Renin and prorenin in the context of COVID-19
Renin is formed by proteolytic or non-proteolytic cleavage of prorenin. While renin production can undergo acute changes due to feedback, prorenin is constitutively secreted. Prorenin levels are elevated in hypertensives (with elevated renin) and diabetics (out of proportion to renin). Renin and prorenin ligate with the prorenin receptor that is present in the heart, kidney, brain, eyes, and on human macrophages and T-cells.27
PRR stimulation by renin/prorenin yields a pro-inflammatory response independent of the angiotensin II pathway. They stimulate the ERK1/2 pathway to increase the production of IL-6 and COX-2.28 The pro-inflammatory action of PRR activation has also been depicted in mouse models of sepsis. Mice treated with PRR blockers had a significantly higher survival rate with reduced production of IL-1β and TNF.29
Angiotensin II-AT1 interaction is a negative regulator of renin release as per classical teaching. The intricacies of the RAS polypeptides, however, suggests differential activation that might be trigger based. AT1 activation upregulates PRR by increasing the binding of cAMP response element-binding protein to the PRR promoter.30 Renin secretion and PRR activation are also upregulated by prostaglandins (PGE2) which is a consequence of COX-2 induction.31
The above-mentioned steps might be the key to a positive feedback loop in the RAS. This loop might be the trigger for a hyper-immune response that leads to the severe manifestations of COVID-19, including a cytokine storm. The higher expression of prorenin in diabetics and hypertensives supports the increased mortality in these groups of patients.