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The kidneys
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
The two main groups of genetically determined renal disease of note are polycystic kidney disease and genetic abnormalities of the glomerular basement membrane. Polycystic kidney disease occurs in two main forms. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of cystic renal disease and one of the most common genetic diseases in the community, affecting approximately 1:500 to 1:1,000 individuals. It accounts for about 10% of patients requiring renal replacement therapy. The disease is genetically heterogeneous and is caused by germline mutation in one of three separate genes: the polycystin 1 gene, which is located on the short arm of chromosome 16 and accounts for 85% of cases; the polycystin 2 gene on the long arm of chromosome 4 (10%–14% of cases); and the third, recently described polycystic kidney disease gene 3 (PKD3) on chromosome 11 is responsible for a minority of cases. These genes regulate the action of the primary cilium and cell polarity. The cysts sometimes cause pain and haematuria but many of the patients with ADPKD remain asymptomatic until adult life. Then there may be a progressive deterioration in renal function, usually during the third or fourth decade, leading to established renal failure, particularly in those with untreated hypertension. The kidneys contain large numbers of cysts and may expand to weigh more than 1 kg (Figure 14.2). The cysts may be several centimetres in diameter and contain serous or blood-stained fluid. Cysts are present throughout the nephron (Figure 14.3).
Renal Medicine
Published in Paul Bentley, Ben Lovell, Memorizing Medicine, 2019
Autosomal dominant type (most common) PKD1 gene, polycystin-1 (80%): cell–cell and cell–matrix membrane receptorPKD2 gene, polycystin-2: Ca2+ channel that interacts with polycystin-1
Structural Determination of the Polycystin-2 Channel by Electron Cryo-Microscopy
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Polycystin-1, encoded by the PKD1 gene, is an 11-membrane-spanning receptor-like protein remarkable for harboring a large extracellular region (>3000 amino acids) that consists of multiple predicted ligand binding and/or adhesive modules.17–19 It has been suggested that polycystin-1 co-assembles with polycystin-2,20–23 forming a receptor/ion channel complex in the primary cilia that contributes to flow and mechanical sensing24 and/or detects and responds to chemical ligands, such as Wnts.25 A conserved amino acid sequence at the very carboxyl end of human polycystin-1 has been identified as a cilia localization signal.26 Besides cilia, plasma membrane, and endoplasmic reticulum (ER) membrane,27,28 the polycystin complex has also been identified in secreted exosomes in urine,29 resembling LOV-1 and PKD-2, two worm polycystin homologues that were also found in exosomes involved in cellular communication.30 Despite extensive efforts by many research groups, it remains incompletely understood how polycystin-1 is activated by ligands and modulated by cellular factors and, once activated, how it regulates downstream effectors and signaling cascades. Nevertheless, polycystin-1 was reported to regulate G-protein signaling,31–38 the Hippo signaling pathway,39 and cellular cAMP levels.40 Polycystin-1 function can also be modulated by direct binding with calmodulin,41 as well as posttranslational modifications such as phosphorylation and palmitoylation.42,43
Renal ciliopathies: promising drug targets and prospects for clinical trials
Published in Expert Opinion on Therapeutic Targets, 2023
Laura Devlin, Praveen Dhondurao Sudhindar, John A. Sayer
Heterozygous mutations in PKD1 and PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2) respectively, account for over 90% of ADPKD patients. PKD1 mutations account for 75–85% of identified mutations, and PKD2 mutations are less common, accounting for 15% of identified mutations and milder phenotypes with KF developing at a later age [41,47]. PC1 and PC2 are located in the primary cilium. PC1 acts as an ion channel and g-protein coupled receptor, and PC2 acts as an ion channel that forms a heteromeric complex with PC1 with fibrocystin, regulating PC1’s localization in kidney epithelia [48,49]. It has traditionally been proposed that the PC1/PC2 complex mediates Ca2+ signaling in the primary cilium, in response to fluid flow; however, more recently, this has been refuted, with the exact pathomechanism unclear [41,45,50,51]. Nevertheless, it is thought that loss or malfunction of PC1/PC2 has implications downstream for multiple pathways, including cAMP, mTOR, EGF, AMPK, and cMyc signaling, which effect orientated cell proliferation [52].
Current and emerging treatment options to prevent renal failure due to autosomal dominant polycystic kidney disease
Published in Expert Opinion on Orphan Drugs, 2020
Gopala K. Rangan, Aarya Raghubanshi, Alissa Chaitarvornkit, Ashley N. Chandra, Robert Gardos, Alexandra Munt, Mark N. Read, Sayanthooran Saravanabavan, Jennifer Q.J. Zhang, Annette T.Y. Wong
PKD1 and PKD2 encode polycystin-1 and polycystin-2 respectively which are members of the transient receptor potential channel protein family [29,43]. Both are membrane proteins and exist as a hetero-oligomeric complex (PKD1:PKD2; 1:3 ratio) on the shaft and basal body of the primary cilia and other subcellular locations (e.g. polycystin-2 is expressed on the endoplasmic reticulum where it acts as a nonselective calcium channel) [44]. The functions of the PKD1/PKD2 complex are not fully clear but evidence to date shows that it is a homeostatic suppressor of multiple signal transduction pathways (TORC1, c-myc-sirtuin, Wnt, Jak-Stat) in response to ciliary bending with fluid flow during quiescence [45]. Intracellular cyclic adenosine monophosphate (cAMP) and calcium are critical intermediate molecules involved in mediating these signaling pathways [45]. Thus, in ADPKD, the reduction of polycystin-1 below a critical threshold produces an abnormal cell characterized by: (i) increased intracellular cAMP and reduced calcium; (ii) an increased utilization of aerobic glycolysis (‘Warburg effect’) [46]; and (iii) increased rate in proliferation, loss of differentiation and a more elastic basement membrane [46].
Design and optimization strategies for the development of new drugs that treat chronic kidney disease
Published in Expert Opinion on Drug Discovery, 2020
Adrián M. Ramos, Beatriz Fernández-Fernández, María Vanessa Pérez-Gómez, Sol María Carriazo Julio, María Dolores Sanchez-Niño, Ana Sanz, Marta Ruiz-Ortega, Alberto Ortiz
ADPKD is the most common inherited kidney disease [27]. Multiple cysts increase the kidney volume, replacing the kidney parenchyma and leading to ESRD by the sixth decade of life [28]. Dysfunction of the polycystin-1/polycystin 2 complex leads to increased intracellular adenosine-3ʹ,5ʹ-cyclic monophosphate (cAMP) levels, which stimulate cyst cell proliferation, and fluid transport into cysts. Cysts disrupt the kidney structure, decreasing the corticomedullary osmotic gradient and the kidney urine concentration capacity, leading to polyuria which drives vasopressin secretion and vasopressin-driven increases in intracellular cAMP. Tolvaptan is a highly selective vasopressin V2 receptor antagonist that in randomized control trials (RCTs) reduced the growth of renal volume by 45% and reduced the slope of loss of eGFR loss by 26% in patients with eGFR >60 ml/min/1.73 m2, and by 35% in patients with eGFR 25–65 ml/min/1.73 m2 [29,30]. According to regulatory agencies, tolvaptan is indicated for patient with CKD G1-G4 [31,32]. Tolvaptan use is limited by the high costs of the medication and adverse effects such as polyuria that may compromise compliance, and idiosyncratic hepatoxicity [30].