pathogenesis of diabetic nephropathy, the functional roles of the tubular renin-angiotensin system with AT1 receptor signaling in diabetic nephropathy are unclear. Tissue hyperactivity of the renin-angiotensin system is inhibited by the angiotensin II type 1 receptor-associated protein ATRAP, which negatively regulates receptor signaling. The highest expression of endogenous ATRAP occurs in the kidney, where it is mainly expressed by tubules but rarely in glomeruli. Here, we found that hyperactivation of angiotensin II type 1 receptor signaling in kidney tubules exacerbated diabetic glomerular injury in a mouse model of streptozotocin-induced diabetic nephropathy. These phenomena were accompanied by decreased expression of CD206, a marker of alternatively activated and tissue-reparative M2 macrophages, in the kidney tubulointerstitium. Additionally, adoptive transfer of M2- polarized macrophages into diabetic ATRAP-knockout mice ameliorated the glomerular injury. As a possible mechanism, the glomerular mRNA levels of tumor necrosis factor-α and oxidative stress components were increased in diabetic knockout mice compared to non-diabetic knockout mice, but these increases were ameliorated by adoptive transfer. Furthermore, proximal tubule-specific ATRAP downregulation reduced tubulointerstitial expression of CD206, the marker of M2 macrophages in diabetic mice. Thus, our findings indicate that tubular ATRAP-mediated functional modulation of angiotensin II type 1 receptor signaling modulates the accumulation of tubulointerstitial M2 macrophages, thus affecting glomerular manifestations of diabetic nephropathy via tubule-glomerular crosstalk.

SARS-CoV-2 spike protein antibody titers 6 months after SARS-CoV-2 mRNA vaccination among patients undergoing hemodialysis in Japan.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is shown to prevent severe illness and death in hemodialysis (HD) patients, but the immune response to vaccines is reduced in this population. This study compared SARS-CoV-2 spike protein antibody titers between HD patients and healthy controls in Japan for up to 6 months following vaccination. METHODS: A multi-institutional retrospective study at five clinics in Japan was conducted using 412 HD patients and 156 healthy controls who received two doses of the BNT162b2 (Pfizer-BioNTech) mRNA vaccine. Anti-SARS-CoV-2 spike protein S1 IgG antibody titers were measured at 1, 3, and 6 months after the second dose. The attenuation speed was calculated as slope (i.e., -ß) using a linear mixed-effects model toward the log-transformed antibody titers. RESULTS: The HD group had significantly lower month 1 antibody titers (Ab-titer-1) than the controls, and these remained lower through month 6 (95% CI: 2617.1 (1296.7, 5240.8) vs. 7285.4 (4403.9, 11,000.0) AU/mL at Ab-titer-1, and 353.4 (178.4, 656.3) vs. 812.0 (498.3, 1342.7) AU/mL at Ab-titer-6 (p < 0.001, respectively)). Lower log Ab-titer-1 levels in the HD group were significantly associated with a lower log Ab-titer-6 (0.90 [0.83, 0.97], p < 0.001). The -ß values in the HD patients and healthy controls were -4.7 ± 1.1 and -4.7 ± 1.4 (year-1), respectively. CONCLUSION: SARS-CoV-2 spike protein antibody titers were significantly lower in HD patients than in healthy controls at 1 (peak) and 6 months after the second vaccination. Low peak antibody titers contributed to low 6-month antibody titers.

Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis.

BACKGROUND: Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients. METHODS: We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized. RESULTS: Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]). CONCLUSIONS: In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.

Potential effective treatment of shortening continuous erythropoietin receptor activator treatment interval combined with iron supplementation in hemodialysis patients.

Our previous randomized controlled trial comparing the total dose of weekly versus biweekly continuous erythropoietin receptor activator (CERA) therapy to maintain optimal hemoglobin (Hb) levels showed no significant differences between the two therapies. This post-hoc analysis assessed whether the total dose of weekly versus biweekly CERA therapy to maintain Hb levels among HD patients differed among groups with or without iron supplementation. Of 107 patients, 40 received intravenous iron supplementation due to iron deficiency (iron group) and 67 did not (non-iron group). In the iron group, the weekly therapy tended to require a lower total CERA dose compared with the biweekly therapy (274 ± 274 vs 381 ± 223 µg/12 weeks, P = 0.051). Changes in circulating hepcidin levels, a negative regulator of intestinal iron uptake, after 2 weeks of CERA treatment were significantly lower in the weekly therapy compared with the biweekly therapy (-4.2 ± 6.3 vs 11.1 ± 7.3 ng/mL, P = 0.015). In the non-iron group, there were no significant differences in total CERA dose or changes in hepcidin levels between the two therapies. Shortening the CERA treatment interval combined with iron supplementation may lead to the more efficient treatment of HD patients with iron deficiency.

Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products.

The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

Aristolochic Acid Induces Renal Fibrosis and Senescence in Mice.

