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 ...