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Taiji Matsusaka

Publications and source records attributed to Taiji Matsusaka.

13 recordsLinked to original sources
PubMed2006

HIV-1 genes vpr and nef synergistically damage podocytes, leading to glomerulosclerosis.

This study aimed to identify the causative gene for HIV-1 associated nephropathy, a paradigmatic podocytopathy. A previous study demonstrated that transgenic expression of nonstructural HIV-1 genes selectively in podocytes in mice with FVB/N genetic background resulted in podocyte injury and glomerulosclerosis. In this study, transgenic mice that expressed individual HIV-1 genes in podocytes were generated. Five of six transgenic mice that expressed vpr developed podocyte damage and glomerulosclerosis. Analysis of an established vpr transgenic line revealed that transgenic mice on FVB/N but not on C57BL/6 genetic background developed podocyte injury by 8 wk of age, with later glomerulosclerosis. Four of 11 transgenic mice that expressed nef also developed podocyte injury. One transgenic line was established from the nef founder mouse with the mildest phenotype. Transgenic mice in this line developed mesangial expansion at 3 wk of age and mild focal podocyte damage at 10 wk of age. Mating with FVB/N mice did not augment nephropathy. None of the transgenic mice that expressed vif, tat, rev, or vpu in podocytes, even with the FVB/N genetic background, developed podocyte injury. For testing effects of simultaneous expression of vpr and nef, these two lines were mated. All nef:vpr double-transgenic mice showed severe podocyte injury and glomerulosclerosis by 4 wk of age. In contrast, all vpr or nef single-transgenic mice in the same litter uniformly showed no or much milder podocyte injury. These findings indicate that vpr and nef each can induce podocyte injury with a prominent synergistic interaction.

AIDS-Associated Nephropathy↗
PubMed2005

Inhibition of endogenous BMP in the glomerulus leads to mesangial matrix expansion.

Bone morphogenetic protein7 (BMP7) attenuates renal tubular and interstitial damage in a variety of experimental models. The function of BMP in the glomerulus is, however, not well understood. In the present study, we generated transgenic mice carrying cDNA for noggin, an endogenous inhibitor of BMPs, driven by the podocyte-specific promoter nephrin. Transgenic founder mice could be divided into two groups based on gross histological analyses at 2 months of age. One group was characterized by the presence of cystic glomeruli with collapsed capillary tufts and a decrease in mesangial cell number, representing a developmental defect during glomerular morphogenesis ("cystic" Tg mice). In contrast, the kidneys appeared to be normal in the other group ("non-cystic" Tg mice). In both groups, however, massive mesangial expansion developed at 10 months of age. The lesion was characterized by the accumulation of fibronectin, but not type I collagen, type IV collagen or laminin. This phenotype is similar to the fibronectin nephropathy. These results suggest that endogenous BMP can have an important role in regulating glomerular structural homeostasis.

Animals↗
PubMed2005

Permanent genetic tagging of podocytes: fate of injured podocytes in a mouse model of glomerular sclerosis.

Injured podocytes lose differentiation markers. Therefore, the true identity of severely injured podocytes remains unverified. A transgenic mouse model equipped with a podocyte-selective injury induction system was established. After induction of podocyte injury, mice rapidly developed glomerulosclerosis, with downregulation of podocyte marker proteins. Proliferating epithelial cells accumulated within Bowman's space, as seen in collapsing glomerulosclerosis. In this study, the fate of injured podocytes was pursued. Utilizing Cre-loxP recombination, the podocyte lineage was genetically labeled with lacZ in an irreversible manner. After podocyte injury, the number of lacZ-labeled cells, which were often negative for synaptopodin, progressively declined, correlating with glomerular damage. Parietal epithelial cells, but not lacZ-labeled podocytes, avidly proliferated. The cells proliferating within Bowman's capsule and, occasionally, on the outer surface of the glomerular basement membrane were lacZ-negative. Thus, when podocytes are severely injured, proliferating parietal epithelial cells migrate onto the visceral site, thereby mimicking proliferating podocytes.

Animals↗
PubMed2005

Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury.

