Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ.

Abstract

Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin-angiotensin system (RAS) and transforming growth factor β (TGFβ) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3-/- mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3-/- mice by olmesartan treatment. Upregulation of TGFβ and activation of its downstream in Col4a3-/- mice were attenuated by olmesartan in Col4a3-/- mice. Intriguingly, TGFβ expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3-/- mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3-/- mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFβ-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFβ feedback loop to counterbalance intrarenal RAS activation.

• Authors: Sang Heon Suh, Hong Sang Choi, Chang Seong Kim, In Jin Kim, Seong Kwon Ma, James W Scholey, Soo Wan Kim, Eun Hui Bae
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 15 (Aug 06 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31390839 (Publication Type: Journal Article)

Chemical References

• Antihypertensive Agents
• Biomarkers
• Imidazoles
• Tetrazoles
• Transforming Growth Factor beta
• olmesartan
• Peptidyl-Dipeptidase A
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2
• ras Proteins

Topics

• Angiotensin-Converting Enzyme 2
• Animals
• Antihypertensive Agents (pharmacology)
• Apoptosis (drug effects)
• Biomarkers
• Biopsy
• Disease Models, Animal
• Fibrosis
• Gene Expression Regulation (drug effects)
• Imidazoles (pharmacology)
• Kidney Tubules (drug effects, metabolism, pathology)
• Mice
• Mice, Knockout
• Nephritis, Hereditary (drug therapy, genetics, metabolism, pathology)
• Peptidyl-Dipeptidase A (genetics, metabolism)
• Tetrazoles (pharmacology)
• Transforming Growth Factor beta (genetics, metabolism)
• Treatment Outcome
• ras Proteins (genetics, metabolism)