2nd Hypertension Treatment Seen to Ease Kidney Fibrosis in Mice, Possibly via Signaling Molecule

2nd Hypertension Treatment Seen to Ease Kidney Fibrosis in Mice, Possibly via Signaling Molecule

An angiotensin receptor blocker approved to treat high blood pressure, called Benicar (olmesartan), may ease kidney scarring in Alport syndrome by altering levels of the signaling molecule transforming growth factor beta (TGFβ), a study in mice reports.

The study “Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ” was published in the International Journal of Molecular Sciences.

Angiotensin receptor blockers (ARBs) target the renin–angiotensin system (RAS), which is implicated in the disease mechanism of Alport.

Previous research in an Alport mouse model found that another hypertension treatment acting on the same pathway as ARBs, called Altace (rampiril, an angiotensin-converting enzyme or ACE inhibitor), also lessened kidney fibrosis (scarring of the kidney tissue that’s observable at the cellular level). Its researchers suggested that treatment may delay kidney failure in patients.

“Blockade of RAS with ACEs or ARBs has demonstrated the renoprotective [protection of the kidney] effect in clinical AS patients as well as in animal models,” researchers in the current study wrote. However, the molecular mechanisms behind these protective effects are is not fully understood.

The team used mice engineered to lack the gene Col4a3 so to have symptoms that mirror human Alport syndrome, including developing kidney disease. Some of these mice were administered Benicar in their drinking water, while others got water without the drug. A few weeks later, the mice were euthanized, and their kidneys were compared. Wild-type mice (without Alport syndrome) were also included for comparison.

Researchers first confirmed that the kidneys of the Alport syndrome mice showed signs of damage and scarring, and that Benicar treatment reduced these signs of fibrosis. As an example, the urine albumin-to-creatinine ratio (a marker of kidney damage) was, on average, 1,119.0 in the untreated Alport syndrome mice and 426.3 in the Benicar-treated mice, a significant difference. (For reference, this ratio was 15.1 in the wild-type mice.)

They then analyzed the levels of various proteins in the mice’s kidneys as a way to assess the mechanism of this change. They focused on TGFβ, a signaling molecule that’s involved in several biological processes. They found that this signaling molecule was present at abnormally high levels in the untreated Alport syndrome mice — but in the Benicar-treated mice, TGFβ levels were lowered to around wild-type levels.

Signaling proteins that act downstream of TGFβ — that is, proteins that help “carry the signal forward” from TGFβ, including Smad4 — were also expressed a higher levels in the untreated Alport syndrome mice and at lower levels in those given Benicar. This suggested that the TGFβ pathway — TGFβ and its downstream effectors — was activated in the kidneys of mice with Alport syndrome, but Benicar treatment lowered this activation.

Further analysis of proteins in the mice’s kidneys, as well as experiments with human-derived cells in dishes, confirmed that the RAS pathway was also upregulated through activation by TGFβ. “Our results indicate compelling evidence that stimulation of kidney tubular epithelial cells with TGFβ triggers activation of classical RAS pathways,” the researchers wrote.

Additional experiments suggested that these two pathways were involved in a feedback loop in which each helped to activate the other, driving kidney damage — and that Benicar may help reduce said damage, at least in part, by interrupting this loop.

“In the present study, we discovered a mechanism by which olmesartan impedes the progression of kidney fibrosis in [mice with Alport syndrome],” the researchers concluded.

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
×
Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
Latest Posts
  • Keratoconus, Alport syndrome
  • Alport and eye health
  • kidney cell model
  • hypertension treatments and Alport