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Exploring the mechanisms of renoprotection against progressive glomerulosclerosis.

Oite T - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2011)

Bottom Line: First, I describe the experimental rat model in which disturbances of vascular regeneration and glomerular hemodynamics lead to irreversible glomerulosclerosis.Third, I provide an in-depth review of the regulatory glomerular hemodynamics at the cellular and molecular levels while focusing on the pivotal role of Ca(2+)-dependent gap junctional intercellular communication in coordinating the behavior of mesangial cells.Last, I show that local delivery of renoprotective agents, in combination with diagnostic imaging of the renal microvasculature, allows the evaluation of the therapeutic effects of angiotensin II receptor and cyclooxygenase activity local blockade on the progression of glomerulosclerosis, which would otherwise lead to renal death.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular Physiology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Japan. oite@med.niigata-u.ac.jp

ABSTRACT
In this review, I introduce the strategy developed by our laboratory to explore the mechanisms of renoprotection against progressive glomerulosclerosis leading to renal death. First, I describe the experimental rat model in which disturbances of vascular regeneration and glomerular hemodynamics lead to irreversible glomerulosclerosis. Second, I discuss the possible mechanisms determining the progression of glomerulosclerosis and introduce a new imaging system based on intravital confocal laser scanning microscopy. Third, I provide an in-depth review of the regulatory glomerular hemodynamics at the cellular and molecular levels while focusing on the pivotal role of Ca(2+)-dependent gap junctional intercellular communication in coordinating the behavior of mesangial cells. Last, I show that local delivery of renoprotective agents, in combination with diagnostic imaging of the renal microvasculature, allows the evaluation of the therapeutic effects of angiotensin II receptor and cyclooxygenase activity local blockade on the progression of glomerulosclerosis, which would otherwise lead to renal death.

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Scheme of the confocal laser scanning microscope and sequential images showing glomerular microcirculation. A confocal laser scanning microscope (CSU-10; Yokogawa Electric Company, Tokyo, Japan) in combination with an image-intensified charge-coupled device video camera (C2400-89; Hamamatsu Photonics KK, Shizuoka, Japan) was used for real-time observation of renal microcirculation, including glomerular blood flow. The left kidney was exposed by a flank and muscle fascia incision, followed by the analysis of microcirculation from the surface of the kidney. Vascular images were obtained by intravenous injection of a solution of fluorescein isothiocyanate (FITC)-labeled dextran (molecular weight 150,000 Da). To measure blood flow, a batch of autologous red blood cells labeled with FITC was injected into the tail vein. In the lower panels, the sequential images of glomerular microcirculation from a normal Munich Wistar rat are presented. Arrows show the sequential images of the same red blood cell flow. VTR: videotape recorder, TV: television. In addition, the real image of glomerular blood flow can be seen in the additional video movie.
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fig04: Scheme of the confocal laser scanning microscope and sequential images showing glomerular microcirculation. A confocal laser scanning microscope (CSU-10; Yokogawa Electric Company, Tokyo, Japan) in combination with an image-intensified charge-coupled device video camera (C2400-89; Hamamatsu Photonics KK, Shizuoka, Japan) was used for real-time observation of renal microcirculation, including glomerular blood flow. The left kidney was exposed by a flank and muscle fascia incision, followed by the analysis of microcirculation from the surface of the kidney. Vascular images were obtained by intravenous injection of a solution of fluorescein isothiocyanate (FITC)-labeled dextran (molecular weight 150,000 Da). To measure blood flow, a batch of autologous red blood cells labeled with FITC was injected into the tail vein. In the lower panels, the sequential images of glomerular microcirculation from a normal Munich Wistar rat are presented. Arrows show the sequential images of the same red blood cell flow. VTR: videotape recorder, TV: television. In addition, the real image of glomerular blood flow can be seen in the additional video movie.

Mentions: Further, we have attempted to directly observe the hemodynamic events occurring in the glomerular circulation under physiopathological conditions. To that purpose, we have developed an intravital real-time confocal laser scanning microscope system in combination with fluorescent tracer labeling,14) as shown in Fig. 4 and the supplemental video movie. This imaging system has allowed the examination of not only glomerular hemodynamic changes but also of the morphological recovery of the glomerular capillaries after glomerular injury with a noninvasive procedure in Munich Wistar rats. The sequence of hemodynamic changes within the glomeruli was analyzed in the reversible 2-kidney and irreversible 1-kidney ATS models.15) The determining point in glomerulosclerosis progression occurs during the period from 7 to 14 days after disease induction, when disturbances of local intraglomerular blood flow persist in the 1-kidney group. It should be pointed out that disturbance of local intraglomerular blood flow showing a significant difference in blood flow velocity at two different fixed parts of tufts within a glomerulus, which we called “turbulence of glomerular hemodynamics,” far precedes progressive glomerulosclerosis, observed 84 days after disease induction. From the viewpoint of hemodynamics, it is well known that a turbulent flow requires more pressure for a given flow rate than a laminar flow does.16) Therefore, it is reasonable to consider that disturbances in intraglomerular blood flow in the 1-kidney model may induce higher shear and hydrostatic stresses along the glomerular capillary walls in the early phase of renal disease, leading to retardation of capillary repair and, finally, to progressive glomerulosclerosis. Such an abnormal blood flow in the 1-kidney model is aggravated at the late stage of glomerulosclerosis, as shown in the sequential video frames of Fig. 5 in which the images of “stop,” “reflow,” and “retrograde flow” were caught in the interstitial microvasculature.


