One of the major obstacles to prevent AKI-CKD transition is the lack of effective methods to follow and predict the ongoing kidney injury after an AKI episode. In the present study, we test the utility of urinary angiotensinogen (UAGT) for dynamically evaluating renal structural changes and predicting AKI-CKD progression by using both mild and severe bilateral renal ischemia/reperfusion injury mice. UAGT returns to pre-ischemic levels 14 days after mild AKI followed by kidney architecture restoration, whereas sustained increase in UAGT accompanies by ongoing renal fibrosis after severe AKI. UAGT at day 14-42 correlates with renal fibrosis 84 days after AKI. For predicting fibrosis at day 84, the area under receiver operating characteristics curve of UAGT at day 14 is 0.81. Persistent elevation in UAGT correlates with sustained activation of intrarenal renin-angiotensin system (RAS) during AKI-CKD transition. Abrogating RAS activation post AKI markedly reduced renal fibrosis, with early RAS intervention (from 14 days after IRI) more beneficial than late intervention (from 42 days after IRI) in alleviating fibrosis. Importantly, UAGT decreases after RAS intervention, and its level at day 14-28 correlates with the extent of renal fibrosis at day 42 post RAS blockade. A pilot study conducted in patients with acute tubular necrosis finds that compared with those recovered, patients with AKI-CKD progression exhibits elevated UAGT during the 3-month follow-up after biopsy. Our study suggests that UAGT enables the dynamical monitoring of renal structural recovery after an AKI episode and may serve as an early predictor for AKI-CKD progression and treatment response.
BackgroundHypertension commonly complicates CKD. Vascular smooth muscle cells (VSMCs) of resistance arteries receive signals from the sympathetic nervous system that induce an endothelial cell (EC)–dependent anticontractile response that moderates vasoconstriction. However, the specific role of this pathway in the enhanced vasoconstriction in CKD is unknown.MethodsA mouse model of CKD hypertension generated with 5/6-nephrectomy (5/6Nx) was used to investigate the hypothesis that an impaired anticontractile mechanism enhances sympathetic vasoconstriction. In vivo, ex vivo (isolated mesenteric resistance arteries), and in vitro (VSMC and EC coculture) models demonstrated neurovascular transmission and its contribution to vascular resistance.ResultsBy 4 weeks, 5/6Nx mice (versus sham) had augmented increases in mesenteric vascular resistance and mean arterial pressure with carotid artery occlusion, accompanied by decreased connexin 43 (Cx43) expression at myoendothelial junctions (MEJs), impaired gap junction function, decreased EC-dependent hyperpolarization (EDH), and enhanced contractions. Exposure of VSMCs to NE for 24 hours in a vascular cell coculture decreased MEJ Cx43 expression and MEJ gap junction function. These changes preceded vascular structural changes evident only at week 8. Inhibition of central sympathetic outflow or transfection of Cx43 normalized neurovascular transmission and vasoconstriction in 5/6Nx mice.Conclusions5/6Nx mice have enhanced neurovascular transmission and vasoconstriction from an impaired EDH anticontractile component before vascular structural changes. These neurovascular changes depend on an enhanced sympathetic discharge that impairs the expression of Cx43 in gap junctions at MEJs, thereby interrupting EDH responses that normally moderate vascular tone. Dysregulation of neurovascular transmission may contribute to the development of hypertension in CKD.
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