Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation in the kidney, liver, and pancreas and is associated often with cardiovascular abnormalities such as hypertension, mitral valve prolapse, and intracranial aneurysms. It is caused by mutations in PKD1 or PKD2, encoding polycystin-1 and -2, which together form a cell surface nonselective cation ion channel. Pkd2-/- mice have cysts in the kidney and pancreas and defects in cardiac septation, whereas Pkd1(del34) -/- and Pkd1(L) -/- mice have cysts but no cardiac abnormalities, although vascular fragility was reported in the latter. Here we describe mice carrying a targeted mutation in Pkd1 (Pkd1(del17-21betageo)), which defines its expression pattern by using a lacZ reporter gene and may identify novel functions for polycystin-1. Although Pkd1(del17-21betageo) +/- adult mice develop renal and hepatic cysts, Pkd1(del17-21betageo) -/- embryos die at embryonic days 13.5-14.5 from a primary cardiovascular defect that includes double outflow right ventricle, disorganized myocardium, and abnormal atrio-ventricular septation. Skeletal development is also severely compromised. These abnormalities correlate with the major sites of Pkd1 expression. During nephrogenesis, Pkd1 is expressed in maturing tubular epithelial cells from embryonic day 15.5. This expression coincides with the onset of cyst formation in Pkd1(del34) -/-, Pkd1(L) -/-, and Pkd2-/- mice, supporting the hypothesis that polycystin-1 and polycystin-2 interact in vivo and that their failure to do so leads to abnormalities in tubule morphology and function.     

Mutant polycystin-2 induces proliferation in primary rat tubular epithelial cells in a STAT-1/p21-independent fashion accompanied instead by alterations in expression of p57KIP2 and Cdk2

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the formation of multiple fluid-filled cysts that destroy the kidney architecture resulting in end-stage renal failure. Mutations in genes PKD1 and PKD2 account for nearly all cases of ADPKD. Increased cell proliferation is one of the key features of the disease. Several studies indicated that polycystin-1 regulates cellular proliferation through various signaling pathways, but little is known about the role played by polycystin-2, the product of PKD2. Recently, it was reported that as with polycystin-1, polycystin-2 can act as a negative regulator of cell growth by modulating the levels of the cyclin-dependent kinase inhibitor, p21 and the activity of the cyclin-dependent kinase 2, Cdk2.

Methods

Here we utilized different kidney cell-lines expressing wild-type and mutant PKD2 as well as primary tubular epithelial cells isolated from a PKD transgenic rat to further explore the contribution of the p21/Cdk2 pathway in ADPKD proliferation.

Results

Surprisingly, over-expression of wild-type PKD2 in renal cell lines failed to inactivate Cdk2 and consequently had no effect on cell proliferation. On the other hand, expression of mutated PKD2 augmented proliferation only in the primary tubular epithelial cells of a rat model but this was independent of the STAT-1/p21 pathway. On the contrary, multiple approaches revealed unequivocally that expression of the cyclin-dependent kinase inhibitor, p57^KIP2, is downregulated, while p21 remains unchanged. This p57 reduction is accompanied by an increase in Cdk2 levels.

Conclusion

Our results indicate the probable involvement of p57^KIP2 on epithelial cell proliferation in ADPKD implicating a new mechanism for mutant polycystin-2 induced proliferation. Most importantly, contrary to previous studies, abnormal proliferation in cells expressing mutant polycystin-2 appears to be independent of STAT-1/p21.     

Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis

BACKGROUND & AIMS: Defects in cilia formation or function have been implicated in several human genetic diseases, including polycystic kidney disease (PKD), Bardet-Biedl syndrome, and primary ciliary dyskinesia. Pancreatic lesions are found in approximately 10% of PKD patients, suggesting a connection between cilia defects and pancreatic pathologies. Here, we investigate the role of cilia in pancreas formation and function by analyzing mice that lack cilia in pancreatic cells. METHODS: Using Cre/lox technology, we conditionally inactivated Kif3a, the gene encoding for a subunit of the kinesin-2 complex that is essential for cilia formation, in pancreatic epithelia. Kif3a mice were studied by immunohistochemical and biochemical methods to assess the morphology and differentiation status of pancreatic cells. RESULTS: Tissue-specific loss of Kif3a in pancreatic cells resulted in severe pancreatic abnormalities including acinar-to-ductal metaplasia, fibrosis, and lipomatosis. Ductal metaplasia appears to be due to expansion of ductal cells rather than transdifferentiation of acinar cells. Cyst formation, aberrant ductal morphology, and extensive fibrosis associated with severe adhesion to adjacent organs were commonly observed in aged Kif3a mutant mice. Deletion of Kif3a using different pancreas-specific Cre strains suggests that these pancreatic phenotypes might be caused by the absence of cilia in ductal cells. Activation of transforming growth factor beta and Mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways may play a role in these phenotypes. CONCLUSIONS: These results demonstrate that the absence of cilia in pancreatic cells produces pancreatic lesions that resemble those found in patients with chronic pancreatitis or cystic fibrosis.     

Polycystic kidney disease--the ciliary connection

CONTEXT: "Cystic degeneration" of the kidneys was first described pathologically in 1841 and "polycystic kidneys" as a clinical syndrome in 1888. The heritable nature in some families was noted in 1899, and autosomal dominant and recessive patterns of inheritance of polycystic kidney disease (PKD) were later recognised. Autosomal dominant PKD is one of the most common human genetic diseases and results from mutations in PKD1 or PKD2. These genes encode two proteins, polycystin-1 and polycystin-2. STARTING POINT: Primary cilia are cellular organelles previously thought by some to be vestigial. New findings from several species, including algae, nematodes, and mice, implicate defects in structure or function of primary cilia as a possible common mechanism central to the development of some forms of recessive PKD. Two recent reports propose a causal link between ciliary dysfunction and autosomal dominant PKD. B Yoder and colleagues (J Am Soc Nephrol 2002; 13:2508-16) show that polycystin-1 and polycystin-2 are localised to primary cilia in cultured renal epithelial cells. S Nauli and colleagues (Nat Genet 2003; 33:129-37) show that polycystin-1 and polycystin-2 function as flow-sensitive mechanosensors in the same signal-transduction pathway. WHERE NEXT? Cystic epithelial cells show many altered cellular properties, including changes in proliferation, apoptosis, adhesion, differentiation, polarity, extracellular matrix synthesis, and fluid transport. The next important steps in PKD research will be to define the physiological roles of primary renal cilia and how defects in ciliary structure and function lead to the development of a cystic phenotype in different forms of PKD.     

Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease

We have previously demonstrated an increase in proapoptotic caspase-3 in the kidney of Han:SPRD rats with polycystic kidney disease (PKD). The aim of the present study was to determine the effect of caspase inhibition on tubular cell apoptosis and proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 weeks of age and then treated with the caspase inhibitor IDN-8050 (10 mg/kg per day) by means of an Alzet (Palo Alto, CA) minipump or vehicle [polyethylene glycol (PEG 300)] for 5 weeks. The two-kidney/total body weight ratio more than doubled in Cy/+ rats compared with +/+ rats. IDN-8050 significantly reduced the kidney enlargement by 44% and the cyst volume density by 29% in Cy/+ rats. Cy/+ rats with PKD have kidney failure as indicated by a significant increase in blood urea nitrogen. IDN-8050 significantly reduced the increase in blood urea nitrogen in the Cy/+ rats. The number of proliferating cell nuclear antigen-positive tubular cells and apoptotic tubular cells in non-cystic and cystic tubules was significantly reduced in IDN-8050-treated Cy/+ rats compared with vehicle-treated Cy/+ rats. On immunoblot, the active form of caspase-3 (20 kDa) was significantly decreased in IDN-8050-treated Cy/+ rats compared with vehicle-treated Cy/+ rats. In summary, in a rat model of PKD, caspase inhibition with IDN-8050 (i) decreases apoptosis and proliferation in cystic and noncystic tubules; (ii) inhibits renal enlargement and cystogenesis, and (iii) attenuates the loss of kidney function.     

