Renal tubule Na,K-ATPase polarity in different animal models of polycystic kidney disease.

Abstract

Apical mislocation of the ubiquitous transport enzyme Na,K-ATPase has been implicated as a feature of cyst development in in vitro studies of human polycystic kidney disease (PKD) epithelia. We undertook an immunohistochemical study of murine glucocorticoid-induced PKD, the pcy mouse, the cpk mouse, and the diphenylthiazole (DPT)-induced rat models of PKD to determine if this feature was common to these models of cyst development. Distribution of Na,K-ATPase was determined with a polyclonal anti-Na,K-ATPase antibody and a nickel-silver-enhanced peroxidase color development system. Results were documented objectively with densitometric techniques. Control animals appropriate to the age, strain, and species of the experimental groups demonstrated the expected polar distribution of Na,K-ATPase to the basolateral surface. This distribution was more marked in mature animals. Tubular dilatation and cystic change, however, were associated with increased apical Na,K-ATPase in all models. The murine models demonstrated decreased basolateral staining for Na,K-ATPase compared with controls, although this was not a feature of the DPT rat model. Abnormal location of Na,K-ATPase is a shared feature of a variety of animal models and human PKD. This may contribute to abnormal fluid and electrolyte flux favoring cyst formation or may represent expression of a less differentiated renal tubule epithelial phenotype.

Motor protein control of ion flux is an early step in embryonic left–right asymmetry

“…(62) Thus, the PCKD LR phenotype suggests that ion flux is a necessary component of LR patterning in mammals and that the primary role of polycystin in LR asymmetry may be by virtue of ion transport and not ciliary action. This possibility is greatly supported by the observations (63)(64)(65) that PCKD cells in both mouse and human exhibit altered electrical polarity (standing long-term cell membrane voltage levels) due to mislocalization of the Na þ /K þ -ATPase protein to the opposite pole of the cell (along the apical-basal axis). Thus, similarly to the situation in chick and frog, recent data in mammals link a LR phenotype to (1) aberrant cell membrane voltage, (2) the P-type cation exchanger (of which the Na þ /K þ -ATPase and H þ /K þ -ATPase are closely-related members), and (3) polarity of ion pump localization along a major cellular axis.…”

Deficiency in Six2 during prenatal development is associated with reduced nephron number, chronic renal failure, and hypertension inBr/+ adult mice

“…Fluid accumulation occurs as a result of aqueous secretion throughout all segments of the nephron while mislocation of Na-K-ATPase to the apical epithelial surface causes secretion of sodium with concomitant water loss (39). It is well-documented that Na-K-ATPase polarity is affected during tubular distension in the genesis of renal cystic lesions (73,96,97). Immunolocalization of Na-K-ATPase in wild-type adult mice showed normal distribution along the tubular basolateral epithelium; however, distended tubules in Br/ϩ mutants showed intense staining throughout the epithelium.…”

Defining a Link with Autosomal-Dominant Polycystic Kidney Disease in Mice with Congenitally Low Expression of Pkd1

“…45 This in turn is associated with basal-to-apical sodium ion transport leading to luminal fluid accumulation. Although apical mislocalization of the Na ϩ /K ϩ -ATPase has been reported in several different models of polycystic kidney disease, 46 it has not been universally accepted as the principal mechanism underlying either fluid secretion or cyst expansion in ADPKD. Immunocytochemical analysis of renal cysts with antibodies directed against Na ϩ /K ϩ -ATPase failed to detect evidence of apical mislocalization.…”