Do hair follicles operate as primitive, multifocal kidney-like excretory (mini-) organs?

Besides their many other functions, hair shafts (HS) also are a repository for potentially noxious compounds. These are neutralized by their deposition within terminally differentiated, avital epithelial cells (trichocytes) that also facilitate the interaction of potential toxins with melanin, a toxin-adsorbent biopolymer. Trichocytes are completely extruded via HS shedding during exogen, an actively controlled process. This underappreciated functional property of the human hair follicle (HF) makes it a bona fide excretory (mini-) organ. Here, we ask whether the ca. 2 million HFs of the human integument operate in part as primitive, spatially dispersed kidney-like excretory organs. Despite the many obvious differences between kidneys and HFs, this provocative hypothesis is also supported by other underappreciated renal-follicular similarities such as anatomical parallels between Bowman's capsule and the anagen hair bulb, renal podocytes and HF winged cells ["Fuegelzellen"], and hypoxia-dependent production of erythropoietin and extensive prostaglandin synthesis by human scalp HFs-just as in the kidney. The proposed kidney-like excretory function of HFs may have constituted a major selection advantage of mammals during evolution and could be clinically relevant. We explain how the many open questions (eg, how are molecules destined to be excreted by hair shaft entrapment recognized, taken up and deposited into hair matrix cells?) can be tested experimentally. Finally, we explore how the therapeutic targeting of kidney-like excretory HF functions may usefully complement classical nephrological therapy (dialysis) and ask whether stimulation of intrafollicular erythropoietin synthesis might become exploitable for the benefit of patients with renal anaemia.

Association between kidney intracapsular pressure and ultrasound elastography.

BACKGROUND: Kidney congestion is a common pathophysiologic pathway of acute kidney injury (AKI) in sepsis and heart failure. There is no noninvasive tool to measure kidney intracapsular pressure (KIP) directly. METHODS: We evaluated the correlation of KIP with kidney elasticity measured by ultrasound surface wave elastography (USWE). We directly measured transcatheter KIP in three pigs at baseline and after bolus infusion of normal saline, norepinephrine, vasopressin, dopamine, and fenoldopam; infiltration of 2-L peritoneal dialysis solution in the intra-abdominal space; and venous, arterial, and ureteral clamping. KIP was compared with USWE wave speed. RESULTS: Only intra-abdominal installation of peritoneal dialysis fluid was associated with significant change in KIP (mean (95% CI) increase, 3.7 (3.2-4.2)] mmHg; P < .001). Although intraperitoneal pressure and KIP did not differ under any experimental condition, bladder pressure was consistently and significantly greater than KIP under all circumstances (mean (95% CI) bladder pressure vs. KIP, 3.8 (2.9-4.) mmHg; P < .001). USWE wave speed significantly correlated with KIP (adjusted coefficient of determination, 0.71; P < .001). Estimate (95% CI) USWE speed for KIP prediction stayed significant after adjustment for KIP hypertension (-0.8 (- 1.4 to - 0.2) m/s; P = .008) whereas systolic and diastolic blood pressures were not significant predictors of KIP. CONCLUSIONS: In a pilot study of the swine model, we found ultrasound surface wave elastography speed is significantly correlated with transcatheter measurement of kidney intracapsular and intra-abdominal pressures, while bladder pressure overestimated kidney intracapsular pressure.

Retinoic acid improves nephrotoxic serum-induced glomerulonephritis through activation of podocyte retinoic acid receptor α.

Proliferation of glomerular epithelial cells, including podocytes, is a key histologic feature of crescentic glomerulonephritis. We previously found that retinoic acid (RA) inhibits proliferation and induces differentiation of podocytes by activating RA receptor-α (RARα) in a murine model of HIV-associated nephropathy. Here, we examined whether RA would similarly protect podocytes against nephrotoxic serum-induced crescentic glomerulonephritis and whether this effect was mediated by podocyte RARα. RA treatment markedly improved renal function and reduced the number of crescentic lesions in nephritic wild-type mice, while this protection was largely lost in mice with podocyte-specific ablation of Rara (Pod-Rara knockout). At a cellular level, RA significantly restored the expression of podocyte differentiation markers in nephritic wild-type mice, but not in nephritic Pod-Rara knockout mice. Furthermore, RA suppressed the expression of cell injury, proliferation, and parietal epithelial cell markers in nephritic wild-type mice, all of which were significantly dampened in nephritic Pod-Rara knockout mice. Interestingly, RA treatment led to the coexpression of podocyte and parietal epithelial cell markers in a small subset of glomerular cells in nephritic mice, suggesting that RA may induce transdifferentiation of parietal epithelial cells toward a podocyte phenotype. In vitro, RA directly inhibited the proliferation of parietal epithelial cells and enhanced the expression of podocyte markers. In vivo lineage tracing of labeled parietal epithelial cells confirmed that RA increased the number of parietal epithelial cells expressing podocyte markers in nephritic glomeruli. Thus, RA attenuates crescentic glomerulonephritis primarily through RARα-mediated protection of podocytes and in part through the inhibition of parietal epithelial cell proliferation and induction of their transdifferentiation into podocytes.

