7 Aug 2019

Scientists reveal new culprit in kidney damage

by Anne Crawford 

A Monash CCS scientist has led a team that found an enzyme widely associated with a number of psychiatric and neurological disorders including depression, may also play an important role in kidney function.

The paper, a collaboration with the Baker Institute, was published recently in Frontiers in Physiology.

Dr Anna Watson led researchers investigating diabetes and hypertension (high blood pressure) and their links with renal dopamine and norepinephrine or noradrenaline. Dopamine and norepinephrine are catecholamines, signalling molecules associated with nerves, in this case autonomous excitatory nerves in the kidney. Dopamine is needed to make norepinephrine, the main signalling network for these excitatory nerves.

“We were using norepinephrine as a marker to see if there is a change in these excitatory nerves in kidneys in animal models of diabetes and high blood pressure,” Dr Watson said. “In diabetes, especially if it is of long duration and with complications, those excitatory nerves could be dying,” she said.

“No one is really looking at these nerves in kidneys. They’re very important to normal kidney function.”

The team found in mouse models of hypertension and of type 1 diabetes that mice with both conditions had very high levels of both catecholamines. They also found an increased level of the enzyme MAO-A, from the family of monoamine oxidases. MAO makes hydrogen peroxide, also a signalling molecule, which causes damage in the body if there is too much of it.

“With hypertension, even though you have increased MAO-A levels and more hydrogen peroxide, the body compensates by increasing antioxidants,” Dr Watson said. “But in diabetes, you don’t have the increased compensation by enhancing antioxidants. We saw a marked increase in MAO in hypertension and concomitant diabetes compared to hypertension or diabetes alone, as well as some of the markers of renal injury.”

The researchers are planning a study to see if blocking this enzyme – and the harmful substances it produces – would have any beneficial effects to people with diabetes and hypertension.

Dr Watson had previously investigated excitatory nerves in the heart before switching to diabetes research. She said an overseas lecture on oxidants gave her the idea to investigate MAO. “They were talking about oxidants and antioxidants and it twigged that there was this enzyme (MAO) that breaks down catecholamines.”

Currently, a method of severing the excitatory nerves to the kidney is used as a treatment of last resort for people with very high blood pressure who are on a number of medications.

“I’d like to see if blocking the enzyme – without cutting any nerves – helps alleviate the amount of kidney damage you get in diabetic patients with high blood pressure,” Dr Watson said.

Said Professor Karin Jandeleit-Dahm, a senior author on the paper; “There is currently no cure for diabetic kidney disease. Our studies could potentially lead to a new treatment approach which, in addition to standard of care, may alleviate the health burden of diabetes and its complications.”

The paper was a “group effort” by those involved, Dr Watson said. It was funded by an NHMRC grant and Diabetes Australia. Dr Watson is an Australian Diabetes Society Skip Martin Fellow.

Watson AMD, Gould EAM, Penfold SA, Lambert GW, Pratama PR, Dai A, Gray S. Diabetes and Hypertension Differentially Affect Renal Catecholamines and Renal Reactive Oxygen Species. Front Physiol. 2019 Apr 16;10:309. doi: 10.3389/fphys.2019.00309. eCollection 2019.

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