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Aims Components of bone morphogenetic protein (BMP) signalling have been implicated in both pathogenesis of pulmonary arterial hypertension (PAH) and endothelial-mesenchymal transition (EndoMT). In particular, the importance of BMP type 2 receptor in these processes has been extensively analysed. However, the contribution of BMP type 1 receptors (BMPR1s) to the onset of PAH and EndoMT remains poorly understood. BMPR1A, one of BMPR1s, was recently implicated in the pathogenesis of PAH, and was found to be down-regulated in the lungs of PAH patients, neither the downstream mechanism nor its contribution to EndoMT has been described. Therefore, we aim to delineate the role of endothelial BMPR1A in modulating EndoMT and pathogenesis of PAH. Methods and results We find that BMPR1A knockdown in endothelial cells (ECs) induces hallmarks of EndoMT, and deletion of endothelial Bmpr1a in adult mice (Bmpr1aiECKO) leads to development of PAH-like symptoms due to excessive EndoMT. By lineage tracing, we show that endothelial-derived smooth muscle cells are increased in endothelial Bmpr1a-deleted mice. Mechanistically, we identify ZEB1 as a primary target for BMPR1A in this setting; upon BMPR1A activation, ID2 physically interacts and sequesters ZEB1 to attenuate transcription of Tgfbr2, which in turn lowers the responses of ECs towards transforming growth factor beta (TGFβ) stimulation and prevents excessive EndoMT. In Bmpr1aiECKO mice, administering endothelial targeting lipid nanoparticles containing siRNA against Tgfbr2 effectively ameliorate PAH, reiterating the importance of BMPR1A-ID2/ZEB1-TGFBR2 axis in modulating progression of EndoMT and pathogenesis of PAH. Conclusions We demonstrate that BMPR1A is key to maintain endothelial identity and to prevent excessive EndoMT. We identify BMPR1A-induced interaction between ID2 and ZEB1 is the key regulatory step for onset of EndoMT and pathogenesis of PAH. Our findings indicate that BMPR1A-ID2/ZEB1-TGFBR2 signalling axis could serve as a potential novel therapeutic target for PAH and other EndoMT-related vascular disorders.

There is emerging evidence that the aberrant pulmonary vascular remodeling that occurs in pulmonary arterial hypertension (PAH) is at least in part driven by the transformation of endothelial cells to mesenchymal cells (EndoMT), but the mechanism driving this pathobiology remains to be fully elucidated. Bone morphogenetic protein (BMP) signaling has been implicated to be involved in EndoMT in different vascular contexts, but the exact mechanism in the pulmonary vasculature remains to be defined. We describe the role of BMP receptor type 1A (BMPR1A or ALK3) as a key factor for maintenance of endothelial fate and suppression of EndoMT in the pulmonary vasculature. We found that inducible endothelial specific deletion of Bmpr1a in mice ( Bmpr1a iECKO ) resulted in spontaneous EndoMT, with significant increase in smooth muscle actin (SMA) positive cells, associated with extensive pulmonary vascular remodeling and fibrosis. Bmpr1a iECKO mice developed spontaneous pulmonary hypertension (PH) that was mediated by augmented TGF-β signaling driven by increased TGFBR2 expression, resulting in aberrant SMAD2/3 activation. Increased TGFBR2 expression in BMPR1A deficient state was secondary to increased activity of the transcription factor TCF3, whose negative inhibition by ID2 is abrogated in BMPR1A deficient state. EndoMT and PH secondary to loss of endothelial BMPR1A was effectively rescued by concurrent knockdown of TGFBR2. Overall, these studies define a mechanism of EndoMT driven by loss of endothelial BMPR1A, and demonstrate the efficacy of inhibiting EndoMT as a potential novel therapeutic strategy in PAH and other EndoMT-related vascular disorders.

Sonoporation can deliver agents to target local organs by systemic administration, while decreasing the associated risk of adverse effects. Sonoporation has been used for a variety of materials and in a variety of organs. Herein, we demonstrated that local sonoporation to the kidney can offer highly efficient transfer of oligonucleotides, which were systemically administrated to the tubular epithelium with high specificity. Ultrasonic wave irradiation to the kidney collapsed the microbubbles and transiently affected the glomerular filtration barrier and increased glomerular permeability. Oligonucleotides were passed through the barrier all at once and were absorbed throughout the tubular epithelium. Tumor necrosis factor alpha (TNFα), which plays a central role in renal ischemia–reperfusion injury, was targeted using small interfering RNA (siRNA) with renal sonoporation in a murine model. The reduction of TNFα expression after single gene transfer significantly inhibited the expression of kidney injury markers, suggesting that systemic administration of siRNA under temporary and local sonoporation could be applicable in the clinical setting of ischemic acute kidney injury.

Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of Aplnr (AplnrECKO) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified in-activation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the Apln−/− and AplnrECKO mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the Apln−/− mice. The impaired glucose utilization in the AplnrECKO mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disease caused by GATA3 mutations. Although several cases with variable renal features have been reported, the presence of histological changes within the glomeruli in adult patients is unclear. We herein report an adult case of HDR syndrome with a novel p.C288W (TGC>TGG) missense mutation in GATA3. His renal histology showed a membranoproliferative glomerulonephritis-like glomerular lesion. Additional renal histological analyses of HDR syndrome patients will be needed to clarify the role of GATA3 in both the developing and adult kidney.

Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). Many investigators have reported that cell death via apoptosis significantly contributed to the pathophysiology of renal IRI. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and induces apoptosis and inflammation. However, the role of TRAIL in renal IRI is unclear. Here, we investigated whether TRAIL contributes to renal IRI and whether TRAIL blockade could attenuate renal IRI. AKI was induced by unilateral clamping of the renal pedicle for 60 min in male FVB/N mice. We found that the expression of TRAIL and its receptors were highly upregulated in renal tubular cells in renal IRI. Neutralizing anti-TRAIL antibody or its control IgG was given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion. We found that TRAIL blockade inhibited tubular apoptosis and reduced the accumulation of neutrophils and macrophages. Furthermore, TRAIL blockade attenuated renal fibrosis and atrophy after IRI. In conclusion, our study suggests that TRAIL is a critical pathogenic factor in renal IRI, and that TRAIL could be a new therapeutic target for the prevention of renal IRI.

Reconstitution of total nephron segments after resection in the adult kidney has not been achieved; however, whether the neonatal kidney can maintain the capacity for neo-nephrogenesis after resection is unknown. We performed partial resection of the kidney in neonatal rats on postnatal days 1 (P1x kidney) and 4 (P4x kidney) and examined morphological changes and relevant factors. The P1x kidney bulged into the newly formed cortex from the wound edge, while nephrogenesis failure was prominent in the P4x kidney. Twenty-eight days post-resection, the glomerular number, cortex area, and collecting duct were preserved in the P1x kidney, whereas these parameters were markedly decreased in the P4x kidney. During normal development, Six2 expression and Six2+ nephron progenitor cells in the cap mesenchyme both rapidly disappear after birth. However, time course analysis for the P1x kidney showed that Six2 expression and Six2+ cells were well preserved in the tissue surrounding the resected area even 2 days after resection. In conclusion, our results indicate that kidneys in early neonate rats retain the capability for neo-nephrogenesis after resection; however, this ability is lost soon after birth, which may be attributed to a declining amount of Six2+ cells.

A 70-year-old woman developed anemia and kidney injury 10 months after mitral valve (MV) repair. Serological findings and Doppler echocardiography suggested hemolytic anemia due to mitral regurgitation jet collision with an annuloplasty ring (MRCR). Since kidney injury persisted even without exacerbation of anemia over 10 months, we performed an MV replacement. The anemia improved rapidly after the surgery; however, the renal function remained chronic kidney disease (CKD) after reoperation. Kidney injury was thought to be due to iron deposition and decreased renal perfusion that caused tubular injury. A comprehensive literature review shows that hemolysis due to MRCR in the early postoperative phase (within 3 postoperative months) can be often ameliorated with endothelialization without the need for reoperation; however, hemolysis in the late postoperative phase can persist even for a long period without reoperation. Chronic hemolysis can lead to kidney injury and progress to CKD even without clinical evidence of exacerbation of anemia. Therefore, in cases of late postoperative phase hemolysis, reoperation should be considered for better management of kidney injury and hemolytic anemia.

A 70-year-old woman developed anemia and kidney injury 10 months after mitral valve (MV) repair. Serological findings and Doppler echocardiography suggested hemolytic anemia due to mitral regurgitation jet collision with an annuloplasty ring (MRCR). Since kidney injury persisted even without exacerbation of anemia over 10 months, we performed an MV replacement. The anemia improved rapidly after the surgery; however, the renal function remained chronic kidney disease (CKD) after reoperation. Kidney injury was thought to be due to iron deposition and decreased renal perfusion that caused tubular injury. A comprehensive literature review shows that hemolysis due to MRCR in the early postoperative phase (within 3 postoperative months) can be often ameliorated with endothelialization without the need for reoperation; however, hemolysis in the late postoperative phase can persist even for a long period without reoperation. Chronic hemolysis can lead to kidney injury and progress to CKD even without clinical evidence of exacerbation of anemia. Therefore, in cases of late postoperative phase hemolysis, reoperation should be considered for better management of kidney injury and hemolytic anemia.

Recent studies have suggested that acute kidney injury (AKI) develops into chronic kidney disease (CKD). However, a mechanism for disease progression from AKI to CKD has not been established. We developed two ischemia–reperfusion injury (IRI) mouse models, a repaired kidney model and an atrophic kidney model, and studied the mechanisms of renal atrophy after IRI by comparing the two models. We found that renal atrophy after IRI depended on tubular apoptosis at 14 days after IRI. Moreover, we found that Tnfα and FasL mRNA were synchronously expressed at the time of tubular apoptosis. To elucidate the relationship between tubular apoptosis and apoptotic ligands, we administered TNFα and FasL neutralizing antibodies according to the time of tubular apoptosis. TNFα blockade significantly repressed tubular apoptosis, resulting in the prevention of renal atrophy. FasL blockade could not repress tubular apoptosis, resulting in renal atrophy. We also found that TNF receptors were expressed in the kidney at 14 days after IRI, but Fas receptor was not. We concluded that renal atrophy after IRI depends on tubular apoptosis induced by the TNFα signaling pathway in the later phase of renal IRI, and that TNFα blockade could be a potential new therapeutic approach for improving renal prognosis after AKI.

