Protein kinase A (PKA) directly phosphorylates aquaporin-2 (AQP2) water channels in renal collecting ducts to reabsorb water from urine for the maintenance of systemic water homeostasis. More than 50 functionally distinct PKA-anchoring proteins (AKAPs) respectively create compartmentalized PKA signaling to determine the substrate specificity of PKA. Identification of an AKAP responsible for AQP2 phosphorylation is an essential step toward elucidating the molecular mechanisms of urinary concentration. PKA activation by several compounds is a novel screening strategy to uncover PKA substrates whose phosphorylation levels were nearly perfectly correlated with that of AQP2. The leading candidate in this assay proved to be an AKAP termed lipopolysaccharide-responsive and beige-like anchor protein (LRBA). We found that LRBA colocalized with AQP2 in vivo, and Lrba knockout mice displayed a polyuric phenotype with severely impaired AQP2 phosphorylation. Most of the PKA substrates other than AQP2 were adequately phosphorylated by PKA in the absence of LRBA, demonstrating that LRBA-anchored PKA preferentially phosphorylated AQP2 in renal collecting ducts. Furthermore, the LRBA–PKA interaction, rather than other AKAP–PKA interactions, was robustly dissociated by PKA activation. AKAP–PKA interaction inhibitors have attracted attention for their ability to directly phosphorylate AQP2. Therefore, the LRBA–PKA interaction is a promising drug target for the development of anti-aquaretics.

Urinary uromodulin, secreted by renal tubular cells, protects against urinary tract infections and kidney stones. In contrast, the intracellular accumulation of uromodulin is associated with hypertension and chronic kidney disease. However, the physiological stimuli for urinary uromodulin secretion remain largely unknown. Here, we showed that desmopressin, a vasopressin type 2 receptor agonist, dramatically increased short-term tubular uromodulin secretion in mice. Immunofluorescence studies and ultracentrifugation-based polymerization assay suggested that desmopressin induced intraluminal polymeric filaments of uromodulin, indicating physiologically functional secretion. As a result of increased excretion, uromodulin abundance in the murine kidney was clearly reduced by desmopressin. We investigated kidney epithelial cells stably expressing uromodulin to clarify the molecular mechanism. Apical uromodulin secretion was clearly increased in response to vasopressin/cAMP signaling, consistent with in vivo experiments. We also demonstrated that the response was dependent on epithelial cell polarity and cyclic AMP-dependent PKA (protein kinase A) signaling pathway. cAMP-mediated activation of proteases was suggested to be involved. In contrast, basolateral secretion of uromodulin was independent of cAMP signaling. Our work revealed vasopressin/cAMP/PKA signaling as a physiological stimulus of urinary uromodulin secretion. This finding may provide the basis for novel treatment strategies for urinary tract infections, kidney stones, and potentially hypertension and chronic kidney disease.

Points c Serum uromodulin levels are higher in healthy female participants than healthy male participants. c Serum uromodulin levels in participants with normal kidney function do not correlate with eGFR but do correlate with body mass index. c Estrogen increases uromodulin production, likely because of noncanonical and half estrogen response elements in the UMOD gene.

Patients with an indwelling tunneled dialysis catheter (TDC) for hemodialysis access are at a high risk of developing methicillin-resistant Staphylococcus aureus (MRSA) infection. MRSA bacteremia complications rarely include infected aneurysm. Here, we report the first case of an infected thoracic aneurysm associated with TDC-related MRSA bacteremia. An 86-year-old Japanese male with a TDC for hemodialysis access developed TDC-related MRSA bacteremia. Intravenous vancomycin was initiated, and the TDC was removed on day 3. Despite removal of the catheter and initiation of vancomycin treatment, MRSA bacteremia persisted. Chest computed tomography (CT) showed no aneurysm; however, calcification of the thoracic aorta was detected on admission. The patient subsequently developed hemosputum. CT revealed a thoracic aneurysm, which turned out to be caused by MRSA bacteremia. The patient eventually died because of the rupture of the infected aneurysm, as confirmed by autopsy. This report demonstrates TDC management in a patient with TDC-related MRSA bacteremia and the importance of investigating a metastatic infection to a calcified artery if bacteremia persists.

Gitelman syndrome (GS), an autosomal recessive kidney disorder, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Generally, diagnosis is made in school‐aged children but multiple cases have been diagnosed in adulthood. This study examines the phenotypic differences between genetically confirmed cases and mutation‐negative cases in adults. A comprehensive screening of 168 genes, including GS‐related genes, was performed for 84 independent individuals who were referred to our institute with a clinical diagnosis of GS. The cases of pseudo‐Bartter syndrome (BS)/GS because of diuretic abuse or other causes, which was determined based on patients' medical records, were excluded during registration. Of these 70 eligible cases for analysis, 27 (38.6%) had genetic confirmation of GS, while 37 (52.8%) had no known variants associated with GS and were considered to be unsolved cases. Note that unsolved cases comprised older, mostly female, individuals with decreased kidney function and multiple basic features of GS. The phenotype of unsolved cases is similar to that of pseudo BS/GS cases, although these cases were excluded in advance. However, the genetic and autoimmune profiles of these unsolved cases have not yet been investigated to date. Therefore, these cases may be categorized into new disease groups.