Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease. 2162 23

Hypertension is common and occurs in the majority of autosomal dominant polycystic kidney disease (ADPKD) patients prior to loss of kidney function. Hypertension relates to progressive kidney enlargement, and is a significant independent risk factor for progression to end-stage renal disease. The pathogenesis of hypertension in ADPKD is complex and depends on many factors that influence each other. High expression of PKD1 and PKD2 genes is present in the cilia of tubular epithelial cells, in endothelial cells and in vascular smooth muscle cells. Decreased or absent polycystin-1 or -2 expression is associated with abnormal vascular structure and function. PKD1/PKD2 deficiency results in reduced nitric oxide levels, altered endothelial response to shear stress with attenuation in vascular relaxation. Activation of the renin-angiotensin-aldosterone system occurs in ADPKD due to decreased nitric oxide production as well as bilateral cyst expansion and intra-renal ischemia. With increasing cyst size, further activation of the renin-angiotensin-aldosterone system occurs, blood pressure increases and a vicious cycle ensues with enhanced cyst growth and hypertension ultimately leading to end-stage renal disease. Inhibition of the angiotensin-aldosterone system is possible with angiotensin-converting enzyme inhibitors and seems to be the first-line treatment for hypertension in these subjects. As suggested by the HALT-PKD study, an aggressive blood pressure control is safe and recommended and is associated with preservation of kidney function and a reduction in total kidney volume over time. A collaborative multidisciplinary approach between nephrologists and cardiologists is necessary for the monitoring of kidney and heart complications.
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PMID:[Cardiovascular risk in polycystic kidney disease]. 2641 87