Matrix metalloproteinase 2 induces epithelial-mesenchymal transition in proximal tubules from the luminal side and progresses fibrosis in mineralocorticoid/salt-induced hypertensive rats

Abstract

Eight weeks of treatment with DOCA/salt activated MMP2, primarily on the apical surface of proximal tubule cells, which induced epithelial-mesenchymal transition from the luminal side and promoted tubulointerstitial fibrosis progression. These MMP2-induced changes occurred via downstream processes regulated by mineralocorticoid receptors.

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

“…In several animal models, increases in angiotensin II and aldosterone enhance oxidative stress in the heart, as is evident from increased nicotinamide adenine dinucleotide phosphate oxidase activity, expression of nicotinamide adenine dinucleotide phosphate oxidase components, and reactive oxygen species formation. 30,34,35 Aldosterone-induced oxidative and nitrosative stress has also been demonstrated in the rat kidney. 29 Increased oxidative stress, inflammation, and fibrosis are evident in several animal models of cardiac and renal diseases (eg, rats post-MI, dogs with HF, and uninephrectomized diabetic rats).…”

“…In response to treatment with aldosterone and salt, rat myocardium displays increased inflammation and upregulated expression of proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-1β, and transforming growth factor-β1 (TGF-β). 25,30 In the rat kidney, aldosterone increases the expression of intercellular adhesion molecule-1. 31 These effects may be mediated by serum-and glucocorticoid-induced protein kinase-1 and transcription factors nuclear factor-κB and activator protein-1, the expression and activity of which, respectively, are stimulated by aldosterone/salt or angiotensin II/salt in animal heart and kidneys.…”

“…31 These effects may be mediated by serum-and glucocorticoid-induced protein kinase-1 and transcription factors nuclear factor-κB and activator protein-1, the expression and activity of which, respectively, are stimulated by aldosterone/salt or angiotensin II/salt in animal heart and kidneys. [29][30][31][32][33] Kidney biopsies from patients with high albuminuria show significant increases in the expression of serum-and glucocorticoid-induced protein kinase-1 and the inflammatory mediators macrophage chemoattractant protein-1, TGF-β, and The direct deleterious effects of aldosterone/MR activation in the heart and kidneys and the common pathophysiological mechanisms involved. The benefits of MRAs in interrupting these pathways are also illustrated.…”

“…23 Administration of aldosterone/salt in rats increases myocardial collagen synthesis and content, fibrosis, and profibrotic factors, including connective tissue growth factor, TGF-β, plasminogen activator inhibitor-1, matrix metalloproteinase-2, and tumor necrosis factor-α. 30,[34][35][36] Renal fibrosis occurs in hypertensive transgenic rats with elevated serum aldosterone and proteinuria, and aldosterone is known to increase the renal expression of the fibrotic proteins osteopontin, fibrinogen, collagen type 1, plasminogen activator inhibitor-1, and connective tissue growth factor. 26,31,37 Oxidative stress is a well-recognized trigger for inflammation and contributes to the development of fibrosis.…”

Deoxycorticosterone Acetate/Salt–Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure

“…Aldosterone has been shown to induce epithelial-to-mesenchymal transition of renal proximal tubular cells in vitro 61 and in vivo. 62 Another source of renal fibrosis are FOXD1-lineage pericytes, which can transform into myofibroblasts. 63 Both cell types are unique to the kidney versus the cardiovascular system and might, therefore, represent an alternative mechanism of aldosterone mediated end organ damage that is independent from endothelial cells.…”