Polycystic kidney disease (PKD) is the fourth most common cause of end-stage renal disease and the most common potentially lethal inherited disease in humans. Early identification of carriers of dominant PKD in the absence of genetic markers is problematic in both humans and the Han:SPRD-cy/+ rat, a model of PKD that shares many features of human disease. We undertook a proton magnetic resonance imaging (MRI) study of young Han:SPRD-cy/+ and unaffected Han:SPRD(-)+/+ animals to determine whether carrier status could be identified based upon image appearance or signal characteristics. Affected animals demonstrated significant prolongation of longitudinal relaxation time (T1) and transverse relaxation time (T2) in both cystic renal cortex and noncystic renal medulla. Both of these measurements correlated significantly with whole kidney section tubular luminal space measurements, a correlate of water space, in the renal cortex, but only T1 in renal medulla showed a relationship to tubular luminal volume measured throughout the kidney. Urine and perchloric acid kidney extracts were studied using proton nuclear magnetic resonance (1H-NMR) spectroscopy to test the hypothesis that imaging differences implied specific urinary and tissue biochemical differences between affected and normal animals. 1H-NMR spectra of urine from cy/+ animals showed significantly increased excretion of alanine, citrate, succinate, and, 2-oxoglutarate but not methylamine compounds compared with +/+ animals. 1H-NMR spectra of aqueous perchloric acid kidney extracts confirmed reduced concentrations of the above ions and others involved in the citric acid cycle, as well the osmolytes betaine, taurine, and glycerophosphocholine PKD in the Han:SPRD-cy/+ rat is associated with distinct early MRI changes and alterations in urinary and tissue levels of organic anions and osmolytes.
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.
Cyst formation in polycystic kidney disease (PKD) involves proliferation of cyst lining epithelial and changes in trans-epithelial fluid and electrolyte transport. In vitro studies have suggested that mislocation of Na,K-ATPase to the apical tubular surface may be an important component of cyst fluid transport. We undertook in vivo studies of Na,K-ATPase location using the "threshold" murine model of glucocorticoid-induced PKD (GIPKD). Using histological, immunohistochemical, and densitometric techniques, we compared cyst formation and the cellular location of Na,K-ATPase in suckling C3H (low threshold for GIPKD) and DBA (high threshold) mice given an inducing dose of 200 mg/kg methylprednisolone acetate. As expected, C3H mice demonstrated greater cyst formation as measured by proportion of section area occupied by the tubule lumen (26.7% vs 15.5%; p < 0.001). Cyst formation was associated with increased Na,K-ATPase staining and increased apical Na,K-ATPase location. MPA treatment in C3H mice resulted in apical staining that exceeded basolateral staining (35.3% of reference window vs 29.8%; p < 0.001). The relatively GIPKD-resistant DBA mice did not show such change in Na,K-ATPase location. These immunohistochemical studies suggest a role for Na,K-ATPase in renal cyst formation.
Cystic change in polycystic kidney disease (PKD) is associated with epithelial hyperplasia, altered fluid and electrolyte transport, and de-differentiation of renal tubular epithelium. The role of polypeptide growth factors as potential modulators of cystic change remains an area of controversy. In this study, the expression of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) were assessed by immunohistochemistry and image analysis in glucocorticoid-induced PKD in the newborn mouse. Newborn C3H mice received either 200 mg/kg methylprednisolone acetate (MPA) or 0.9% saline as a control. EGF expression was not detected in significant quantities in either MPA-treated or control animals. TGF alpha, however, was expressed in immature control kidney in a largely basolateral distribution. Expression increased significantly in association with cystic change in MPA-treated animals and was localized to the apical cell surface, implying altered polarity of secretion. There is no evidence that EGF is a mitogen in this early developmental model of PKD. TGF alpha, however, may be an important mediator of cystic change in immature or de-differentiated renal tubular epithelium.
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