Altered Expression Pattern of Polycystin-2 in Acute and Chronic Renal Tubular Diseases

Abstract

Abstract. Polycystin-2 represents one of so far two proteins found to be mutated in patients with autosomal-dominant polycystic kidney disease. Evidence obtained from experiments carried out in cell lines and with native kidney tissue strongly suggests that polycystin-2 is located in the endoplasmic reticulum. In the kidney, polycystin-2 is highly expressed in cells of the distal and connecting tubules, where it is located in the basal compartment. It is not known whether the expression of polycystin-2 in the kidney changes or whether it can be manipulated under certain instances. Therefore, the distribution of polycystin-2 under conditions leading to acute and chronic renal failure was analyzed. During ischemic acute renal failure, which affects primarily the S3 segment of the proximal tubule, a pronounced upregulation of polycystin-2 and a predominantly combined homogeneous and punctate cytoplasmic distribution in damaged cells was observed. After thallium-induced acute injury to thick ascending limb cells, polycystin-2 staining assumed a chicken wire-like pattern in damaged cells. In the (cy/ϩ) rat, a model for autosomal-dominant polycystic kidney disease in which cysts originate predominantly from the proximal tubule, polycystin-2 immunoreactivity was lost in some distal tubules. In kidneys from (pcy/pcy) mice, a model for autosomal-recessive polycystic kidney disease in which cyst formation primarily affects distal tubules and collecting ducts, a minor portion of cyst-lining cells cease to express polycystin-2, whereas in the remaining cells, polycystin-2 is retained in their basal compartment. Data show that the expression and cellular distribution of polycystin-2 in different kinds of renal injuries depends on the type of damage and on the nephron-specific response to the injury. After ischemia, polycystin-2 may be upregulated by the injured cells to protect themselves. It is unlikely that polycystin-2 plays a role in cyst formation in the (cy/ϩ) rat and in the (pcy/pcy) mouse.Autosomal-dominant polycystic kidney disease (ADPKD) has an approximate prevalence of 1:1000 (1,2) and accounts for 8 to 10% of all cases of end-stage renal disease in Western countries (3-7). Although this hereditary disorder affects primarily the kidney, additional extrarenal manifestations emphasize the systemic character of the disease. As a result of major efforts over the last few years, the two most frequently mutated genes in ADPKD, PKD1 (8) and PKD2 (9), have been identified. Mutations in the PKD1 gene are responsible for approximately 85% of all ADPKD cases, whereas the majority of the remaining patients experience mutations in the PKD2 gene (10 -13). A very small group of ADPKD patients possibly carry mutations in genes that are as yet unidentified (14 -17). Although there is a high degree of similarity with respect to the spectrum of renal and extrarenal disease manifestations between the two forms, patients with PKD2 mutations have a milder phenotype and a delayed onset compared with patients with mutations in the PKD1 ...

Filamin-A Increases the Stability and Plasma Membrane Expression of Polycystin-2

“…Immunohistochemistry studies using staged mouse embryos indicated that PC2 expression is developmentally regulated and that this regulation is important for embryo development [ 47 ]. In adult mice, PC2 was also reported to be markedly up-regulated by renal ischaemic injury [ 48 – 50 ], indicating the importance of PC2 for the recovery from ischaemia. Studies of PC2-dependent ADPKD in mouse model also showed that both PC2 knock-out and knock-in mice develop typical renal cysts and an increase in cell proliferation and apoptosis, which are reflective of human ADPKD phenotypes [ 14 , 15 ].…”

Pathways to Recovery and Loss of Nephrons in Anti-Thy-1 Nephritis

“…The rats from group 1 were sacrificed by whole body perfusion (see below) 2 wk after disease induction, the rats from group 2 after 5 wk, and those from group 3 after 10 wk. Twenty-four-hour urine collections were performed on day 10 (all animals), day 30 (animals from groups 2 and 3), and day 65 (rats from group 3); the excretion of total protein (Coomassie) and albumin (ELISA) was recorded as described previously (6).…”

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

“…22 PKD1-haploinsufficient kidney cells, therefore, might be unable to achieve the required PC1 activity level when exposed to IR. Although studies on the ischemia/ PC2 relation have brought some potential contributions to this question, 23,24 the relationship between PC1 and IR is basically unknown. By coordinating cell planar polarity in renal tubules, PC1 might exert a protective effect after an ischemic insult.…”