This study aimed to generate a mouse model of acquired glomerular sclerosis. A model system that allows induction of podocyte injury in a manner in which onset and severity can be controlled was designed. A transgenic mouse strain (NEP25) that expresses human CD25 selectively in podocytes was first generated. Injection of anti-Tac (Fv)-PE38 (LMB2), an immunotoxin with specific binding to human CD25, induced progressive nonselective proteinuria, ascites, and edema in NEP25 mice. Podocytes showed foot process effacement, vacuolar degeneration, detachment and downregulation of synaptopodin, WT-1, nephrin, and podocalyxin. Mesangial cells showed matrix expansion, increased collagen, mesangiolysis, and, later, sclerosis. Parietal epithelial cells showed vacuolar degeneration and proliferation, whereas endothelial cells were swollen. The severity of the glomerular injury was LMB2 dose dependent. With 1.25 ng/g body wt or more, NEP25 mice developed progressive glomerular damage and died within 2 wk. With 0.625 ng/g body wt of LMB2, NEP25 mice survived >4 wk and developed focal segmental glomerular sclerosis. Thus, the study has established a mouse model of acquired progressive glomerular sclerosis in which onset and severity can be preprogrammed by experimental maneuvers.

Animals↗
PubMed2005

Podocyte damage damages podocytes: autonomous vicious cycle that drives local spread of glomerular sclerosis.

PURPOSE OF REVIEW: For some time, the so-called vicious cycle has been believed to underlie progression of glomerular sclerosis. This mechanism describes a circumstance when loss of some glomeruli imposes injurious stress on the remnant glomeruli. Evidence from recent genetic approaches, however, has prompted revision of this classical view and now points toward a new direction of investigations. RECENT FINDINGS: Whereas experimental maneuvers that selectively injure mesangial cells have failed to induce glomerular sclerosis, genetic approaches that target visceral epithelial cells, or podocytes, in embryos and adult animals regularly produce glomerular sclerosis. Association between podocyte damage and glomerular sclerosis observed in many human diseases and animal models have identified podocyte injury as a common, if not universal, trigger leading to glomerular sclerosis. The process from podocyte injury to sclerosis is remarkably rapid, and the rate of progression depends upon the degree of initial podocyte injury. A single brief injurious stimulus on a podocyte activates a 'domino effect', whereby progressive damage of the initially hit podocyte spreads to involve cells that escaped the initial insult. SUMMARY: The mouse, a species highly useful for studying the function of specific gene products, is notoriously resistant to development of glomerular sclerosis in adulthood. However, recent genetic engineering in this species has overcome this disadvantage and brought about a new dimension to our understanding of the mechanisms involved in progressive glomerular sclerosis.

Animals↗
PubMed2005

Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy.

BACKGROUND: Human immunodeficiency virus (HIV)-1-associated nephropathy (HIVAN) is characterized by collapsing focal and segmental glomerulosclerosis (FSGS) and microcystic tubular dilatation. HIV-1 infection is also associated with other forms of nephropathy, including mesangial hyperplasia. Since HIV-1 gene products are detected in podocytes and other renal cells, it remains uncertain whether podocyte-restricted HIV-1 gene expression can account for the full spectrum of renal lesions involving nonpodocytes. METHODS: To define the role of podocyte-restricted HIV-1 gene expression in the progression of HIVAN, we generated transgenic mice that express nonstructural HIV-1 genes selectively in podocytes. RESULTS: Four of the seven founder mice developed proteinuria and nephropathy. In a subsequently established transgenic line, reverse transcription-polymerase chain reaction (RT-PCR) analysis detected mRNAs for vif, vpr, nef, and spliced forms of tat and rev, but not vpu, in the kidney. In situ hybridization localized HIV-1 RNA to the podocyte. Transgenic mice on FVB/N genetic background exhibited cuboidal morphology of podocytes with reduced extension of primary and foot processes at 2 weeks of age. After 3 weeks of age, these mice developed massive and nonselective proteinuria with damage of podocytes and other glomerular cells and, after 4 weeks of age, collapsing FSGS and microcystic tubular dilatation. In marked contrast, transgenic mice with C57BL/6 genetic background showed either normal renal histology or only mild mesangial expansion without overt podocyte damage. CONCLUSION: The present study demonstrates that podocyte-restricted expression of HIV-1 gene products is sufficient for the development of collapsing glomerulosclerosis in the setting of susceptible genetic background.

AIDS-Associated Nephropathy↗
PubMed2005

Rapid downregulation of beta-actin-based CAG promoter and filamentous actin in injured podocytes.

