Alteration in Prorenin-Renin Homeostasis, A Key Contributor to Renin-Angiostensin-System Pathway in The Pathogenesis of Diabetic Nephropathy: A Systematic Review

Abstract

BACKGROUND Diabetic nephropathy is part of the microvascular complication of diabetes mellitus alongside neuropathy and retinopathy. Many mechanisms have been presented as the pathophysiology of diabetic nephropathy but this could be attributed to the renin-angiotensin system. The alteration in prorenin and renin homeostasis has been reported in patients with diabetes mellitus, it's noticed to a reduction in conversion of prorenin to renin thereby leading to accumulation of prorenin binding to (pro)renin. AIM This article is targeted at explaining the contributory roles of the alteration in the prorenin and renin homeostasis in the pathogenesis of diabetic nephropathy and explaining why some of the drugs that act along renin-angiotensin pathways, especially angiotensin receptor blockers can be very helpful in the management of diabetic nephropathy. METHODS A careful literature search was made on some scientific databases such as PubMed, EMBase, Google Scholar, Research Gate, and others using a very sensitive search strategy on researches that are related to the effects of the renin-angiotensin pathway on diabetic nephropathy focusing mainly on the use Handle Receptor Protein (HRP) and Angiotensin Receptor Blocker (ARB) in the management of diabetic nephropathy. RESULTS The review of different articles shows that HRP, especially when used alongside Angiotensinogen Converting Enzyme Inhibitor (ACEI) increases plasma renin activities, and reduces the progression and development of glomeruli sclerosis, tubular injury, podocyte injury, and proteinuria. Also, ARBs such as losartan and irbesartan were found to reduce relative risk for primary composite endpoint death of nephrons, serum creatinine level, and progression to end-stage renal disease. CONCLUSION Binding of prorenin which accumulates in diabetic Mellitus to (pro)renin receptor causes non-proteolytic activation at higher concentrations and also releases profibrotic molecules which are injurious to the nephrons. This can be inhibited by the use of handle region peptide (HRP) which is a competitive antagonist of prorenin or the use of angiotensin receptor blocker which aids binding of angiotensin II to the AT2 receptor leading to vasodilatory, anti-inflammatory anti-proliferative, antihypertrophic and antifibrotic effects which antagonize those produced by prorenin.