Kidney

Tubular epithelial cell (TEC)-macrophage crosstalk contributes to aldosterone (Aldo)-dependent renal fibrosis in hypertension. Extracellular ATP (eATP) can act as a mediator of TEC-macrophage crosstalk. However, whether and how eATP functions in Aldo-induced renal injury remain unknown. A deoxycorticosterone acetate (DOCA)-salt-induced hypertensive mouse model and a primary mouse renal tubular epithelial cell (mTEC)-bone marrow-derived macrophage (BMDM) coculture model were developed. To investigate the relationship between Aldo/MR and eATP signaling in TEC-macrophage crosstalk, specific inhibitors, adeno-associated virus (AAV)-shRNA and small interfering RNA (siRNA) were used. scRNA-seq analysis of kidneys from DOCA-salt mice was performed for verification. Urinary ATP levels and renal pannexin1 (PANX1, an ATP efflux channel) expression increased significantly in DOCA-salt mice, whereas the selective mineralocorticoid receptor (MR) antagonist finerenone treatment reduced urinary ATP levels, PANX1 expression, tubular injury, and macrophage-related inflammation. Inhibiting PANX1-eATP-P2X7 signaling with the PANX1 inhibitor probenecid, specifically knocking down tubular PANX1, or using the eATP ectonucleotidase apyrase or the P2X7 blocker AZ10606120 mitigated renal tubular damage and NLRP3-mediated pyroptosis in the renal cortex of DOCA-salt mice. Similarly, in mTECs, finerenone suppressed Aldo-induced ATP release and PANX1 upregulation. A luciferase assay confirmed the binding site of MR to the PANX1 transcription promoter. Coculture of BMDMs with mTECs under Aldo stimulation significantly increased NLRP3-mediated BMDM pyroptosis and migration. However, these effects were reversed by treating the mTECs with MR or PANX1 siRNA. Similar results were observed after treatment with apyrase or AZ10606120 in the coculture system. scRNA-seq analysis further identified the activation of P2X7/NLRP3-related pyroptosis pathway in macrophages from DOCA-salt mice. In conclusion, TECs play a critical role in macrophage pyroptosis in Aldo-induced renal injury. eATP is a key messenger involved in TEC-macrophage crosstalk. PANX1-eATP-P2X7 signaling mediates TEC‒macrophage interactions to exacerbate Aldo-driven renal inflammation in hypertension. Mechanism through which Aldo/MR-induced PANX1-eATP-P2X7 signaling activation promotes macrophage pyroptosis in hypertensive renal injury.

BACKGROUNDAcute interstitial nephritis (AIN) is a common cause of acute kidney injury (AKI), but the diagnosis may be missed as kidney biopsies are rarely obtained when acute tubular injury (ATI) is suspected.METHODSThe Kidney Precision Medicine Project is a cohort study that obtains kidney biopsies from individuals with AKI, which undergo pathologic and molecular interrogation. We compared ATI and AIN cases among the first 60 AKI participants.RESULTSOn clinicopathologic adjudication, 30 patients (50%) had a primary adjudicated diagnosis of ATI, 13 (22%) patients had AIN, 9 (15%) had diabetic nephropathy, and 3 (5%) had other conditions. There were increased interstitial white blood cells and tubulitis (P < 0.05 for both) in AIN compared with ATI. Prior to biopsy, the treating clinician suspected ATI in 83% of the cases with adjudicated ATI, while the treating clinician suspected AIN in 54% of the cases with AIN. Tissue transcriptomic signatures showed enrichment of proinflammatory signaling and increased expression of CXCL9, a chemokine induced by IFN-γ, in myeloid cells of participants with AIN. CXCL9 localized to inflammatory infiltration in spatial transcriptomic data.CONCLUSIONAdjudication of kidney biopsies revealed distinct pathologic and molecular profiles between ATI and AIN. Kidney biopsy should be considered more frequently in AKI, as AIN is clinically underrecognized.TRIAL REGISTRATIONClinicalTrials.gov NCT04334707.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases grants U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, U24DK114886, UH3DK114926, UH3DK114861, UH3DK114915, and UH3DK114937.

Background and objectivesEnlarged perivascular spaces (EPVSs) in the basal ganglia (BG-EPVS) are an important marker of cerebral small vessel disease (cSVD), and EPVS in the centrum semiovale (CSO-EPVS) are part of the diagnostic criteria for cerebral amyloid angiopathy. We aimed to investigate associations of EPVS with reduced estimated glomerular filtration rate (eGFR) and glomerular hyperfiltration (higher than normal eGFR), which have scarcely been studied previously.MethodsIn this cross-sectional study, we used pooled individual patient data from the Microbleeds International Collaborative Network which includes patients with ischemic stroke or transient ischemic attack. We investigated associations of impaired kidney function, defined as an eGFR of 30-60 or 2, and glomerular hyperfiltration, defined as eGFR above the age-adjusted and sex-adjusted 95th centile, with BG-EPVS and CSO-EPVS severity. EPVS were rated according to a validated 5-point ordinal scale, and combined cSVD burden was rated using a validated 5-point ordinal scale with 1 point assigned for the presence of each of the following: severe white matter hyperintensities, ≥1 cerebral microbleed, ≥1 lacune, and BG-EPVS ≥11. Normal glomerular filtration was defined as eGFR ≥60 without hyperfiltration. We used multivariable ordinal logistic regression models to estimate risk of increased EPVS and cSVD burden severity adjusted for age, sex, and comorbidities.ResultsSeven thousand two hundred fifty-four patients (mean age 71 ± 13 years, 43% female) were included in the analysis, 357 with glomerular hyperfiltration, 1,692 with eGFR 30-60, and 256 with eGFR p p = 0.011). Associations of eGFR 30-60 and eGFR DiscussionGlomerular hyperfiltration was independently associated with EPVS severity, in both the basal ganglia and centrum semiovale. eGFR <30 was independently associated with total cSVD burden. A key limitation was a lack of repeated eGFR measurements.