Press release


Sympathetic neurons used to combat polycystic kidney disease

Paris, March 29, 2002


Using an atypical research model, the neuron, Patrick Delmas, of the "Intégration des Informations Sensorielles Laboratory" (CNRS – Marseille), and the research teams of Dr. Jing Zhou(1) and Professor David A. Brown(2) , have achieved significant results with the function of polycystin-1, a human kidney protein whose mutations have been associated with 85% of all cases of polycystic kidney disease. Their work will enable the identification of the metabolic pathways activated by polycystin-1 and provide valuable information about the cellular mechanisms responsible for this disease. These results were published in the March 29 issue of the Journal of Biological Chemistry.

Autosomal dominant polycystic kidney disease (called ADPKD) is a serious genetic disease with an incidence rate of 1 per 1000 births, which afflicts about 80,000 people in France. Fluid-filled cysts form in the kidneys of ADPKD patients and gradually compress and destroy healthy renal tissue. The disease is one of the primary causes of chronic kidney failure and almost half of all cases require either dialysis or transplantation. The probability of end-stage kidney failure requiring dialysis is 20-25% by the age of 50, 40% by the age of 60, and between 50 and 70% by the age of 70. Treatment to slow the progress of kidney failure in ADPKD patients has thus far been disappointing.

ADPKD is caused by the mutation of two genes, PKD1 and PKD2, respectively located on autosomal chromosomes(3) 16 and 4. The first gene, PKD1, is responsible for the synthesis of a glycoprotein called polycystine-1 whose function is still poorly understood. This protein is found in the tubular epithelia of the kidney and in the hepatic, biliary and pancreatic canaliculi of polycystic kidneys. Mutations of the PKD1 gene lead to a dysfunction in the cellular differentiation of renal epithelium.

The second gene, PKD2, is responsible for the synthesis of a much smaller protein, polycystin-2, which plays a role in calcium transport. PKD2 mutations may have repercussions on fluid secretion and the growth of cysts.

The study of polycystin-1 has long been frustrated by the difficulty posed by its expression(4) in conventional cells lines due to its large size. To enable the expression of this protein, the researchers cultured sympathetic neurons(5) from rats. Polycystin-1 genes of different species (humans and mice) were introduced inside the nucleus of the neurons using an intranuclear microinjection technique. This method proved very effective for studying polycystin-1 functions. The work of Patrick Delmas and his associates demonstrated that polycystin-1 behaves like a membrane receptor that couples with G-proteins(6) , activating them in an unpredictable manner.

With this work, the researchers are among the first to propose a function for polycystin-1 and suggest a molecular explanation for the development of polycystic kidney disease: G-proteins regulate a variety of enzymes such as adenylate cyclase and protein kinases. These enzymes are known to play a key role in controlling the secretion of fluids, cell proliferation, and differentiation, three basic functions that are severely disrupted in ADPKD.

Researchers suggested that the mutations of polycystin-1 affect its integrity, thus activating pathogenic responses through the abnormal stimulation of G-proteins. The identification of the functions of polycystin-1 may well pave the way toward developing new therapeutic strategies for treating polycystic kidney disease.

Delmas P., et al.. Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2, Journal of Biological Chemistry, March 29, 2002.

(1)Renal Division, Harvard Medical School, Boston
(2)Wellcome Laboratory for Molecular Pharmacology, UCL, London
(3)Autosomes are non sex-determining chromosomes. In humans, there are 23 pairs of chromosomes of which 22 are autosomal. The 23rd pair are the sex-determining chromosomes X and Y (heterosomes).
(4)Method employed to introduce a minigene inside the host cell to study its functions

(5)Superior cervical ganglia neurons that were part of the autonomous nervous system and maintained in primary culture
(6)Coupling proteins associated with membrane receptors provide signal transduction from the extracellular medium to the intracellular medium and regulate cellular metabolism

Researcher Contact:
Patrick Delmas
Tel: +33 4 91 16 41 19

Life Sciences Department, Communications Contact:
Marie-Pascale Corneloup-Brossollet
Tel: +33 1 44 96 46 48

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