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Altered expression pattern of polycystin-2 in acute and chronic renal tubular diseases
Nicholas Obermüller1, Yiqiang Cai, Bettina Kränzlin
1Medical Research Center, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany.
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/+) 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/+) rat and in the (pcy/pcy) mouse.
Insights
Polycystin-2 expression changes in kidney injury, with upregulation during ischemia potentially aiding cell protection. Its role in cyst formation in polycystic kidney disease models appears unlikely.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Medicine
Background:
- Polycystin-2 (PC2) is implicated in autosomal-dominant polycystic kidney disease (ADPKD).
- PC2 is primarily localized to the endoplasmic reticulum and basal compartment of kidney tubule cells.
- The dynamic expression of PC2 in response to renal injury is not well understood.
Purpose of the Study:
- To investigate the expression and cellular distribution of polycystin-2 in various models of acute and chronic kidney injury.
- To determine if polycystin-2 expression changes in response to renal failure.
- To assess the potential role of polycystin-2 in cystogenesis in polycystic kidney disease.
Main Methods:
- Immunohistochemical analysis of polycystin-2 distribution in rat and mouse kidney tissues.
- Examination of kidneys from models of ischemic acute renal failure, thallium-induced injury, autosomal-dominant polycystic kidney disease ((cy/+) rat), and autosomal-recessive polycystic kidney disease ((pcy/pcy) mouse).
Main Results:
- Ischemic acute renal failure showed pronounced polycystin-2 upregulation with cytoplasmic distribution in damaged proximal tubule cells.
- Thallium injury to thick ascending limb cells resulted in a "chicken wire-like" polycystin-2 pattern.
- In ADPKD models, polycystin-2 immunoreactivity was altered, with some distal tubule cells losing expression or showing basal retention, but its role in cyst formation was deemed unlikely.
Conclusions:
- Polycystin-2 expression and distribution are nephron-specific and injury-dependent.
- Upregulation of polycystin-2 following ischemia may represent a protective cellular response.
- Polycystin-2 does not appear to be a primary driver of cyst formation in the studied polycystic kidney disease models.