Biology subjects

Matsuoka, D.

Publications and source records attributed to Matsuoka, D..

3 recordsLinked to original sources

bioRxiv2025

Hypoxia-Induced Metabolic Reprogramming and Markings of Cell Fate in Concentric Arterial Hypertrophy

Chronic inhibition of the renin-angiotensin system (RAS), while widely used to treat hypertension, can lead to an underrecognized form of vascular disease marked by concentric arteriolar and arterial hypertrophy (CAAH). Here, using two lineage-traced mouse models of genetic renin deletion and sustained RAS blockade, we uncover a pathogenic cascade initiated by renin-lineage cell fate reprogramming. Loss of endocrine identity and transformation of smooth muscle cells drives a shift toward a fibrotic, inflammatory, and secretory phenotype that remodels the extracellular matrix and promotes vascular thickening and luminal narrowing. Integrated transcriptomic, proteomic, and metabolomic profiling revealed a hypoxia-linked metabolic switch--characterized by succinate accumulation and NAD+ depletion--coupled to Hif activation and disease progression. We identify Cdh13 and collagens (including Col1a1 and Col12a1) as early urinary biomarkers and define a 10-gene molecular signature of CAAH with potential clinical application. These findings establish renin-lineage cell plasticity and metabolic dysfunction as central drivers of CAAH and nominate candidate biomarkers for early detection and therapeutic targeting in RAS-inhibited patients.

physiology↗

bioRxiv2025

Renin Cells Drive Kidney Neurovascular Development and Arterial Remodeling when Renin Activity is Deficient

Renin cells synthesize and release the hormone-enzyme renin to regulate blood pressure and fluid-electrolyte homeostasis. Their function and identity depend on communication with surrounding cells and nerve fibers within complex kidney structure. Because renin cells are rare -0.01 % of kidney cells-conventional histological approaches cannot capture their interaction with nerve fibers and surrounding cells within the nephron and its vasculature. Using a novel ultrabright renin cell-specific tdTomato reporter mouse, high-resolution 3D imaging, and single-cell RNA-Seq, we mapped the interactions of renin cells with growing axons during normal kidney vascular development, in response to threats to homeostasis, and a severe arterial disease caused by a defective renin enzyme. During embryonic kidney development, stromal and renin cell progenitors assemble the arterioles, express axon attractants and neurotrophins that establish the precise innervation of renin cells and arterioles in a centrifugal pattern. Hypotension and sodium depletion led to an increase in the volume and number of renin cells along the arterioles. Renin enzymatic deficiency led to hypertrophy and endocrine transformation of renal arterioles, aberrant axon sprouting and sympathetic hyperinnervation suggesting a feed-forward mechanism whereby renin cells and axons co-induce each other, orchestrate neurovascular development and arteriolar remodeling when renin cells are over stimulated.

developmental biology↗

bioRxiv2024

Angiotensin II elicits robust calcium oscillations coordinated within juxtaglomerular cell clusters to suppress renin secretion.

BACKGROUNDJuxtaglomerular (JG) cells are sensors that control blood pressure (BP) and fluid-electrolyte homeostasis. They are arranged as clusters at the tip of each afferent arteriole. In response to a decrease in BP or extracellular fluid volume, JG cells secrete renin, initiating an enzymatic cascade that culminates in the production of angiotensin II (AngII), a potent vasoconstrictor that restores BP and fluid-electrolyte homeostasis. In turn, AngII exerts negative feedback on renin release concomitantly with increased intracellular Ca2+, preventing excessive circulating renin and hypertension. However, within their native structural organization, the intricacies of intracellular Ca2+ signaling dynamics and their sources remain uncharacterized. METHODSWe generated mice expressing the JG cell-specific genetically encoded Ca2+ indicator (GCaMP6f) to investigate Ca2+ dynamics within JG cell clusters ex vivo and in vivo. For ex vivo Ca2+ imaging, acutely prepared kidney slices were perfused continuously with a buffer containing variable Ca2+ and AngII concentrations {+/-} Ca2+ channel inhibitors. For in vivo Ca2+ image capture, native mouse kidneys were imaged in situ using multi-photon microscopy with and without AngII administration. ELISA measurements of renin concentrations determined acute renin secretion ex vivo and in vivo, respectively. RESULTSEx vivo Ca2+ imaging revealed that JG cells exhibit robust and coordinated intracellular oscillatory signals with cell-cell propagation following AngII stimulation. AngII dose-dependently induced stereotypical burst patterns characterized by consecutive Ca2+ spikes, which inversely correlated with renin secretion. Pharmacological channel inhibition identified key sources of these oscillations: endoplasmic reticulum Ca2+ storage and release, extracellular Ca2+ uptake via ORAI channels, and intercellular communication through gap junctions. Blocking ORAI channels and gap junctions reduced AngII inhibitory effect on renin secretion. In vivo Ca2+ imaging demonstrated robust intracellular and intercellular Ca2+ oscillations within JG cell clusters under physiological conditions, exhibiting spike patterns consistent with those measured in ex vivo preparations. Administration of AngII enhanced the Ca2+ oscillatory signals and suppressed acute renin secretion in vivo. CONCLUSIONAngII elicits coordinated intracellular and intercellular Ca2+ oscillations within JG cell clusters, ex vivo and in vivo. The effect is driven by endoplasmic reticulum-derived Ca2+ release, ORAI channels, and gap junctions, leading to suppressed renin secretion.

cell biology↗