Review
| Rev Diabet Stud,
2021,
17(1):1-10 |
DOI 10.1900/RDS.2021.17.1 |
Molecular Mechanisms Involved in Intrarenal Renin-Angiotensin and Alternative Pathways in Diabetic Nephropathy - A Review
Elham Bahreini1, Yousef Rezaei-Chianeh1, Mohsen Nabi-Afjadi2
1Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
2Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
Address correspondence to: Elham Bahreini, e-mail: bahreini.e@iums.ac.ir
Manuscript submitted November 3, 2020; resubmitted December 6, 2020; accepted December 12, 2020.
Keywords: nephropathy, vascular endothelial growth factor, glomerular filtration rate, angiotensin, angiotensin-converting enzyme, local renin-angiotensin system
Abstract
Uncontrolled or chronic hyperglycemia causes kidney failure induced by the dysfunction of biomolecules and upregulation of inflammatory cytokines and growth factors. The renin-angiotensin system (RAS) is incorporated in the regulation of renal hemodynamics. In a healthy state, local RAS is independent of systemic RAS. However, in pathological conditions such as chronic hyperglycemia, angiotensin II (Ang II) increases locally and causes tissue damage, mainly through the induction of oxidative stress, inflammation, and upregulation of some growth factors and their receptors. Such tissue events may cause disruption of the glomerular filtration barrier, thickening and hypertrophy of the glomerular basement membrane, microvascular hyperpermeability, proteinuria, and finally decrease in the glomerular filtration rate (GFR). Reduced GFR causes the kidney to sense falsely a low blood pressure condition and respond to it by stimulating systemic and local RAS. Therefore, patients with diabetic nephropathy (DN) suffer from chronic hypertension. In contrast to local RAS, there are alternative pathways in the kidney that act protectively by reducing tissue Ang II. Such autoregulatory and protective mechanisms are weakened in chronic kidney disease. Previously, it was presumed that systemic RAS inhibitors such as ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) could prevent renal damage by controlling blood pressure and proteinuria. However, the progression of renal failure to end-stage renal disease (ESRD), despite such treatments, indicates the presence of factors other than Ang II. This review highlights the molecular mechanism in renal disease and discusses pharmaceutical and therapeutic approaches.
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