Glomerular visceral epithelial cells or podocytes are located on the outer surface of the glomerular basement membrane and play an indispensable role as a filtration barrier. The core cytoskeleton of the foot processes is actin filaments, which play an important role in maintaining the unique structure of podocytes. We previously established a transgenic mouse line (NEP25), which expresses human (h)CD25 selectively on podocytes. By injecting an hCD25-targeted recombinant immunotoxin (LMB2), podocyte injury can be induced on demand. After LMB2 injection, NEP25 mice develop nephrotic syndrome with downregulation of podocyte-specific proteins. In the present study, we genetically labeled podocytes with lacZ linked with beta-actin-based CAG promoter. Utilizing the Cre-loxP system, this labeling was confined to the podocyte lineage. Without LMB2, all podocytes were positive for lacZ. After LMB2 injection, lacZ expression was rapidly downregulated, before podocytes showed any discernible morphological changes. Confocal imaging of filamentous (F)-actin-binding Alexa 488-phalloidin revealed that the normal continuous pattern of F-actin distribution in podocytes was punctuated after LMB2 injection. These collectively suggest that disturbance of actin filaments may be one of the key initial events leading to subsequent podocyte damage.

Actin Cytoskeleton↗
PubMed2004

Suppression of cyclosporine a nephrotoxicity in vivo by transforming growth factor beta receptor-immunoglobulin G chimeric protein.

BACKGROUND: Transforming growth factor (TGF)beta is implicated in the pathogenesis of cyclosporine A (CsA) nephrotoxicity. We examined the efficacy of TGF beta receptor (R)II/immunoglobulin (Ig)G Fc, a soluble chimeric protein consisting of the extracellular domain of human TGF beta RII and IgG1 Fc, on CsA nephrotoxicity in mice. METHODS: Subcutaneous injection of CsA (25 mg/kg/d) was given daily to mice maintained on a low-sodium diet. On days 1 and 7, an expression vector carrying cDNA for either TGF beta RII/IgG Fc or beta-galactosidase was transfected into the skeletal muscles by electroporation. At 2 or 3 weeks of CsA administration, plasma and renal TGF beta 1 levels, and tubulointerstitial injury and fibrosis were evaluated. RESULTS: After 2 weeks of CsA administration, plasma and renal TGF beta 1 levels increased to the maximum and then declined toward the baseline levels. Renal TGF beta 1 mRNA remained elevated until 3 weeks. Tubulointerstitial alterations became appreciable in 2 weeks and intensified by 3 weeks. At 2 weeks, the TGF beta RII/IgG Fc intervention abolished the increase in plasma TGF beta 1, attenuated the increase in renal TGF beta 1 by 50%, and markedly suppressed the histologic alterations. At 3 weeks, the histologic alterations remained markedly suppressed by the intervention, with no appreciable effects on the renal TGF beta 1 mRNA and protein. CONCLUSION: The introduction of TGF beta RII/IgG Fc by gene transfer effectively abrogated CsA-induced tubulointerstitial alterations. Suppression of tubulointerstitial changes was evident at 3 weeks when renal TGF beta 1 mRNA and protein were comparable to those with CsA alone, indicating that early anti-TGF beta intervention is effective in suppressing the progression of CsA nephrotoxicity despite persistent increases in renal TGF beta 1 expression.

Animals↗
PubMed2004

Local actions of endogenous angiotensin II in injured glomeruli.

A previous study showed that exogenous angiotensin II (AngII) induces proliferation of glomerular cells through systemic actions of AngII. In the present study, the authors examined the mode of actions of endogenous AngII in injured kidneys that were made deficient in AT1 by using in vivo transfection of antisense oligodeoxynucleotide (AS-ODN). Thy-1 nephritis was induced in rats by injection of mAb 1-22-3. Four days later, glomerular transfection was performed by unilateral whole-kidney electroporation after AT1 AS-ODN delivery through the left renal artery (n = 7). The expression of renal AT1 was assessed by autoradiography. The effect of the AS-ODN transfection was assessed 3 d later and compared with transfection with control ODN (n = 6), systemically administered pharmacologic AT1 antagonist losartan (n = 5) as well as untreated Thy-1 animals (n = 5). Fluorescence-labeled AS-ODN was found transfected in almost all glomeruli and localized primarily to the mesangium. Compared with the contralateral untransfected kidney in both normal and Thy-1 rats, AS-ODN suppressed cortical AT1 expression by some 70%. The AS-ODN transfected kidneys of Thy-1 rats had significantly lower glomerular mesangial cell proliferation (7.38 +/- 0.68 cells/glomerulus) and extracellular matrix accumulation (0.262 +/- 0.009) than kidneys transfected with control ODN (10.94 +/- 0.51 cells/glomerulus and 0.342 +/- 0.031), contralateral untransfected kidneys (9.56 +/- 1.01 cells/glomerulus and 0.371 +/- 0.011), or kidneys that were exposed to Thy-1 alone (10.45 +/- 1.06 cells/glomerulus and 0.359 +/- 0.013). There were no significant differences in systolic BP among groups. In glomeruli, immunohistochemistry detected no difference in AT2 receptor expression, number of ED1-positive macrophages or number of apoptotic cells among groups. Thus, in renal injury induced by Thy-1 nephritis, selective suppression of mesangial AT1 expression by AS-ODN significantly reduced mesangial cell proliferation and matrix. These data provide in vivo evidence that injured glomeruli are sensitive to local tissue actions of AngII, which promote proliferation and matrix accumulation within the glomerulus.

