Non-Haemodynamic Mechanisms Underlying Hypertension-Associated Damage in Target Kidney Components

Abstract

Arterial hypertension (AH) is a global challenge that greatly impacts cardiovascular morbidity and mortality worldwide. AH is a major risk factor for the development and progression of kidney disease. Several antihypertensive treatment options are already available to counteract the progression of kidney disease. Despite the implementation of the clinical use of renin–angiotensin aldosterone system (RAAS) inhibitors, gliflozins, endothelin receptor antagonists, and their combination, the kidney damage associated with AH is far from being resolved. Fortunately, recent studies on the molecular mechanisms of AH-induced kidney damage have identified novel potential therapeutic targets. Several pathophysiologic pathways have been shown to play a key role in AH-induced kidney damage, including inappropriate tissue activation of the RAAS and immunity system, leading to oxidative stress and inflammation. Moreover, the intracellular effects of increased uric acid and cell phenotype transition showed their link with changes in kidney structure in the early phase of AH. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for hypertensive nephropathy management in the future. In this review, we would like to focus on the interactions of pathways linking the molecular consequences of AH to kidney damage, suggesting how old and new therapies could aim to protect the kidney.

Novel Insights into the Molecular Mechanisms of Atherosclerosis

“…UA has been found to activate the RAAS and promote the expression of angiotensinogen, angiotensin-converting enzyme, and AngII receptors, as well as stimulate oxidative stress, inflammation, and smooth muscle cell proliferation. Additionally, UA and AngII together may lead to a more complex inflammatory and oxidative response compared with their individual effects [102][103][104][105][106][107].…”

A Role for Sodium-Glucose Cotransporter 2 Inhibitors in the Treatment of Chronic Kidney Disease: A Mini Review

“…In DKD, glomerular endothelial cells undergo necrosis or apoptosis and are detached from the basement membrane into the circulatory system, leading to a reduction in the number of glomerular endothelium and impaired endothelial integrity, which is an important process in the formation of proteinuria. Empagliflozin and dapagliflozin could attenuate tumor necrosis factor α (TNFα)-induced endothelial inflammation, furthermore increase NO bioavailability and inhibit TNFα-induced reactive oxygen species production, exerting improved endothelial cell function [ 56 , 57 ]. Canagliflozin reduced vascular smooth muscle cells (VSMCs) proliferation and migration in a concentration-dependent manner [ 58 , 59 ].…”

“…Canagliflozin reduced vascular smooth muscle cells (VSMCs) proliferation and migration in a concentration-dependent manner [ 58 , 59 ]. Meanwhile, empagliflozin and dapagliflozin had similar effects on the proliferation and migration of VSMCs [ 57 – 59 ]. In this regard, the vascular effects of SGLT2 inhibitors by improving endothelial cell function and regulating the proliferation and migration of VSMCs was an important mechanism for exerting a preventive effect for DKD.…”