Study shows healthy kidneys despite high blood pressure

BERLIN: Scientists found that unless you happen to have a PDE3A gene mutation, high blood pressure eventually damages the kidneys. According to research published in 'Kidney International' by a team led by Enno Klussmann of the Max Delbruck Centre and the DZHK, a mutation that causes severe hypertension also shields the kidneys from harm.

"This mutation causes extremely high blood pressure, but the kidneys still work normally even after years of having the condition," said Dr Enno Klussmann, head of the Anchored Signalling Lab in Berlin. He and his team at the Max Delbruck Center and at the German Center for Cardiovascular Research (DZHK), have now published their results in "Kidney International."

Getting to the heart of the matter

Last year, researchers discovered that the gene mutation responsible for causing extremely high blood pressure and short fingers (hypertension and brachydactyly, or HTNB) also protects the heart from hypertension-induced damage. Only the brain remains vulnerable: "Without treatment, patients with HTNB - a genetic disease that occurs in just 10 to 20 families globally - tend to die relatively young from a stroke," said Klussmann. "So even children have to take antihypertensive drugs to control their blood pressure." But with medication, it can be hard to bring the blood pressure down to an average level.

After discovering that the mutated PDE3A gene protected the heart, Klussmann and his team began investigating a female patient's kidneys in Germany and two HTNB rat models. The patient received treatment from Dr Stephan Walter at MVZ Nierenzentrum Limburg, a specialist kidney centre. The rat models had the same PDE3A mutation as human patients (PDE3A stands for the enzyme phosphodiesterase 3A) and were developed by researchers led by Professor Michael Bader. Bader heads the Molecular Biology of Peptide Hormones Lab at the Max Delbruck Center. He and Walter are also authors of the latest study.

All parameters in the normal range

In patients with severe HTNB, the PDE3A gene was mutated in two places and these mutations cause the encoded enzyme to become hyperactive. "We don't yet fully understand why that happens, or how the mutation damages the vessels and the brain while protecting the heart and the kidneys," said Klussmann. He and his team could, however, show that the kidneys of the Limburg patient are working perfectly normally. "We found that the secretion of the renin - a hormone-like enzyme that's produced in the kidneys and heavily involved in controlling blood pressure - is actually suppressed in her case," said Anastasiia Sholokh, a researcher in Klussmann's team and lead author of the study. "Her aldosterone levels are normal." Aldosterone is a hormone made in the adrenal glands. Like renin, it can cause blood pressure to rise. "Conventional parameters of kidney function like glomerular filtration rate and albumin levels in the blood and urine also indicate that her kidneys are healthy," said Sholokh.

Imitating the mutation's effects

The kidney tissue in the HTNB rats also showed no signs of inflammation or fibrosis (increased production of connective tissue that causes organs to harden). The transcriptome, which shows what genes were active, was also unchanged in the rats' kidneys. "What we did find is reduced expression of the protein amphiregulin in certain regions of the organ," said Sholokh. "Since high levels of amphiregulin are likely to damage the kidneys, the suppressed production probably helps to protect them." "We showed that hypertension doesn't always automatically lead to kidney damage," said Klussmann, summing up. "Now we want to examine the protective effect of the mutated PDE3A gene and see if we can mimic it with appropriate therapeutic agents." This could eventually help patients with hypertension avoid developing chronic kidney disease.