Exploring the mechanisms of renoprotection against progressive glomerulosclerosis.

Oite T - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2011)

Scheme of the confocal laser scanning microscope and sequential images showing glomerular microcirculation. A confocal laser scanning microscope (CSU-10; Yokogawa Electric Company, Tokyo, Japan) in combination with an image-intensified charge-coupled device video camera (C2400-89; Hamamatsu Photonics KK, Shizuoka, Japan) was used for real-time observation of renal microcirculation, including glomerular blood flow. The left kidney was exposed by a flank and muscle fascia incision, followed by the analysis of microcirculation from the surface of the kidney. Vascular images were obtained by intravenous injection of a solution of fluorescein isothiocyanate (FITC)-labeled dextran (molecular weight 150,000 Da). To measure blood flow, a batch of autologous red blood cells labeled with FITC was injected into the tail vein. In the lower panels, the sequential images of glomerular microcirculation from a normal Munich Wistar rat are presented. Arrows show the sequential images of the same red blood cell flow. VTR: videotape recorder, TV: television. In addition, the real image of glomerular blood flow can be seen in the additional video movie.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig04: Scheme of the confocal laser scanning microscope and sequential images showing glomerular microcirculation. A confocal laser scanning microscope (CSU-10; Yokogawa Electric Company, Tokyo, Japan) in combination with an image-intensified charge-coupled device video camera (C2400-89; Hamamatsu Photonics KK, Shizuoka, Japan) was used for real-time observation of renal microcirculation, including glomerular blood flow. The left kidney was exposed by a flank and muscle fascia incision, followed by the analysis of microcirculation from the surface of the kidney. Vascular images were obtained by intravenous injection of a solution of fluorescein isothiocyanate (FITC)-labeled dextran (molecular weight 150,000 Da). To measure blood flow, a batch of autologous red blood cells labeled with FITC was injected into the tail vein. In the lower panels, the sequential images of glomerular microcirculation from a normal Munich Wistar rat are presented. Arrows show the sequential images of the same red blood cell flow. VTR: videotape recorder, TV: television. In addition, the real image of glomerular blood flow can be seen in the additional video movie.
Mentions: Further, we have attempted to directly observe the hemodynamic events occurring in the glomerular circulation under physiopathological conditions. To that purpose, we have developed an intravital real-time confocal laser scanning microscope system in combination with fluorescent tracer labeling,14) as shown in Fig. 4 and the supplemental video movie. This imaging system has allowed the examination of not only glomerular hemodynamic changes but also of the morphological recovery of the glomerular capillaries after glomerular injury with a noninvasive procedure in Munich Wistar rats. The sequence of hemodynamic changes within the glomeruli was analyzed in the reversible 2-kidney and irreversible 1-kidney ATS models.15) The determining point in glomerulosclerosis progression occurs during the period from 7 to 14 days after disease induction, when disturbances of local intraglomerular blood flow persist in the 1-kidney group. It should be pointed out that disturbance of local intraglomerular blood flow showing a significant difference in blood flow velocity at two different fixed parts of tufts within a glomerulus, which we called “turbulence of glomerular hemodynamics,” far precedes progressive glomerulosclerosis, observed 84 days after disease induction. From the viewpoint of hemodynamics, it is well known that a turbulent flow requires more pressure for a given flow rate than a laminar flow does.16) Therefore, it is reasonable to consider that disturbances in intraglomerular blood flow in the 1-kidney model may induce higher shear and hydrostatic stresses along the glomerular capillary walls in the early phase of renal disease, leading to retardation of capillary repair and, finally, to progressive glomerulosclerosis. Such an abnormal blood flow in the 1-kidney model is aggravated at the late stage of glomerulosclerosis, as shown in the sequential video frames of Fig. 5 in which the images of “stop,” “reflow,” and “retrograde flow” were caught in the interstitial microvasculature.

Bottom Line: First, I describe the experimental rat model in which disturbances of vascular regeneration and glomerular hemodynamics lead to irreversible glomerulosclerosis.Third, I provide an in-depth review of the regulatory glomerular hemodynamics at the cellular and molecular levels while focusing on the pivotal role of Ca(2+)-dependent gap junctional intercellular communication in coordinating the behavior of mesangial cells.Last, I show that local delivery of renoprotective agents, in combination with diagnostic imaging of the renal microvasculature, allows the evaluation of the therapeutic effects of angiotensin II receptor and cyclooxygenase activity local blockade on the progression of glomerulosclerosis, which would otherwise lead to renal death.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular Physiology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Japan. oite@med.niigata-u.ac.jp

ABSTRACT
In this review, I introduce the strategy developed by our laboratory to explore the mechanisms of renoprotection against progressive glomerulosclerosis leading to renal death. First, I describe the experimental rat model in which disturbances of vascular regeneration and glomerular hemodynamics lead to irreversible glomerulosclerosis. Second, I discuss the possible mechanisms determining the progression of glomerulosclerosis and introduce a new imaging system based on intravital confocal laser scanning microscopy. Third, I provide an in-depth review of the regulatory glomerular hemodynamics at the cellular and molecular levels while focusing on the pivotal role of Ca(2+)-dependent gap junctional intercellular communication in coordinating the behavior of mesangial cells. Last, I show that local delivery of renoprotective agents, in combination with diagnostic imaging of the renal microvasculature, allows the evaluation of the therapeutic effects of angiotensin II receptor and cyclooxygenase activity local blockade on the progression of glomerulosclerosis, which would otherwise lead to renal death.

Show MeSH
Related in: MedlinePlus