Review

Molecular Mechanisms Involved in Intrarenal Renin-Angiotensin and Alternative Pathways in Diabetic Nephropathy - A Review

Elham Bahreini¹, Yousef Rezaei-Chianeh¹, Mohsen Nabi-Afjadi²

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.

Abbreviations: ACE: Angiotensin-converting enzyme; ACEIs: ACE inhibitors; ADH: antidiuretic hormone; AGEs: advanced glycation end products; AMP: alanyl aminopeptidase; Ang II: angiotensin II; APA: aminopeptidase A; AT1R: angiotensin II receptor 1; AT2R: angiotensin II receptor 2; DN: diabetic nephropathy; ESRD: end-stage renal disease; Flk-1: fetal liver kinase 1; Flt-1: Fms-like tyrosine kinase 1; GBM: glomerular basement membrane; GFB: glomerular filtration barrier; GFR: glomerular filtration rate; GN: glomerulonephritis; HIF-1α: hypoxia-inducible factor α subunit; HO-1: heme oxygenase 1; ICAM-1: intercellular adhesion molecule 1; IFN: interferon; IL: interleukin; NEP: neprilysin; NO: nitric oxide; PAI: plasminogen activator inhibitors; RAS: renin-angiotensin system; PEP: prolyl endopeptidase; PHD: prolyl hydroxylase; Plt: platelet; PRCP: prolyl carboxypeptidase; RNS: reactive nitrogen species; ROS: reactive oxygen species; SMC: smooth muscle cell; TGF-β: transcription growth factor; VCAM-1: vascular cell adhesion molecule 1; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor

1. Introduction

Diabetic nephropathy (DN) is a long-term kidney disease that occurs in people suffering from chronic diabetes mellitus [1]. As DN progresses, the most important structural changes occur in glomeruli. Glomerulonephritis (GN) is an inflammatory process in the glomeruli or small blood vessels in the kidney that is characterized by DN through diffuse or nodular sclerosing glomerulonephritis [2]. Glomerulosclerosis is associated with the thickening of the glomerular basement membrane (GBM) induced by an increase in the mesangial matrix that contains large amounts of collagen, especially types IV and VI, laminin, and fibronectin. [3]. Mesangial expansion restricts the glomerular capillary surface area, disturbs the filtering process, and allows the protein leaking from the blood into the urine [4]. Thus, the early stages of glomerulosclerosis are defined by proteinuria that is characterized by a positive microalbuminuria test caused by the progression of glomerular hypertrophy, GBM thickening, hyperperfusion, and hyperfiltration [5].

Acknowledgments: The authors declare that they have no competing interests.

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