The pathogenesis of polycystic kidney disease

Polycystic kidney disease (PKD) is a genetic or acquired disorder characterized by progressive distention of multiple tubular segments and manifested by fluid accumulation, growth of non-neoplastic epithelial cells and remodeling of the extracellular matrix resulting ultimately in some degree of renal functional impairment, with the potential for regression following removal of the inductive agent(s). It is due to an aberration of one or more factors regulating tubular morphogenesis. Human PKD can pursue a rapid course with renal failure occurring perinatally (infantile PKD) or an indolent course without renal failure developing during the life of the individual (adult PKD). Human acquired PKD develops in atrophic and scarred end-stage kidneys with non-cystic forms of renal disease. Cell proliferation, fluid secretion, impaired cell-cell and cell-matrix interaction, defective function of the Golgi apparatus, cell undifferentiation, and an abnormal matrix have been implicated in the pathogenesis of PKD based on clinical and experimental studies. Under normal conditions, the dynamic turnover of tubular epithelia and matrices are tightly regulated to maintain tubular morphology. The basic defect in PKD is tubular dysmorphogenesis. Our finding indicates that the principal phenotypic features of autosomal dominant PKD (ADPKD) are altered structure and function of the Golgi complex, altered structure and composition of the matrix and cell undifferentiation, al1 of which are probably interrelated. If the gene product of the ADPKD 1 gene results in a defective matrix, the abnormal Golgi function and cell differentiation may be due to faulty matrix-cell communication

Knockout of aminopeptidase A in mice causes functional alterations and morphological glomerular basement membrane changes in the kidneys

Aminopeptidase A is one of the most potent enzymes within the renin-angiotensin system in terms of angiotensin II degradation. Here, we examined whether there is a kidney phenotype and any compensatory changes in other renin angiotensin system enzymes involved in the metabolism of angiotensin II associated with aminopeptidase A deficiency. Kidneys harvested from aminopeptidase A knockout mice were examined by light and electron microscopy, immunohistochemistry and immunofluorescence. Kidney angiotensin II levels and the ability of renin angiotensin system enzymes in the glomerulus to degrade angiotensin II ex vivo, their activities, protein and mRNA levels in kidney lysates were evaluated. Knockout mice had increased blood pressure and mild glomerular mesangial expansion without significant albuminuria. By electron microscopy, knockout mice exhibited a mild increase of the mesangial matrix, moderate thickening of the glomerular basement membrane but a striking appearance of knob-like structures. These knobs were seen in both male and female mice and persisted after the treatment of hypertension. In isolated glomeruli from knockout mice, the level of angiotensin II was more than three-fold higher as compared to wild type control mice. In kidney lysates from knockout mice angiotensin converting enzyme activity, protein and mRNA levels were markedly decreased possibly as a compensatory mechanism to reduce angiotensin II formation. Thus, our findings support a role for aminopeptidase A in the maintenance of glomerular structure and intra-kidney homeostasis of angiotensin peptides