Ciliotherapy: a novel intervention in polycystic kidney disease

Background Ciliopathies are a group of diseases associated with abnormal structure or function of primary cilia. Ciliopathies include polycystic kidney disease （PKD）, a pathology associated with vascular hypertension. We previously showed that cilia length regulates cilia function, and cilia function is required for nitric oxide （NO） biosynthesis in endothelial cells. Because patients with PKD show abnormal sensory cilia function, the aim of our current study was to search for a targeted therapy focused on primary cilia, which we refer to as ＇cilio- therapy＇. Methods and Results In the present studies, our in vitro analyses refined fenoldopam as an equipotent and more specific dopa- minergic agonist to regulate cilia length and function. Our in vivo studies indicated that fenoldopam increased cilia length and serum NO thereby reducing blood pressure in a PKD mouse model. Our crossover, multicenter, double-blind and placebo-controlled clinical study further indicated that cilia-targeting therapy showed an overall reduction in mean arterial pressure in PKD patients. Conclusions Overall, our studies provide the first evidence of ciliotherapy as an innovative intervention in patients with abnormal primary cilia.     

Cyst formation in the PKD2 (1-703) transgenic rat precedes deregulation of proliferation-related pathways

Background

Polycystic Kidney Disease is characterized by the formation of large fluid-filled cysts that eventually destroy the renal parenchyma leading to end-stage renal failure. Although remarkable progress has been made in understanding the pathologic mechanism of the disease, the precise orchestration of the early events leading to cyst formation is still unclear. Abnormal cellular proliferation was traditionally considered to be one of the primary irregularities leading to cyst initiation and growth. Consequently, many therapeutic interventions have focused on targeting this abnormal proliferation, and some have even progressed to clinical trials. However, the role of proliferation in cyst development was primarily examined at stages where cysts are already visible in the kidneys and therefore at later stages of disease development.

Methods

In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0-60 days after birth) we performed gene expression profiling and phenotype analysis by measuring various kidney parameters.

Results

Phenotype analysis demonstrated that renal cysts appear immediately after birth in the PKD2 transgenic rat model (PKD2 (1-703)). On the other hand, abnormal proliferation occurs at later stages of the disease as identified by gene expression profiling. Interestingly, other pathways appear to be deregulated at early stages of the disease in this PKD model. Specifically, gene expression analysis demonstrated that at day 0 the RAS system is involved. This is altered at day 6, when Wnt signaling and focal adhesion pathways are affected. However, at and after 24 days, proliferation, apoptosis, altered ECM signaling and many other factors become involved.

Conclusions

Our data suggest that cystogenesis precedes deregulation of proliferation-related pathways, suggesting that proliferation abnormalities may contribute in cyst growth rather than cyst formation.     

The fate of bone marrow-derived cells carrying a polycystic kidney disease mutation in the genetically normal kidney

ABSTRACT: BACKGROUND: Polycystic Kidney Disease (PKD) is a genetic condition in which dedifferentiated and highly proliferative epithelial cells form renal cysts and is frequently treated by renal transplantation. Studies have reported that bone marrow-derived cells give rise to renal epithelial cells, particularly following renal injury as often occurs during transplantation. This raises the possibility that bone marrow-derived cells from a PKD-afflicted recipient could populate a transplanted kidney and express a disease phenotype. However, for reasons that are not clear the reoccurrence of PKD has not been reported in a genetically normal renal graft. We used a mouse model to examine whether PKD mutant bone marrow-derived cells are capable of expressing a disease phenotype in the kidney. METHODS: Wild type female mice were transplanted with bone marrow from male mice homozygous for a PKD-causing mutation and subjected to renal injury. Y chromosome positive, bone marrow-derived cells in the kidney were assessed for epithelial markers. RESULTS: Mutant bone marrow-derived cells were present in the kidney. Some mutant cells were within the bounds of the tubule or duct, but none demonstrated convincing evidence of an epithelial phenotype. CONCLUSIONS: Bone marrow-derived cells appear incapable of giving rise to genuine epithelial cells and this is the most likely reason cysts do not reoccur in kidneys transplanted into PKD patients.     

