Renin the show: neuropilin‐1's role in regulating juxtaglomerular cells

In this issue of The Journal of Physiology, Shen et al. describe how neuropilin-1 mediates juxtaglomerular cell (JGC) fate and renin production (Shen et al., 2024). Renin is an enzyme that catalyses the conversion of angiotensinogen to angiotensin I, a key step in renin–angiotensin–aldosterone system's regulation of kidney sodium reabsorption, glomerular filtration rate (GFR) and blood pressure. Granules within JGCs, which are modified vascular smooth muscle cells of the nephron, store and release renin into the circulation via the afferent arterioles. JGCs are positioned adjacent to the macula densa, a specialized segment of the distal nephron that senses sodium delivery and signals to JGCs to adjust their renin secretion accordingly. When sodium delivery to the macula densa is decreased due to low blood pressure, decreased GFR, or decreased sodium intake, a signal is sent to JGCs to increase renin secretion. The secreted renin increases the formation of angiotensin I, which is then converted to angiotensin II and increases GFR and renal sodium retention (Sequeira-Lopez & Gomez, 2021). Renin is therefore a vital regulator of water and electrolyte homeostasis, and developing a comprehensive knowledge of the processes regulating its production and secretion is an important objective in the field of renal physiology. However, research examining JGC renin production is scant, and mechanistic understanding of this process remains poorly understood. Neuropilin-1 is a membrane-bound coreceptor for members of the vascular endothelial growth factor and semaphorin receptor families. Neuropilin-1 therefore participates in many cellular processes like angiogenesis, neuronal development, cell survival and cell migration. Given the versatility of neuropilin-1 and its expression in JGCs, it stands to reason that it may regulate JGC renin production (Pellet-Many et al., 2011). To investigate the role of neuropilin-1 in JGC renin production, the authors used a myelin protein zero-Cre (P0-Cre) driver to constitutively eliminate expression of neuropilin-1 in select kidney cells, namely JGCs and resident fibroblasts. RNAscope and immunofluorescent staining revealed that knockouts had a slight decrease in total renin positive area that was the result of both a reduction in the total number of renin expressing JGCs and in the density of renin granules within JGCs. The authors also observed reduced renin protein levels in neuropilin-1 knockout kidneys, although this surprisingly did not result in reduced levels in circulation. To further examine the consequences of neuropilin-1 deletion on JGC renin production, the authors subjected P0-Cre neuropilin-1 knockout mice to a low salt dietary challenge. Knockout mice had a delayed response to low salt diet, with circulating renin levels not increasing until 24 h after the challenge, whereas control mice were able to increase renin within 8 h. Despite the inability of neuropilin-1 knockout mice to increase renin production at 8 h, their sodium excretion decreased, suggesting an increase in sodium reabsorption. Neuropilin-1 knockouts failed to further decrease their sodium excretion at 24 h, however, highlighting a discrepancy between renin levels and sodium excretion in these mice. The authors also noted that vascular smooth muscle cells along the afferent arterioles initiated their own renin production in neuropilin-1 knockout mice. These findings implicate neuropilin-1 as a regulator of JGC function. The authors detail reduced kidney renin levels in neuropilin-1 knockout mice but are careful to point out that this is likely a function of both reduced JGC counts and fewer renin granules within JGCs. The authors' key findings were that neuropilin-1 knockout mice had a delayed renin increase when challenged with a low salt diet, and that the eventual increase in renin was likely attributed to de novo renin production by afferent arteriole vascular smooth muscle cells not expressing neuropilin-1. Interestingly, the authors' discovery that neuropilin-1 knockout reduced the number of JGCs may explain this phenomenon, as the remaining JGCs capable of renin secretion may have been able to sustain a higher basal level of renin section in order to maintain appropriate circulating levels during homeostasis but could have been unable to sufficiently increase their renin secretion when stimulated. It will be important in future studies to clarify whether or not the perceived renin-related effects of P0-Cre neuropilin-1 knockout are wholly due to reduced JGC numbers. One possibility is that neuropilin-1 knockout resulted in the inability of JGCs to successfully survive and migrate to their proper anatomical location during development (Bartlett et al., 2017), leaving maximum renin secretory capacity reduced. Development and utilization of an inducible knockout could elucidate whether this is the case by allowing normal neuropilin-1 signalling during development and then knocking it out at a later time point. Additionally, the authors' results argue for an ability of non-JGCs to convert to renin producing cells in extreme circumstances and suggest a novel plasticity of the renin secretion system, although this concept will require additional investigation. These findings reveal neuropilin-1 as a novel regulator of JGC fate and, either directly or indirectly, renin production. There are many avenues to explore with future studies including non-juxtaglomerular effects of P0-Cre neuropilin-1 knockout that could explain the discrepancy between renin levels and sodium excretion observed in this study such as renal sympathetics and other acute systems that impact sodium reabsorption/excretion. The use of classic techniques like single nephron isolation and micropuncture would aid greatly in elucidating the direct impact of juxtaglomerular neuropilin-1 knockout on renin synthesis and secretion. Nevertheless, Shen et al.'s findings represent an important step toward a more complete understanding of neuropilin-1's regulatory effects on JGCs and renin production. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. 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