Cardiovascular disease begins early in the course of renal decline and is a life-limiting problem in patients with CKD. The increased burden of cardiovascular disease is due, at least in part, to calcification of the vessel wall. The uremic milieu provides a perfect storm of risk factors for accelerated calcification, but elevated calcium and phosphate levels remain key to the initiation and progression of vascular smooth muscle cell calcification in CKD. Vascular calcification is a highly regulated process that involves a complex interplay between promoters and inhibitors of calcification and has many similarities to bone ossification. Here, we discuss current understanding of the process of vascular calcification, focusing specifically on the discrete and synergistic effects of calcium and phosphate in mediating vascular smooth muscle cell apoptosis, osteochondrocytic differentiation, vesicle release, calcification inhibitor expression, senescence, and death. Using our model of intact human vessels, factors initiating vascular calcification in vivo and the role of calcium and phosphate in driving accelerated calcification ex vivo are described. This work allows us to link clinical and basic research into a working theoretical model to explain the pathway of development of vascular calcification in CKD.
Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and hypomagnesemia. We retrospectively reviewed radiographic and laboratory data for all patients from a single center who had been screened for an HNF1B mutation. We found heterozygous mutations in 21 (23%) of 91 cases of renal malformation. All mutation carriers had abnormal fetal renal ultrasonography. Plasma magnesium levels were available for 66 patients with chronic kidney disease (stages 1 to 3). Striking, 44% (eight of 18) of mutation carriers had hypomagnesemia (Ͻ1.58 mg/dl) compared with 2% (one of 48) of those without mutations (P Ͻ 0.0001). The median plasma magnesium was significantly lower among mutation carriers than those without mutations (1.68 versus 2.02 mg/dl; P Ͻ 0.0001). Because hypermagnesuria and hypocalciuria accompanied the hypomagnesemia, we analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. These results extend the phenotype of HNF1B mutations to include hypomagnesemia. HNF1B regulates transcription of FXYD2, which participates in the tubular handling of Mg 2ϩ , thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.
Diabetes mellitus (DM) is the major cause of end-stage renal disease (ESRD) globally, and novel treatments are urgently needed. Current therapeutic approaches for diabetic nephropathy (DN) are focussing on blood pressure control with inhibitors of the renin-angiotensin-aldosterone system, on glycaemic and lipid control, and life-style changes. In this review, we highlight new molecular insights aiding our understanding of the initiation and progression of DN, including glomerular insulin resistance, dysregulation of cellular substrate utilisation, podocyte-endothelial communication, and inhibition of tubular sodium coupled glucose reabsorption. We believe that these mechanisms offer new therapeutic targets that can be exploited to develop important renoprotective treatments for DN over the next decade.
Ureteric contractions propel foetal urine from the kidney to the urinary bladder. Here, we show that mouse ureteric smooth muscle cell (SMC) precursors express the transcription factor teashirt 3 (TSHZ3), and that Tshz3-null mutant mice have congenital hydronephrosis without anatomical obstruction. Ex vivo, the spontaneous contractions that occurred in proximal segments of wildtype embryonic ureter explants were absent in Tshz3 mutant ureters. In vivo, prior to the onset of hydronephrosis, mutant proximal ureters failed to express contractile SMC markers, whereas these molecules were detected in controls. Mutant embryonic ureters expressed Shh and Bmp4 transcripts as normal, with appropriate expression of Ptch1 and pSMAD1/5/8 in target SM precursors, whereas myocardin, a key regulator for SMC differentiation, was not expressed in Tshz3-null ureters. In wild-type embryonic renal tract explants, exogenous BMP4 upregulated Tshz3 and myocardin expression. More interestingly, in Tshz3 mutant renal tract explants, exogenous BMP4 did not improve the Tshz3 phenotype. Thus, Tshz3 is required for proximal ureteric SMC differentiation downstream of SHH and BMP4. Furthermore, the Tshz3 mutant mouse model of 'functional' urinary obstruction resembles congenital pelvi-ureteric junction obstruction, a common human malformation, suggesting that TSHZ, or related, gene variants may contribute to this disorder.
