There is accumulating circumstantial evidence suggesting that endothelial cell dysfunction contributes to the “no-reflow” phenomenon in postischemic kidneys. Here, we demonstrated the vulnerability...

Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells

A large body of evidence has accrued indicating that voltage-gated Ca 2+ channel subtypes, including L-, T-, N-, and P/Q-type, are present within renal vascular and tubular tissues, and the blockade of these Ca 2+ channels produces diverse actions on renal microcirculation. Because nifedipine acts exclusively on L-type Ca 2+ channels, the observation that nifedipine predominantly dilates afferent arterioles implicates intrarenal heterogeneity in the distribution of L-type Ca 2+ channels and suggests that it potentially causes glomerular hypertension. In contrast, recently developed Ca 2+ channel blockers (CCBs), including mibefradil and efonidipine, exert blocking action on L-type and T-type Ca 2+ channels and elicit vasodilation of afferent and efferent arterioles, which suggests the presence of T-type Ca 2+ channels in both arterioles and the distinct impact on intraglomerular pressure. Recently, aldosterone has been established as an aggravating factor in kidney disease, and T-type Ca 2+ channels mediate aldosterone release as well as its effect on renal efferent arteriolar tone. Furthermore, T-type CCBs are reported to exert inhibitory action on inflammatory process and renin secretion. Similarly, N-type Ca 2+ channels are present in nerve terminals, and the inhibition of neurotransmitter release by N-type CCBs (eg, cilnidipine) elicits dilation of afferent and efferent arterioles and reduces glomerular pressure. Collectively, the kidney is endowed with a variety of Ca 2+ channel subtypes, and the inhibition of these channels by their specific CCBs leads to variable impact on renal microcirculation. Furthermore, multifaceted activity of CCBs on T- and N-type Ca 2+ channels may offer additive benefits through nonhemodynamic mechanisms in the progression of chronic kidney disease.

Ca2+ channel subtypes and pharmacology in the kidney.

Although calcium antagonists are used as a first-line antihypertensive agent, controversy attends the renal microvascular effects of calcium antagonists. Since calcium antagonists elicit predominant vasodilation of the afferent arteriole, they might ostensibly aggravate glomerular hypertension. Recently, novel types of calcium antagonists have been developed, some of which are reported to dilate efferent as well as afferent arterioles. The present review attempted to characterize the renal microvascular action of calcium antagonists, and evaluated the consequences of renal injury following the treatment with these antagonists. In contrast to predominant afferent arteriolar action of conventional calcium antagonists (e.g. nifedipine, nicardipine, amlodipine and diltiazem), novel antagonists (e.g. manidipine, nilvadipine, benidipine and efonidipine) potently dilated both afferent and efferent arterioles. The vasodilator action on efferent arterioles appears to be mediated in part by the blockade of T-type calcium channels, particularly through the inhibition of the intracellular calcium release mechanism. The comparison of the anti-proteinuric action of calcium antagonists in subtotally nephrectomized rats showed that efonidipine and enalapril, both possessing vasodilator action on efferent arterioles, exerted more prominent action than other calcium antagonists. Finally, in patients with chronic renal disease, a 48-week treatment with efonidipine reduced proteinuria, and this effect was seen even when the mean arterial blood pressure failed to reach below 100 mm Hg. In conclusion, although calcium antagonists potently inhibit afferent arteriolar constriction, efferent arteriolar responses to these agents vary, depending on the types of calcium antagonists used. These divergent actions of these agents on the efferent arteriole may alter differently the glomerular hemodynamics, and could affect the final outcome of underlying renal diseases.

/pdf/role-of-actions-of-calcium-antagonists-on-efferent-42597yfiyo.pdf

Role of Actions of Calcium Antagonists on Efferent Arterioles – with Special References to Glomerular Hypertension

Hydrogen sulfide (H2S) has recently been found to play beneficial roles in ameliorating several diseases, including hypertension, atherosclerosis and cardiac/renal ischemia–reperfusion injuries. Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), the main enzymes in the transsulfuration pathway, catalyze H2S production in mammalian tissues. However, the distributions and precise roles of these enzymes in the kidney have not yet been identified. The present study examined the localization of both enzymes in the normal kidney and the effect of the H2S donor sodium hydrosulfide (NaHS) in the renal peritubular capillary (PTC) under conditions of diabetic nephropathy, using pancreatic β-cell-specific calmodulin-overexpressing transgenic mice as a model of diabetes. In the normal kidney, we detected expression of both CBS and CSE in the brush border and cytoplasm of the proximal tubules, but not in the glomeruli, distal tubules and vascular endothelial cells of renal PTCs. Administration of NaHS increased PTC diameter and blood flow. We further evaluated whether biosynthesis of H2S was altered in a spontaneous diabetic model that developed renal lesions similar to human diabetic nephropathy. CSE expression was markedly reduced under diabetic conditions, whereas CBS expression was unaffected. Progressive diabetic nephropathy showed vasoconstriction and a loss of blood flow in PTCs that was ameliorated by NaHS treatment. These findings suggest that CSE expression in the proximal tubules may also regulate tubulointerstitial microcirculation via H2S production. H2S may represent a target of treatment to prevent progression of ischemic injury in diabetic nephropathy.