OBJECTIVE: This open-label, randomized controlled trial investigated the effects of cilnidipine, an L/N-type calcium channel blocker (CCB), in patients with chronic kidney disease (CKD). METHODS: Sixty patients with CKD and well-controlled hypertension being treated with a renin—angiotensin system (RAS) inhibitor and an L-type CCB (L-CCB) were randomly assigned either to switch from the L-CCB to cilnidipine after a 4-week observation period or to continue with L-CCB treatment. Blood pressure, heart rate and renal function were monitored for 12 months. Data were available for analysis from 50 patients: 24 from the cilnidipine group and 26 from the L-CCB group. RESULTS: Blood pressure was well controlled in both groups. After 12 months, proteinuria and heart rate were significantly decreased in the cilnidipine group, but proteinuria increased and heart rate remained unchanged in the L-CCB group. There was a significant positive correlation between the percentage changes in proteinuria and heart rate. CONCLUSIONS: Cilnidipine has antihypertensive effects equivalent to those of L-CCBs. In patients with CKD, proteinuria can be decreased by switching from an L-CCB to cilnidipine, thereby improving renal function.

Background/Aims: Peritoneal fibrosis leads to discontinuation of peritoneal dialysis. Although aldosterone promotes tissue fibrosis in many organs, its contribution to peritoneal fibrosis and the underlying mechanism are poorly understood. The present study investigated the direct effect of aldosterone on cultured rat peritoneal fibroblasts (RPFs). Methods: The expression of aldosterone synthase (CYP11B2), mineralocorticoid receptors (MRs), 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), serum- and glucocorticoid-inducible protein kinase 1 (SGK1), and connective tissue growth factor (CTGF) mRNA was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR). To determine the role of reactive oxygen species (ROS) induced by aldosterone, an active oxygen assay with several inhibitors was used. The ability of RPFs to produce aldosterone was examined by enzyme immunoassay. Small interfering RNA (siRNA) of SGK1 was transfected into cultured cells using lipofectamine. Results: CYP11B2, MRs, and 11β-HSD2 were expressed in RPFs. The release of aldosterone from RPFs into the culture medium was confirmed. Aldosterone increased the expression of SGK1 mRNA via ROS generation. Spironolactone, apocynin, and tempol significantly reduced SGK1 expression. Aldosterone upregulated CTGF transcripts significantly. SGK1 gene silencing suppressed aldosterone-induced CTGF expression. Conclusion: The local aldosterone system acts directly as a profibrotic factor via ROS-mediated SGK1 in RPFs.

Peritonitis due to nontuberculous mycobacterium in peritoneal dialysis (PD) patients is rare. However, when it occurs, PD catheter removal is required in most cases because of resistance to antibiotic therapy. We report a case of Mycobacterium abscessus peritonitis subsequent to tunnel infection after PD catheter-replacement surgery. The patient underwent this surgery as her tunnel infection had not resolved following the usual 3 month course of antibiotic therapy. After surgery, tunnel infection of the second catheter and peritonitis occurred. Nontuberculous mycobacteria were detected on acid-fast stain from both the old and new exit-site drainage and the peritoneal effluent. The mycobacteria were identified as M. abscessus. Removal of the new catheter and surgical excision of the previous catheter tunnel were performed and multiple antibiotics were started. After 3 months the postsurgical wounds had healed completely. This case demonstrates the importance of further evaluation of unidentified PD catheter-related infections, including an examination for nontuberculous mycobacterium.

Sodium restriction is important in the treatment of chronic kidney disease; however, it is sometimes difficult to achieve. Decreased taste sensitivity may be a factor influencing inadequate control of oral salt intake and subsequent high blood pressure. To measure this, the gustatory threshold (recognition and detection) for salty taste was determined in 29 patients with chronic kidney disease using a sodium-impregnated test strip and relevant factors determining taste sensitivity were analyzed. Compared with 11 healthy volunteers, recognition and detection thresholds were increased in the patients with chronic kidney disease. Oral sodium intake correlated positively but serum zinc correlated negatively with the recognition threshold. Patients with diabetic nephropathy had a higher detection threshold than non-diabetic patients. Both recognition and detection thresholds were increased in patients with diuretic administration. After 1 week of sodium restriction, the average recognition threshold decreased significantly. Our study verified that latent taste dysfunction and zinc deficiency are common in patients with chronic kidney disease. Further, the recognition threshold for salty taste improved even after a short period of salt restriction.