Polycystic kidney: a problem of tubule expansion lies at the base of polycystic kidney disease

New light has been shed on the molecular mechanisms that lie at the base of one of the most common genetic diseases, autosomal dominant polycystic kidney, which in Italy alone affects 60 thousand people: the announcement comes in a study published in Nature Communications* by the research group of the Dulbecco Telethon Institute headed by Alessandra Boletta at the Genetics and Cell Biology department of the San Raffaele Hospital for Treatment and Research in Milano.

This work makes an important contribution to understanding the mechanism by means of which cysts form on the kidneys in this condition, which continues to baffle scientists and for which there is no effective cure: the disease gradually leads to renal failure, and sufferers must then undergo dialysis, or, where possible, a kidney transplant.

The underlying cause of the disease - in which "balloons" gradually form and fill up with liquid that progressively damages the kidney – are defects affecting two genes, PKD1 and PKD2, which contain the information for two proteins called polycystin 1 and 2. In 85% of patients, the genetic defect is present in PKD1.

«Although it's been almost twenty years since the two genes associated with the disease were identified» commented Alessandra Boletta «we have not yet been able to understand exactly why the absence of polycystin 1 leads to the formation of cysts. Following the justifiable initial enthusiasm – the identification of the disease gene is always the first fundamental step on the long road towards a cure – we realised we were looking at a very large protein, the paucity of which makes it difficult to be studied in the laboratory: PKD1 is not found inside the cell, but on the external membrane, which it goes through 11 times, like a coil; this makes it difficult to handle in order to understand the function it normally carries out in the organism and why its absence leads to the formation of cysts».

Nonetheless, in recent years researchers have succeeded in developing cellular and animal models of the disease, allowing them to piece together a number of elements of the puzzle. The most widely accepted hypothesis is that the two polycystins are important for the proper development of the renal tubules, which are responsible for collecting urine as it builds up.

«In this study, we have shown in an animal model devoid of Pkd1 how the lack of a functional version of this protein prevents the renal tubules from forming properly, causing them to have a larger diameter than normal. This suggests that polycystin 1 might have this role, but we are not yet able to establish for sure whether the expansion of the renal tubules can, in effect, contribute to the formation of cysts» said Maddalena Castelli, the main author of the study.«In this work, however, we have shown that polycystin carries out this function thanks to its ability to regulate cell polarisation, i.e. the ability of cells to orient themselves in space».

Understanding the molecular bases of a disease is a lengthy process, made up of small steps forward, with the need for a rethinking phase on various occasions: «but this is the only way we can identify a specific treatment, which does not exist yet» commented Dr. Boletta. «Polycystic kidney disease appears late and progresses slowly, so it would be sufficient to find a way to slow down the formation of the cysts and their tendency to expand into the surrounding tissue. If we were able to neutralise their impact on the rest of the kidney, for example by reducing their capacity to produce fluid and expand, patients could live with the condition, without it impacting and damaging their quality of life. To do this, however, we must understand exactly which mechanisms are affected by the genetic defect. This could allow us to design carefully targeted, and thus effective, forms of treatment. The lack of this essential knowledge may be the reason why a number of therapeutic approaches attempted thus far have proved unsuccessful».

The study was financed by Telethon-Italy (TCR05007 and GGP12183) to A.B. and by the NIH (1R01DK09505) to T.C. and H.R. A.B. is an Associate Telethon Scientist. 

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