Abstract Renal juxtaglomerular renin‐producing cells and preglomerular vascular smooth muscle cells (VSMCs) are specialized pericytes with notable plasticity. Preglomerular VSMCs can convert to renin‐producing cells during severe hypotension or salt depletion, and renin cells can transform into erythropoietin (EPO)‐producing cells when hypoxia‑inducible factor (HIF)‐2α is stabilized through deletion of prolyl‐4‐hydroxylases (PHD) 2 and 3. These findings raise the question of whether PHD2 and PHD3 likewise regulate the endocrine plasticity of preglomerular VSMCs. To investigate the role of PHD2 and/or PHD3 in (preglomerular) contractile pericytes, inducible mouse models with smooth muscle myosin heavy chain (SMMHC)‐specific deletion of PHD2 and/or PHD3 were examined under basal conditions or after stimulation of renin production by treating the mice with a low‐salt diet and angiotensin converting enzyme inhibitor enalapril (LSE). At baseline, none of the deletions altered renin production or induced EPO expression in preglomerular pericyte‐like VSMCs, despite HIF‐2α stabilization in PHD2/PHD3‐deficient mice. However, HIF‐2α stabilization resulting from PHD2 or PHD2/PHD3 deletion triggered EPO production in interstitial SMMHC + contractile pericytes. LSE treatment induced renin in VSMCs and extraglomerular mesangial cells of control, SMMHC CreERT2 PHD2 ff and SMMHC CreERT2 PHD3 ff mice. In contrast, VSMCs of PHD2/PHD3‐deficient mice produced EPO rather than renin, while renin induction persisted only in mesangial cells. Notably, this LSE‐induced EPO production was reversible despite ongoing HIF‐2α stabilization. Transcriptional changes indicated a shift in PHD2/PHD3‐deficient VSMCs from a contractile/renin cell‐like to a contractile/EPO cell‐like signature. These findings indicate that HIF‐2α stabilization determines the endocrine product of preglomerular VSMCs and interstitial pericytes. Notably, loss of PHD2/PHD3 does not compromise the plasticity of VSMCs to reversibly adopt endocrine functions. image Key points Smooth muscle myosin heavy chain (SMMHC)‐specific deletion of the prolyl‑4‑hydroxylases PHD2 and PHD3 stabilized hypoxia‑inducible factor (HIF)‑2α in preglomerular pericyte‑like vascular smooth muscle cells (VSMCs), prompting a transcriptional shift from a contractile/renin cell‑like toward a more contractile/EPO cell‑like signature without activating erythropoietin (EPO) transcription. A reduction in systolic blood pressure through treatment with low‐salt diet and angiotensin converting enzyme inhibitor enalapril induced EPO synthesis instead of renin in preglomerular PHD2/PHD3‐deficient VSMCs. Transformation of preglomerular VSMCs into EPO‐producing cells was reversible despite persistent HIF‐2α stabilization. SMMHC cell‐specific deletion of PHD2 and PHD2/PHD3 activated EPO production in interstitial contractile pericytes independent of systolic blood pressure. Short‑term HIF‑2α stabilization was insufficient to induce EPO production in preglomerular VSMCs or contractile pericytes. Τaken together these findings demonstrate that HIF‐2α stabilization governs the endocrine output of preglomerular VSMCs and interstitial pericytes. Notably, the loss of PHD2/PHD3 does not impair the capacity of VSMCs to reversibly assume endocrine functions.
Firmke et al. (Mon,) studied this question.