U.S. Department of Health and Human Services

Kidney Diseases Branch

Jeffrey B. Kopp, M.D., Chief

​Research Images

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In vitro cyst formationA confocal image of mutant cells forming a cyst in vitro is depicted. Cells are stained with fluorescent markers for cell membrane (red) and nucleus (blue). The large image (center) is the surface of the cyst. The two smaller images (top and left) show vertical slices of the cyst cut through the blue and red lines, respectively. Note the empty space in the two smaller images, confirming that the cells form a cyst.In vitro cyst formationEnlarge
Hnf4α is a disease modifier.Network pathway analysis suggests that HNF4 is a node in gene networks of polycystic kidney disease (left). Kidney histology is also depicted and is confirming a modifier effect of Hnf4 in the severity of Pkd1cystogenesis (right). Note the left kidney, in which Pkd1 and Hnf4are deleted, has more and larger cyststhan the kidney in which only Pkd1 was deleted. Hnf4α is a disease modifier.Enlarge
In vitro tube formationThe lab has been generating cell lines that can be used for in vitro analysis of tube versus cyst formation. Cells isolated from Pkd1cond/cond kidney collecting ducts and subsequently immortalized form tubes when grown in collagen matrices.In vitro tube formationEnlarge
Genomics and Metabolomics of Polycystic Kidney Disease.A heatmap plot showing that a subset of differentially expressed genes separates mutant and control kidneys in both pre-cystic (P12) and cystic (P14) kidneys (left) and a Principal Component Plot showing that the pattern of metabolites expressed in the urine of control and cystic animals is different, consistent with our gene array data (right).Genomics and Metabolomics of Polycystic Kidney Disease.Enlarge
Changes in gene networks reflect aging rather than Pkd1 inactivation

Dendogram summarizing correlation structure of Weighted Gene Correlation Network Analysis module eigengenes and corresponding kidney histology. Results suggest that the network structure changes more dramatically with age than with genotype, in contrast to kidney morphology. (Menezes and Germino, WIREs Syst Biol Med 2015. doi: 10.1002/wsbm.1289)

Dendogram summarizing correlation structure of Weighted Gene Correlation Network Analysis module eigengenes and corresponding kidney histology.Enlarge
PodocytesPodocytes surround the glomerular capillaries; their actin-rich foot processes inter-digitate with processes from other podocytes and attach to the glomerular basement membrane. The slit diaphragms between these foot processes prevent passage of large macromolecules from plasma into the urinary space.PodocytesEnlarge
C22 PeakWe set out to find susceptibility genes for focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy, two diseases of the glomerular podocyte that are more common among African Americans. An admixture scan found an excess of African origin genetic segments in individuals with kidney disease compared to controls. The primary genetic variants that account for this admixture peak are coding variants in APOL1, encoding apolipoprotein L1.C22 PeakEnlarge
PCA trajectoriesThe principal component analysis of cDNA microarray data depicted demonstrates that global gene expression patterns are distinct for two different types of acute kidney injury. The trajectories reflect time-dependent divergence from the normal state.PCA trajectoriesEnlarge
Telemetry blood pressureMiniaturized pressure transducers were catheterized into mouse carotid arteries, blood pressure was monitored in conscious, freely moving mice, and data was collected by radiotelemetry. Baseline mean arterial pressure was measured over several days, revealing diurnal variation. Mouse strains C57BL/6, 129S3, and CD-1 exhibit substantial differences in baseline blood pressure.Telemetry blood pressureEnlarge
Microparticles and fibrin deposition in sepsisCalpastatin-overexpressing transgenic mice, which are protected from sepsis-induced microparticle release and mortality, have restored susceptibility to fibrin deposition in liver and lung blood vessels when microparticles are reconstituted.Microparticles and fibrin deposition in sepsisEnlarge
Polyductin undergoes Notch-1 like processingThe laboratory has shown that polyductin, the gene product encoded by the gene (PKHD1) mutated in human ARPKD, undergoes Notch-1 like post-translational processing with regulated shedding of an ectodomain and release of an intracellular C-terminal (Cover, Hum Mol Genet Vol 16, April 2007; Kaimori et al, same issue, pp942-956)Polyductin undergoes Notch-1 like processingEnlarge
Polycystin-1 (PC1) and Polycystin-2 (PC2) form a receptor-channel complex at the cell membraneTop: The lab has previously shown that the PKD1 and PKD2 gene products form a heteromeric complex at the cell membrane. Our group is focused on identifying what the complex senses and how it signals its response. (Qian et al, Nat Genet 16: 179-183, 1997; Hanoaka et al, Nature 408: 990-994, 2000). Bottom: Numerous proteins associated with cystic kidneys (‘‘cystoproteins’’) localize to the primary cilium and basal body complex but are also found in other intracellular compartments. AJ, adherens junction; BB, basal body; Cen, centriole; ER, endoplasmic reticulum; FAP, focal adhesion plaque; TJ, tight junction. (Menezes et al, Methods Cell Biol 94:273-297, 2009).Polycystin-1 (PC1) and Polycystin-2 (PC2) form a receptor-channel complex at the cell membraneEnlarge
Non-canonical Wnt signaling and tubular morphogenesisPlanar cell polarity might be involved in the establishment of normal tubular architecture in several different ways, including directional cell division, preservation of cellular spatial orientation information, and/or convergent extension/directional cell migration. Disruption of any of these processes could potentially result in cyst formation (Germino GG. Nature Genet, 37:455-457, 2005; Menezes et al, Methods Cell Biol 94:273-297, 2009).Non-canonical Wnt signaling and tubular morphogenesisEnlarge
Human cystic kidneyA human cystic kidney removed from an individual with autosomal dominant polycystic kidney disease is depicted. For comparison, a normal adult kidney is approximately the size of a human fist.Human cystic kidneyEnlarge
Normal adult mouse kidneyTop: Normal adult mouse kidney stained with markers that distinguish proximal (green) and distal tubules (red). The image highlights the complex tubular structure of the kidney. (Cover, Nat Med Vol. 13, December 2007; Piontek et al, same issue 1490-1495). Bottom: Immunofluorescent image of a cystic mouse kidney stained for tubular markers.Normal adult mouse kidneyEnlarge