Angiotensin II↗
PubMed2004

[Podocyte injury and glomerular sclerosis].

Recently, our understanding of podocytes has been greatly advanced by genetic analysis of human kidney diseases and corresponding animal models, establishment of podocyte cell lines, and discovery of podocyte specific promoters that facilitate transgenic research. Accumulating data indicate that podocyte injury initiates the process of the disease progression to glomerular sclerosis, a hallmark of chronic renal failure. In the progression to glomerular sclerosis, damages that initially affect only podocytes propagate to mesangial cells, glomerular endothelial cells and parietal epithelial cells. However, the mechanism underlying the propagation of injury from podocytes to other glomerular cells is largely unknown. Several recent topics regarding the mechanism of podocyte injury are also discussed.

AIDS-Associated Nephropathy↗
PubMed2002

The renin angiotensin system and kidney development.

When angiotensin II or AT1 receptor is experimentally inhibited during the perinatal period, either by pharmacological intervention or genetic manipulation, the kidney develops with profound structural abnormalities. Most prominent are hypertrophy of arterial vasculatures and atrophy of the papilla. Although the mechanism by which the vascular hypertrophy occurs remains unknown, study of the atrophic papilla gives us a new clue for understanding the physiological role of angiotensin. Mutant mice completely devoid of AT1 receptor fail to develop the renal pelvis and the ureteral peristaltic movement. Normally, angiotensin and AT1 receptor are transiently up-regulated around the renal outlet at birth. Thus angiotensin II induces the peristaltic machinery during the perinatal period in a timely fashion to accommodate the dramatic increase in urine production that occurs during the transition from intra- to extra-uterine life. Further studies revealed that in adult animals angiotensin augments the peristaltic movement when the urinary tract is partially obstructed, thereby protecting the kidney from hydronephrosis. This newly discovered function of angiotensin to protect kidney architecture at the time of urine outflow obstruction is reminiscent of its similar kidney structure-protecting function that is active during arterial blood flow obstruction.

Animals↗
PubMed2002

Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis.

We examined the in vivo function of the angiotensin II type 1 receptor (Agtr1) on macrophages in renal fibrosis. Fourteen days after the induction of unilateral ureteral obstruction (UUO), wild-type mice reconstituted with marrow lacking the Agtr1 gene (Agtr1(-/-)) developed more severe interstitial fibrosis with fewer interstitial macrophages than those in mice reconstituted with Agtr1(+/+) marrow. These differences were not observed at day 5 of UUO. The expression of profibrotic genes - including TGF-beta1, alpha1(I) collagen, and alpha1(III) collagen - was substantially higher in the obstructed kidneys of mice with Agtr1(-/-) marrow than in those with Agtr1(+/+) marrow at day 14 but not at day 5 of UUO. Mice with Agtr1(-/-) marrow were characterized by reduced numbers of peripheral-blood monocytes and macrophage progenitors in bone marrow. In vivo assays revealed a significantly impaired phagocytic capability in Agtr1(-/-) macrophages. In vivo treatment of Agtr1(+/+) mice with losartan reduced phagocytic capability of Agtr1(+/+) macrophages to a level comparable to that of Agtr1(-/-) macrophages. Thus, during urinary tract obstruction, the Agtr1 on bone marrow-derived macrophages functions to preserve the renal parenchymal architecture, and this function depends in part on its modulatory effect on phagocytosis.

Animals↗