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Renal tubular dysgenesis is a clinical disorder that is observed in fetuses and characterized by the absence or poor development of proximal tubules, early onset and persistent oligohydramnios that leads to the Potter sequence, and skull ossification defects. It may be acquired during fetal development or inherited as an autosomal recessive disease. It was shown recently that autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system. This study analyzed the clinical expression of the disease in 29 fetus/neonates from 18 unrelated families and evaluated changes in renal morphology and expression of the renin-angiotensin system. The disease was uniformly severe, with perinatal death in all cases as a result of persistent anuria and hypoxia related to pulmonary hypoplasia. Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments. They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries. Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families. Angiotensinogen and angiotensin-converting enzyme were absent or present in only small amounts in the proximal tubule, in correlation with the severity of tubular abnormalities. No specific changes were detected in angiotensin II receptor expression. The severity and the early onset of the clinical and pathologic expression of the disease underline the major importance of this system in fetal kidney function and development in humans. The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis.

Alport syndrome is an inherited nephropathy characterized by alterations of the glomerular basement membrane because of mutations in type IV collagen genes. COL4A5 mutations, causing X-linked Alport syndrome, frequently result in the loss of the alpha5 chains of type IV collagen in basement membranes. This is associated with the absence of the alpha3(IV) and alpha4(IV) chains and increased amounts of alpha1(IV) and alpha2(IV) in glomerular basement membranes. The mechanisms resulting in such a configuration are still controversial and are of fundamental importance for understanding the pathology of the disease and for considering gene therapy. In this article we studied, for the first time, type IV collagen expression in kidneys from X-linked Alport syndrome patients, using in situ hybridization and immunohistochemistry. We show that, independent of the type of mutation and of the level of COL4A5 transcription, both COL4A3 and COL4A4 genes are actively transcribed in podocytes. Moreover, using immunofluorescence amplification, we were able to demonstrate that the alpha3 chain of type IV collagen was present in the podocytes of all patients. Finally, the alpha1(IV) chain, which accumulates within glomerular basement membranes, was found to be synthesized by mesangial/endothelial cells. These results strongly suggest that, contrary to what has been found in dogs affected with X-linked Alport syndrome, there is no transcriptional co-regulation of COL4A3, COL4A4, and COL4A5 genes in humans, and that the absence of alpha3(IV) to alpha5(IV) in glomerular basement membranes in the patients results from events downstream of transcription, RNA processing, and protein synthesis.

Autosomal-dominant polycystic kidney disease, one of the most frequent human genetic disorders, is genetically heterogeneous. Most cases result from mutations of PKD1 or PKD2 encoding polycystin-1 or polycystin-2, respectively. Polycystin-1 is a large transmembrane protein containing several domains involved in cell-cell and/or cell-matrix interactions. Polycystin-2 is transmembrane glycoprotein sharing homology with some families of cation channels. Despite a large number of reports, the tissue distribution of these two proteins, especially of polycystin-1, is still debated. We investigated the expression pattern of PKD1 and PKD2 transcripts and proteins during human embryogenesis and kidney development, using Northern blot analysis, in situ hybridization, and immunohistochemical methods. For each gene, the expression pattern of transcripts and protein was concordant. In human 5- to 6-week-old embryos, both genes are widely expressed, mainly in neural tissue, cardiomyocytes, endodermal derivatives, and mesonephros. At this age, PKD2 but not PKD1 expression is observed in the ureteric bud and the uninduced metanephros. Thereafter, PKD2 is diffusely expressed at all stages of nephron development, whereas high PKD1 expression first appears in differentiated proximal tubules. Proximal tubule expression of both genes decreases from weeks 20 to 24 onwards. PKD1 transcripts, later restricted to distal tubules in fetal nephrogenesis, are no longer detected in adult kidneys, which nevertheless maintain a faint expression of polycystin-1, whereas persistent expression of PKD2 transcripts and protein is observed throughout nephrogenesis. Overall, contrary to previous observations, we found profound differences in the spatiotemporal expression of PKD1 and PKD2 during nephrogenesis, PKD2 being expressed earlier and more diffusely than PKD1. These data suggest that polycystins could interact with different partners, at least during kidney development.