Kidney Renin Release under Hypoxia and Its Potential Link with Nitric Oxide: A Narrative Review

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  Figure 1. The expression of renin in kidneys under hypoxia. From the embryonic stage, renin expression is located along vascular and around collecting ducts and proximal tubules. As the kidneys develop, renin precursor cells gradually disappear and most of them differentiate into intrinsic renal cells (like pericytes, mesangial cells, and smooth muscle cells). Renin-expressing tubular cells in the embryonic stage also disappear in the adult period. After kidney development is complete, only a small number of renin-expressing cells are maintained and are restricted to the juxtaglomerular (JG) apparatus in adult mammals. The expression of renin increases under hypoxia, which is observed in both JG cells and other intrinsic renal cells. The descendants of renin precursor cells can transform into their pre-differentiated states to re-express the renin gene. Also, renin-expressing tubular cells in the embryonic stage can re-express renin in response to hypoxia.

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  Figure 2. Possible mechanism regulating renin expression under hypoxia. Notch signaling is activated under hypoxia and then the Notch intracellular domain (NICD) translocates into nuclear and binds with the co-effector recombination signal sequence binding protein J kappa (REBPJ) to form the transcription complex. The transcription complex has a specific binding sequence and binds with the promoter of the renin gene, which finally induces renin transcription. Nitric oxide (NO) is essential to regulate renin secretion. Hypoxia can promote NO production by increasing nitric oxide synthase (NOS), especially neuronal-type NOS (nNOS), transcription. Increased NO can stimulate soluble guanylate cyclase (sGC) and increase cyclic guanosine monophosphate (cGMP). Then, cGMP-mediated inhibition of phosphodiesterase (PDE) 3 prevents cAMP degradation and stimulates renin secretion. The activation of hypoxia-inducible factor (HIF) signaling is a hypoxia protection mechanism. Under normoxic conditions, HIF-α subunits are hydroxylated by the prolyl 4-hydroxylase domain (PHD) and then degraded by the von Hippel–Lindau tumor suppressor protein (VHL). Under hypoxia, the hydroxylation of HIF-α byVHL is…