/pdf/distribution-of-hydrogen-sulfide-h2s-producing-enzymes-and-2fee8re5u4.pdf

Distribution of hydrogen sulfide (H2S)-producing enzymes and the roles of the H2S donor sodium hydrosulfide in diabetic nephropathy

Little is known about the mechanisms responsible for the adaptation and changes in the capillary network of hindlimb unweighting (HU)-induced atrophied skeletal muscle, especially the coupling between functional and structural alterations of intercapillary anastomoses and tortuosity of capillaries. We hypothesized that muscle atrophy by HU leads to the apoptotic regression of the capillaries and intercapillary anastomoses with their functional alteration in hemodynamics. To clarify the three-dimensional architecture of the capillary network, contrast medium-injected rat soleus muscles were visualized clearly using a confocal laser scanning microscope, and sections were stained by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) and with anti-von Willebrand factor. In vivo, the red blood cell velocity of soleus muscle capillaries were determined with a pencil-lens intravital microscope brought into direct contact with the soleus surface. After HU, the total muscle mass, myofibril protein mass, and slow-type myosin heavy chain content were significantly lower. The number of capillaries paralleling muscle fiber and red blood cells velocity were higher in atrophied soleus. However, the mean capillary volume and capillary luminal diameter were significantly smaller after HU than in the age-matched control group. In addition, we found that the number of anastomoses and the tortuosity were significantly lower and TUNEL-positive endothelial cells were observed in atrophied soleus muscles, especially the anastomoses and/or tortuous capillaries. These results indicate that muscle atrophy by HU generates structural alterations in the capillary network, and apoptosis appears to occur in the endothelial cell of the muscle capillaries.

/pdf/regression-of-capillary-network-in-atrophied-soleus-muscle-1p1863s4ho.pdf

Regression of capillary network in atrophied soleus muscle induced by hindlimb unweighting

We developed a videomicroscope system with a charge-coupled device camera and evaluated it in the investigation of the glomerular microcirculation in normal [Wistar-Kyoto (WKY)], spontaneously hype...

https://www.physiology.org/doi/pdf/10.1152/ajprenal.2001.281.3.F571

In vivo visualization of characteristics of renal microcirculation in hypertensive and diabetic rats.

Several types of experimental techniques have been developed for the evaluation of renal microcirculation. Although each methodology possesses excellent and unique characteristics, it requires substantial artificial manipulation that might alter the renal microvascular responsiveness. To circumvent such limitation of previous ex vivo or in vitro approaches to glomerular microcirculation, we have developed a pencil lens-probe charge-coupled device (CCD) intravital videomicroscopic system which allows us to evaluate both systemic hemodynamics and renal microcirculation. Furthermore, real-time images of afferent and efferent arterioles as well as glomeruli can be continuously assessed, which would facilitate the functional characterization of these microvessels in vivo. Finally, the tapered nature of the CCD probe of this videomicroscopy may allow direct observation of the renal microvasculature in small animals (e.g., rats and mice). In conclusion, this novel technique is a valuable tool for unveiling the in vivo, in situ and intact renal microvascular behavior, and may provide further approaches to the understanding of renal microcirculation.

Direct in vivo visualization of renal microcirculation by intravital CCD videomicroscopy.

There have been developed several types of experimental techniques for evaluation of renal microcirculation. Although each methodology possesses excellent and unique characteristics, it requires substantial artificial manipulation that might alter the renal microvascular responsiveness. To circumvent such limitations of previous ex vivo or in vitro approaches to glomerular microcirculation, we have developed a pencil lens probe CCD intravital videomicroscopic system that allows us to evaluate both systemic hemodynamics and renal microcirculation. Furthermore, real time images of afferent and efferent arterioles as well as glomeruli can be continuously assessed, which would facilitate the functional characterization of these microvessels in vivo. Finally, the tapered nature of the CCD probe of this videomicroscopy may allow direct observation of the renal microvasculature in small animals. In conclusion, this novel technique is a valuable tool for unveiling the in vivo, in situ, and intact renal microvascular behavior, and may provide further approaches to the understanding of renal microcirculation.

Direct in vivo visualization of glomerular microcirculation by intravital pencil lens-probe CCD videomicroscopy.

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In vivo visualization of characteristics of renal microcirculation in hypertensive and diabetic rats.

Direct in vivo visualization of renal microcirculation by intravital CCD videomicroscopy.

Direct in vivo visualization of glomerular microcirculation by intravital pencil lens-probe CCD videomicroscopy.