Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human life-threatening monogenic disorders. The disease is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease, and may include extrarenal manifestations. ADPKD is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC2 is a non-selective cation channel permeable to Ca(2+), while PC1 is thought to function as a membrane receptor. The cyst cell phenotype includes increased proliferation and apoptosis, dedifferentiation, defective planar polarity, and a secretory pattern associated with extracellular matrix remodeling. The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca(2+) signaling. The intracellular Ca(2+) homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. Activated mammalian target for rapamycin (mTOR) and cell cycle dysregulation are also significant features of PKD. Based on the identification of pathways altered in PKD, a large number of preclinical studies have been performed and are underway, providing a basis for clinical trials in ADPKD and helping the design of future trials.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease, affecting all races
While the cystic manifestations are characterized by age-dependent occurrence of bilateral, multiple renal cysts and cysts that may be present in the liver, seminal vesicles, pancreas, arachnoid membrane, and spinal meninges, the noncystic alterations include vascular anomalies mainly represented by intracranial aneurysms and dolichoectasias, aortic root dilatation and mitral valve prolapse, as well as abdominal wall hernias and colon diverticula [2]
While mice homozygous for Pkd1 null mutations die prenatally with massively cystic kidneys, pancreatic cysts, skeletal defects [15], and cardiac www.bjournal.com.br and vascular abnormalities, homozygotes for a mutation that prevents PC1 cleavage but keeps the expression of its non-cleavable form develop a postnatal distal nephron cystic phenotype [16]. This renal cystic phenotype, in turn, is rapidly progressive, leading to significantly enlarged kidneys, loss of renal function, and death of the vast majority of animals by 1 month of age. These findings suggest that the non-cleavable form of PC1 is critical for embryogenesis, whereas the protein cleavage is essential for postnatal development and maintenance of distal nephron segments
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease, affecting all races. A generated Pkd2-overexpressing transgenic mouse developed renal cysts, as well as increased cell proliferation, apoptosis and v-raf murine sarcoma viral oncogene homolog B1 (B-Raf)-dependent extracellular signal-regulated protein kinase (ERK) activation [23]. According to a key study, when Pkd1 inactivation occurred before P13 the mice developed a rapidly progressive renal cystic phenotype, whereas later inactivation was followed by very late cyst formation [24].
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