Vascular transcriptional and metabolic changes precede progressive intrarenal microvascular rarefaction in autosomal...

The mechanisms contributing to progressive kidney damage in autosomal dominant polycystic kidney disease (ADPKD) remain unclear. Renal microvascular (MV) rarefaction plays an important role in kidney disease, but its natural history, underlying mechanisms, and contributions to renal disease progression in ADPKD remain unknown. We hypothesized that intrarenal MV rarefaction is present early on and is preceded by vascular transcriptional and metabolic changes. Pkd1^RC/RC and wild type (WT) mice (n = 16 each) were studied at 1, 6, and 12 mo. Total kidney volume (TKV) was measured in vivo (MRI), whereas renal MV architecture [three-dimensional (3-D) micro-computed tomography, 3-D micro-CT], capillary density, perivascular fibrosis, and histomorphometric parameters were assessed ex vivo. In randomly selected Pkd1^RC/RC and WT kidneys (n = 5, each/time point), mRNA-sequencing was performed to identify differentially expressed vasculature-related genes (differentially expressed genes, DEGs). Next, in young humans with ADPKD and matched controls (n = 10 each), plasma cellular energy metabolites were determined (LC-MS/MS), validated in an extended cohort (n = 32 and n = 16, respectively), and correlated with markers of disease severity and progression. Gene-metabolite interaction networks were generated to integrate DEGs in Pkd1^RC/RC at 1 mo with metabolites dysregulated in individuals with ADPKD, which were further quantified in WT and Pkd1^RC/RC kidneys. Renal MV density was preserved at 1 mo but progressively decreased at 6 and 12 mo, associated with capillary loss and perivascular fibrosis. A total of 110, 48, and 201 DEGs were identified at 1, 6, and 12 mo, respectively. Plasma gamma-aminobutyric acid (GABA), homocysteine (Hcy), and asymmetric dimethyl arginine (ADMA) levels were higher in humans with ADPKD vs. controls, interacted with DEGs implicated in inflammatory and innate immune response and Hcy metabolism, and correlated with TKV and renal blood flow. Our data demonstrate that intrarenal MV abnormalities present early in ADPKD and are preceded by vascular transcriptional and metabolic changes. The renal microcirculation may constitute an important therapeutic target in ADPKD, and its underlying biomarkers may serve to monitor its progression.NEW & NOTEWORTHY We provide the first longitudinal and most comprehensive analysis of the intrarenal microvasculature in a slowly progressive model of autosomal dominant polycystic kidney disease (ADPKD) and integrate the findings with studies in a young cohort of individuals with ADPKD. We identified vasculature-related pathways that could be targeted for therapeutic interventions and contribute promising, noninvasive biomarkers in patients with ADPKD. Alterations of the intrarenal microcirculation may affect drug delivery; a better understanding of its longitudinal changes may aid in treatment management.