The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated ß-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

The circadian clock is disrupted in mice with adenine-induced tubulointerstitial nephropathy.

Chronic Kidney Disease (CKD) is increasing in incidence and has become a worldwide health problem. Sleep disorders are prevalent in patients with CKD raising the possibility that these patients have a disorganized circadian timing system. Here, we examined the effect of adenine-induced tubulointerstitial nephropathy on the circadian system in mice. Compared to controls, adenine-treated mice showed serum biochemistry evidence of CKD as well as increased kidney expression of inflammation and fibrosis markers. Mice with CKD exhibited fragmented sleep behavior and locomotor activity, with lower degrees of cage activity compared to mice without CKD. On a molecular level, mice with CKD exhibited low amplitude rhythms in their central circadian clock as measured by bioluminescence in slices of the suprachiasmatic nucleus of PERIOD 2::LUCIFERASE mice. Whole animal imaging indicated that adenine treated mice also exhibited dampened oscillations in intact kidney, liver, and submandibular gland. Consistently, dampened circadian oscillations were observed in several circadian clock genes and clock-controlled genes in the kidney of the mice with CKD. Finally, mice with a genetically disrupted circadian clock (Clock mutants) were treated with adenine and compared to wild type control mice. The treatment evoked worse kidney damage as indicated by higher deposition of gelatinases (matrix metalloproteinase-2 and 9) and adenine metabolites in the kidney. Adenine also caused non-dipping hypertension and lower heart rate. Thus, our data indicate that central and peripheral circadian clocks are disrupted in the adenine-treated mice, and suggest that the disruption of the circadian clock accelerates CKD progression.

Effect of renin-angiotensin system blockers on contrast-induced acute kidney injury in patients with normal or mild-to-moderate reduced kidney function undergoing coronary angiography: A systematic review and meta-analysis.

INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is a major complication after coronary angiography (CAG) or percutaneous coronary intervention (PCI) and is associated with increased morbidity and mortality. It remains controversial whether renin-angiotensin system (RAS) blockers increase or decrease CI-AKI. In this meta-analysis, we investigated the association between RAS blockers and CI-AKI in patients with normal kidney function or mild-to-moderate chronic kidney disease (CKD). MATERIALS AND METHODS: We performed a systematic search of PubMed, EMBASE, clinicaltrials.gov, and the Cochrane Library up to December 2019 for studies that assessed the association between RAS blockers and CI-AKI events after CAG/PCI. The primary outcome was the development of CI-AKI. Odds ratios (ORs) with corresponding 95% confidence interval (CI) were synthesized. RESULTS: Five randomized controlled trials (RCTs) and five observational studies were included, accounting for a total of 7,420 patients. Unstratified, RAS blocker administration was significantly associated with an increased risk of CI-AKI (pooled OR = 1.63, 95% CI 1.19 - 2.25, p = 0.003). However, the effect was not observed in RCTs (pooled OR = 1.22, 95% CI 0.54 - 2.74, p = 0.63). Sensitivity analysis in observational studies showed significant association (pooled OR = 1.77, 95% CI 1.22 - 2.55, p = 0.003) with high heterogeneity and evidence of publication bias. CONCLUSION: In patients with relatively-preserved renal function, the association of RAS blockers with an increased risk of CI-AKI after contrast media exposure was inconclusive, as sensitivity analysis showed conflicting results and bias. Although this study did not demonstrate significant evidence, it indicated that clinicians need to be vigilant in assessing the potential risk for RAS blockers to cause CI-AKI in low-risk patients.

The pathophysiological role of angiotensin receptor-binding protein in hypertension and kidney diseases: Oshima Award Address 2019.

Excessive activation of the tissue renin-angiotensin system through angiotensin II (Ang II) type 1 receptor (AT1R) plays a pivotal role in the pathogenesis of hypertension and related organ injury. AT1R-associated protein (ATRAP/Agtrap) was identified as a molecule specifically interacting with the carboxyl- terminal domain of AT1R. The results of in vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R including kidney. The results of in vivo study employing genetic engineered mice with modified ATRAP expression showed that ATRAP inhibits cardiovascular injuries provoked by Ang II-induced hypertension, along with preserving physiological AT1R signaling. In addition, we have shown that ATRAP functions as an endogenous modulator so as to prevent hypertension in response to pathological stimuli, by regulating renal sodium handling. Furthermore, ATRAP may have an AT1R-independent function of renal proximal tubule to protect aging and fibrosis. These results suggest the clinical potential benefit of an ATRAP activation strategy in the treatment of hypertension and cardiorenal and vascular diseases.

Improved home BP profile with dapagliflozin is associated with amelioration of albuminuria in Japanese patients with diabetic nephropathy: the Yokohama add-on inhibitory efficacy of dapagliflozin on albuminuria in Japanese patients with type 2 diabetes study (Y-AIDA study).

BACKGROUND: The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria. METHODS: We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24. RESULTS: Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR. CONCLUSIONS: In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.