The planar cell polarity (PCP) pathway, incorporating non-canonical Wnt signalling, controls embryonic convergent (CE) extension, polarized cell division and ciliary orientation. It also limits diameters of differentiating renal tubules, with mutation of certain components of the pathway causing cystic kidneys. Mutations in mouse Vangl genes encoding core PCP proteins cause neural tube defects (NTDs) and Vangl2 mutations also impair branching of embryonic mouse lung airways. Embryonic metanephric kidneys also undergo branching morphogenesis and Vangl2 is known to be expressed in ureteric bud/collecting duct and metanephric mesenchymal/nephron lineages. These observations led us to investigate metanephroi in Vangl2 mutant mice, Loop-tail (Lp). Although ureteric bud formation is normal in Vangl2Lp/Lp embryos, subsequent in vivo and in vitro branching morphogenesis is impaired. Null mutant kidneys are short, consistent with a CE defect. Differentiating glomerular epithelia express several PCP genes (Vangl1/2, Celsr1, Scrib, Mpk1/2 and Fat4) and glomeruli in Vangl2Lp/Lp fetuses are smaller and contain less prominent capillary loops than wild-type littermates. Furthermore, Vangl2Lp/+ kidneys had modest reduction in glomerular numbers postnatally. Vangl2Lp/Lp metanephroi contained occasional dilated tubules but no overt cystic phenotype. These data show for the first time that a PCP gene is required for normal morphogenesis of both the ureteric bud and metanephric mesenchyme-derived structures. It has long been recognized that certain individuals with NTDs are born with malformed kidneys, and recent studies have discovered VANGL mutations in some NTD patients. On the basis of our mutant mouse study, we suggest that PCP pathway mutations should be sought when NTD and renal malformation co-exist.
Angiopoietin-2 (Ang-2) modulates embryonic vascular differentiation primarily by inhibiting the antiapoptotic effects of Ang-1 on endothelia that express the Tie-2 receptor. Ang-2 is transiently expressed by developing glomeruli but is downregulated with normal maturation. Glomerular Ang-2 expression is, however, markedly upregulated in animal models of diabetic nephropathy and glomerulonephritis, both leading causes of human chronic renal disease, affecting 10% of the world population. It was hypothesized that Ang-2 might have significant roles in the pathobiology of glomerular disease. Mice with inducible podocyte-specific Ang-2 overexpression were generated. When the transgene was induced in adults for up to 10 wk, mice had significant increases in both albuminuria and glomerular endothelial apoptosis, with significant decreases of both vascular endothelial growth factor-A and nephrin proteins, critical for maintenance of glomerular endothelia and filtration barrier functional integrity, respectively. There was, however, no significant change of systemic BP, creatinine clearance, or markers of renal fibrosis, and podocytes appeared structurally intact. In kidneys of young animals in which Ang-2 had been upregulated during organogenesis, increased apoptosis occurred in just-formed glomeruli. In vitro, short-term exposure of isolated wild-type murine glomeruli to exogenous Ang-2 led to decreased levels of vascular endothelial growth factor-A protein. These novel results provide insight into molecular mechanisms underlying proteinuric disorders, highlight potentially complex interactions between subsets of glomerular cells, and emphasize how a vascular growth factor that has critical roles in normal development may be harmful when re-expressed in the context of adult disease.
Although the response of kidneys acutely damaged by ischemia or toxins is dominated by epithelial destruction and regeneration, other studies have begun to define abnormalities in the cell biology of the renal microcirculation, especially with regard to peritubular capillaries. We explored the integrity of peritubular capillaries in relation to expression of vascular endothelial growth factor (VEGF)-A, hypoxia-inducible factor (HIF)-alpha proteins, and von Hippel-Lindau protein (pVHL) in mouse folic acid nephropathy, a model in which acute tubular damage is followed by partial regeneration and progression to patchy chronic histological damage. Throughout a period of 14 days, in areas of cortical tubular atrophy and interstitial fibrosis, loss of VEGFR-2 and platelet endothelial cell adhesion molecule-expressing peritubular capillaries was preceded by marked decreases in VEGF-A transcript and protein levels. Nephrotoxicity was associated with tissue hypoxia, especially in regenerating tubules, as assessed by an established in situ method. Despite the hypoxia, levels of HIF-1 alpha, a protein known to up-regulate VEGF-A, were reduced. During the course of nephrotoxicity, levels of pVHL, a factor that destabilizes HIF-1 alpha, increased significantly. We speculate that that down-regulation of VEGF-A may be functionally-implicated in the progressive attrition of peritubular capillaries in areas of tubular atrophy and interstitial fibrosis; VEGF-A down-regulation correlates with a loss of HIF-1 alpha expression which itself occurs in the face of increased tissue hypoxia.
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