实验性慢性肾缺血模型肾小管-间质细胞a-平滑肌肌动蛋白的表达和意义

目的:观察单侧肾动脉狭窄(RAS)大鼠模型慢性肾缺血组织中肾小管-间质a-平滑肌肌动蛋白(a-SMA)的表达和意义。 方法:建立Goldblatt单侧RAS大鼠模型,观察大鼠慢性缺血肾脏在90天内不同阶段的病理改变;应用免疫组化法检测肾小管-间质a-SMA及波形蛋白(vimentin)在不同时间点的表达;应用免疫荧光双标记激光共聚焦显微镜观察细胞角蛋白(cytokeratin,CK)与a-SMA在肾小管上皮细胞中的共定位情况。 结果:RAS术后第5天首先出现肾小管vimentin阳性,术后第7天肾间质可见少量的a-SMA阳性细胞并随时间递增。通过连续切片观察到,vimentin阳性的肾小管周围肾间质细胞a-SMA表达增强,并与肾小管间质纤维化程度基本一致。当慢性缺血状态持续存在时,后期(术后第45天至90天)少数损伤的肾小管上皮细胞表达a-SMA。应用免疫荧光双标记激光共聚焦显微镜观察发现,部分a-SMA阳性的肾小管上皮细胞同时表达CK,并且个别细胞还有向间质游走的趋势。 结论:在慢性肾缺血早期Vimentin阳性的肾小管上皮细胞本身可能诱导了肾间质固有细胞发生肌成纤维细胞转分化,参与肾间质纤维化的发生和发展;在慢性肾缺血后期,肾小管上皮细胞转分化可能是导致肾纤维化进行性发展的关键环节。     

Drug-induced renal failure: update on new medications and unique mechanisms of nephrotoxicity

Medications cause renal failure through a variety of mechanisms. Hemodynamic renal failure may result from drugs that reduce renal prostaglandins and hence renal blood flow and glomerular filtration rate. A relatively new group of drugs with this potential is the cyclooxygenase-2 selective inhibitors. Direct renal tubular toxicity has also been described with a number of new medications with unique effects on the epithelial cells of the kidney. These include the antiviral agents cidofovir, adefovir, and tenofovir as well as the bisphosphonate pamidronate. Additionally, crystal deposition in the kidney may promote the development of renal failure. Several different drugs have been described to induce crystal nephropathy, including the antiparasitic drug sulfadiazine, the antiviral agent acyclovir, and the protease inhibitor indinavir. Finally, an unusual form of renal failure characterized by swollen, vacuolated proximal tubular cells can develop from hyperosmolar substances. Agents recently described to induce an "osmotic nephrosis" include intravenous immunoglobulin and the plasma expander hydroxyethyl starch.     

Prevalence of Cysts in Seminal Tract and Abnormal Semen Parameters in Patients with Autosomal Dominant Polycystic Kidney Disease

