Hypertension and renal failure: at San Raffaele Hospital identified a new gene variant for the precision medicine

A single gene polymorphism could be at the origin of arterial hypertension and renal failure: this is the result of a study published last January on American Journal of Kidney Diseases, one of the most prestigious nephrology magazines. Among the authors of the article is Prof. Paolo Manunta, Associate Professor of Nephrology and Director of the School of Specialization in Nephrology at the Vita-Salute San Raffaele University of Milan.

Photo credit: ShutterStock
Photo credit: ShutterStock

Our Clinical Research Group is interested in the study of the genetics of complex kidney diseases, particularly those that affect a large part of the population. This is the case, for example, of arterial hypertension, which affects 30-40% of adults“, says Prof. Manunta. “Our work is focused on the search for gene variants that can lead to an increase in blood pressure. We have thus identified a single nucleotide variant (C-> A) in the Lanosterol synthase gene that codes for an enzyme that is part of the biosynthetic chain of endogenous ouabain.

Endogenous ouabain is a hormone longtime considered a key factor in hypertension; it was identified in the early 90s; it is produced and secreted by the adrenal glands and hypothalamus. Elevated circulating levels of endogenous ouabain have been reported in 40-50% of hypertensive patients and associated with a progressive deterioration of renal function.

One of the complications of hypertension is renal failure which, if untreated, can lead to dialysis. In this last work, we have shown that patients with the A variant of Lanosterol Synthase are more susceptible to the development of acute kidney damage compared to the carriers of the C variant. In collaboration with the Cardiac Surgery and Cardiac Surgery Intensive Care Units of our Hospital, we have selected a group of 1000 patients undergoing cardiac surgery. Of all those in whom acute renal failure occurred, about 30% were found to be carriers of variant A”.

Several substances are extracted from the seeds and roots of Strophanthus gratus, including the ouabain, a recognized inhibitor of the sodium/potassium pump. Endogenous ouabain was named after this substance, produced in humans by the adrenal glands, which performs a similar inhibitory function. Photo credit: ShutterStock
Several substances are extracted from the seeds and roots of Strophanthus gratus, including the ouabain, a recognized inhibitor of the sodium/potassium pump. Endogenous ouabain was named after this substance, produced in humans by the adrenal glands, which performs a similar inhibitory function. Photo credit: ShutterStock

The same variant has been studied in 400 hypertensive patients followed-up for years at the Hypertension Outpatient Clinic; it was found to be more frequent among those patients who developed chronic renal failure.

“Although the two populations are different and display different phases of renal disease, the variant of Lanosterol Synthase involved is the same”.

Furthermore, the content of endogenous ouabain in the renal tissue of patients operated for other renal diseases was measured. Patients with the A variant have higher concentrations of ouabain in renal tissue, especially in the cortex, suggesting a greater affinity for the hormone”.

Logo of the Genomics of Renal Diseases and Hypertension Unit, directed by Prof. Paolo Manunta
Logo of the Genomics of Renal Diseases and Hypertension Unit, directed by Prof. Paolo Manunta

This finding highlights the role of endogenous ouabain as a new potential therapeutic target in the prevention of renal failure and renal damage associated with hypertension.

Prof. Manunta concludes: “The next step will be to confirm these data on a larger patient population. Furthermore, we are already developing a murine model for this gene variant of Lanosterol Synthase in order to evaluate the possible onset of hypertension, the levels of renal and circulating endogenous ouabain. On this animal model, we will be able to test an anti-ouabain drug – rostafuroxin, which is undergoing clinical trials – in the prevention of hypertensive and renal diseases”.

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