Background and objectives: Autosomal dominant polycystic kidney disease is a systemic disorder with a wide range of extrarenal involvement. The scope of this study was to analyze the prevalence of seminal cysts and to correlate these findings with the sperm parameters in patients with autosomal dominant polycystic kidney disease.Design, setting, participants, & measurements: A prospective study enrolled 30 adult men with autosomal dominant polycystic kidney disease. Of these 30 patients, 22 agreed to provide a semen sample for analysis, and 28 of 30 agreed to undergo an ultrasound rectal examination. Data obtained from the semen tests and from the ultrasound study were compared.Results: Cysts in the seminal tract were present in 10 (43.47%) of 28 individuals. Twenty of 22 patients showed abnormal semen parameters, with asthenozoospermia as the most common finding. No correlation between ultrasound findings and sperm abnormalities was observed.Conclusions: The presence of cysts in the seminal tract is remarkably high (43.47%); however, this finding does not correlate with sperm abnormalities, which are also a frequent finding, especially asthenozoospermia. This semen abnormality is probably related to the abnormal function of polycystins. More attention should be paid to reproductive aspects in the initial evaluation of patients with autosomal dominant polycystic kidney disease before their ability to conceive is further impaired by uremia.Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders, occurring in approximately one of 1000 individuals in the general population. ADPKD is a genetically heterogeneous disorder caused by mutations in either the PKD1 or the PKD2 gene, which encode for the proteins polycystin-1 and polycystin-2, respectively. Most ADPKD cases (>80%) are due to mutations of the PKD1 gene and are associated with an earlier onset and faster disease progression than the PKD2 phenotype. ADPKD has been widely studied during the past decade, having shed new light on polycystin structure and function. Polycystin-1 and -2 are highly conserved ubiquitous transmembrane proteins that, in the kidney, are located in epithelial cells of renal tubules, in particular in the primary cilia at the luminal side of the tubules, as well as in other areas of the renal cell epithelium. Polycystin-1 is a large protein with a long extracellular N-terminal region, 11 transmembrane domains, and a short intracellular C-terminal tail. Polycystin-2 is structurally related to the transient receptor potential channel family, and it is known to function as a nonselective cation channel permeable to Ca². Polycystin-1 and -2 form heteromeric complexes and co-localize in the primary cilium of renal epithelial cells. The primary cilium is a long nonmotile tubular structure located in the apical surface of epithelial cells in renal tubules. Its function was unknown for a long time; however, recent studies proposed a role of the primary cilium as a mechanoreceptor that may sense changes in apical fluid flow and may be able to transduce them into an intracellular Ca²⁺ signaling response (1). This model involves the participation of polycystin-1 as a mechanical sensor of ciliary bending induced by luminal fluid flow. Bending of the cilium would cause a conformational change in polycystin-1 that would in turn activate polycystin-2–associated Ca²⁺ channel, increasing the intracellular Ca²⁺ concentration and triggering intracellular signaling pathways leading to normal kidney development.Many extrarenal features are well known in ADPKD. Hepatic cysts are the most common extrarenal manifestation of ADPKD. More than 75% of individuals who have ADPKD and are older than 60 yr have hepatic cysts (2). The prevalence of intracranial aneurysms is approximately 10%, and the prevalence of pancreatic cysts is 6 to 9%; however, other extrarenal organ involvement, such as aortic abdominal aneurysms, colonic diverticulae, and cardiac valve abnormalities, has been questioned for ADPKD. Other rare associations have been reported, but their prevalence remains unknown. This could be the case for thoracic aortic aneurysm, hernias, and seminal tract cysts.There have been several case reports on cysts in epididymis, seminal vesicles, prostate, and testes in patients with ADPKD. Also some cases of infertility have been reported. Even a structural abnormality in the sperm from some patients with ADPKD has been reported; however, ADPKD is not a disease that is considered to cause infertility. Fewer than 10% of cases are sporadic, and in the remaining 90%, the disease has been inherited independently from the mother or the father. Moreover, large pedigrees are frequent. The aim of this study was to determine the prevalence of cysts in the seminal tract and to correlate it with sperm parameters.     

Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney.

Polycystic kidney disease 1 (PKD1) is the major locus of the common genetic disorder autosomal dominant polycystic kidney disease. We have studied PKD1 mRNA, with an RNase protection assay, and found widespread expression in adult tissue, with high levels in brain and moderate signal in kidney. Expression of the PKD1 protein, polycystin, was assessed in kidney using monoclonal antibodies to a recombinant protein containing the C terminus of the molecule. In fetal and adult kidney, staining is restricted to epithelial cells. Expression in the developing nephron is most prominent in mature tubules, with lesser staining in Bowman's capsule and the proximal ureteric bud. In the nephrogenic zone, detectable signal was observed in comma- and S-shaped bodies as well as the distal branches of the ureteric bud. By contrast, uninduced mesenchyme and glomerular tufts showed no staining. In later fetal (>20 weeks) and adult kidney, strong staining persists in cortical tubules with moderate staining detected in the loops of Henle and collecting ducts. These results suggest that polycystin's major role is in the maintenance of renal epithelial differentiation and organization from early fetal life. Interestingly, polycystin expression, monitored at the mRNA level and by immunohistochemistry, appears higher in cystic epithelia, indicating that the disease does not result from complete loss of the protein.     

Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II

The embryonic cellular events that set the asymmetry of the genetic control circuit controlling left-right (L-R) axis determination in mammals are poorly understood. New insight into this problem was obtained by analyzing mouse mutants lacking the KIF3A motor subunit of the kinesin-II motor complex. Embryos lacking KIF3A die at 10 days postcoitum, exhibit randomized establishment of L-R asymmetry, and display numerous structural abnormalities. The earliest detectable abnormality in KIF3A mutant embryos is found at day 7.5, where scanning electron microscopy reveals loss of cilia ordinarily present on cells of the wild-type embryonic node, which is thought to play an important role in setting the initial L-R asymmetry. This cellular phenotype is observed before the earliest reported time of asymmetric expression of markers of the L-R signaling pathway. These observations demonstrate that the kinesin-based transport pathway needed for flagellar and ciliary morphogenesis is conserved from Chlamydomonas to mammals and support the view that embryonic cilia play a role in the earliest cellular determinative events establishing L-R asymmetry.     

A case of primary human immunodeficiency virus infection with severe rhabdomyolysis without acute renal failure

Subjects with primary human immunodeficiency virus (HIV) infection often have acute retroviral syndrome. Some develop rhabdomyolysis, which can lead to acute renal failure. A 21-year-old man admitted for consciousness disturbance was initially considered to have aseptic meningitis associated with primary HIV infection. On hospitalization day 3, he developed severe rhabdomyolysis with elevated serum creatine kinase (CK) of 218,100 IU/L with serum creatinine normal at 0.9 mg/dL. Following massive extracellular fluid infusion and urinary alkalinization, serum CK decreased smoothly, without renal failure. Severe rhabdomyolysis was concomitant with systemic inflammatory response syndrome (SIRS) only on admission day. Acute renal failure in those with rhabdomyolysis may be influenced by renal possibly due to SIRS and tubular damage from reactive oxygen species, rather than by tubular obstruction by myoglobin casts, although this depends on the extent of myolysis. Acute renal failure is prevented in those with primary HIV infection developing rhabdomyolysis, based on renal blood flow control, if condition causing SIRS do not become a complication.     

Gross hematuria rapidly deteriorated renal function in a patient with polycystic kidney disease and Klippel-Trenaunay-Weber syndrome

A case of polycystic kidney disease (PKD) associated with Klippel-Trenaunay-Weber syndrome is described. A 58-year-old man with chronic renal failure experienced urinary retention following gross hematuria. Intermittent drainage was necessary for significant urination for five days. Thereafter his urinary retention was relieved, but renal failure progressively developed and hemodialysis was started. Right hydronephrisis and hydroureter disappeared one month later. In spite of relief of obstruction, of which the cause was likely blood clots, renal function was not restored. Obstructive nephropathy was most likely explicable for notable deterioration in renal function. Our case might have susceptibilities to PKD development in terms of angiogenesis.     

Cystic liver diseases. Genetics and cell biology

In 50% of cases, polycystic liver disease is associated with autosomal dominant polycystic kidney disease, which is caused by mutations in the PKD1 and PKD2 genes that encode polycystin-1 and -2, respectively. These proteins form a polycystin-1/2 complex on the plasma membrane, including that localized on the surface of primary cilia, where they act as mechanosensors. Polycystin-1 acts as a (mechano)receptor of environmental signals, and polycystin-2 as a calcium channel mediating intracellular transduction. Isolated autosomal dominant polycystic liver disease is caused by mutations in PRKCSH that encodes hepatocystin, a protein of the endoplasmic reticulum, which may participate in the N-glycosylation and maturation of proteins addressed to the cell surface. Congenital hepatic fibrosis whether it is accompanied by bile duct dilatations (Caroli's syndrome) or not, may be associated with autosomal recessive polycystic kidney disease, which is caused by mutations in PKHD1 that encodes fibrocystin, a protein of primary cilia. Genetic defects in fibrocystin cause ciliary dysfunction, presently considered as a major pathogenic event in cystogenesis. Excessive cell proliferation, a hallmark of cystic biliary epithelium, occurs in combination with deregulation of the epidermal growth factor (EGF) and probably also estrogen receptors. EGF receptor antagonists inhibit kidney and liver cyst development in animal models, and are currently under investigation in phase I and II clinical trials in patients with autosomal dominant polycystic kidney disease.