Curved and folded micropatterns in 3D cell culture and tissue engineering.

Cells live in a highly curved and folded micropatterned environment within the human body. Hence, there is a need to develop engineering paradigms to replicate these microenvironments in order to investigate the behavior of cells in vitro, as well as to develop bioartificial organs for tissue engineering and regenerative medicine. In this chapter, we first motivate the need for such micropatterns based on anatomical considerations and then survey methods that can be utilized to generate curved and folded micropatterns of relevance to 3D cell culture and tissue engineering. The methods surveyed can broadly be divided into two classes: top-down approaches inspired by conventional 2D microfabrication and bottom-up approaches most notably in the self-assembly of thin patterned films. These methods provide proof of concept that the high resolution, precise and reproducible patterning of cell and matrix microenvironments in anatomically relevant curved and folded geometries is possible. A specific protocol is presented to create curved and folded hydrogel micropatterns.

Pathogenesis and progression of proteinuria.

Progressive albuminuria is the sine qua non of diabetic nephropathy. It is not only a marker of renal damage but also significantly contributes to its development and progression. However, the precise mechanisms by which escalating amounts of albumin leave the blood stream, cross the endothelial glycocalyx, the glomerular basement membrane and the slit pores between the foot processes of the podocytes, transit through Bowman's space, bypass the resorptive mechanisms of the nephron and ultimately pass into the urineremain hotly debated. Certainly, diabetes is associated with significant dysfunction at each of these levels, and will be discussed in detail in this review. Moreover, dilation of the afferent and constriction of the efferent arterioles triggered by defective autoregulation and subsequently by loss of peritubular capillaries also act to increase the glomerular transcapillary hydrostatic pressure and facilitate a far greater transit of albumin into the urine. Importantly, none of these mechanisms exists in isolation. Indeed, the most likely reason for progression of albuminuria is the fact that dysfunction initiated by compromise of one component will inevitably modify other parts, and ultimately affect the whole nephron function. From this 'holonephric' view of albuminuria, the best treatment will be a combination that can promote regression and restore the integrity of the entire pathway, as while fixing one part may slow the process, because of the integrated nature of renal function, it will not completely prevent nephropathy.

Parietal epithelial cells: their role in health and disease.

Parietal epithelial cells of Bowman's capsules were first described by Sir William Bowman in 1842 in his paper On the Structure and Use of the Malpighian Bodies of the Kidney [London, Taylor, 1842], but since then their functions have remained poorly understood. A large body of evidence has recently suggested that parietal epithelial cells represent a reservoir of renal progenitors in adult human kidney which generate novel podocytes during childhood and adolescence, and can regenerate injured podocytes. The discovery that parietal epithelial cells represent a potential source for podocyte regeneration suggests that podocyte injury can be repaired. However, recent results also suggest that an abnormal proliferative response of renal progenitors to podocyte injury can generate hyperplastic glomerular lesions that are observed in crescentic glomerulonephritis and other types of glomerular disorders. Taken together, these results establish an entirely novel view that changes the way of thinking about renal physiology and pathophysiology, and suggest that understanding how self-renewal and fate decision of parietal epithelial cells in response to podocyte injury may be perturbed or modulated will be crucial for obtaining novel tools for prevention and treatment of glomerulosclerosis.

Renal capsule as a stem cell niche.

Renal resident stem cells were previously reported within the renal tubules and papillary area. The aim of the present study was to determine whether renal capsules harbor stem cells and whether this pool can be recruited to the renal parenchyma after ischemic injury. We demonstrated the presence of label-retaining cells throughout the renal capsule, at a density of ∼10 cells/mm(2), and their close apposition to the blood vessels. By flow cytometry, in vitro cultured cells derived from the renal capsule were positive for mesenchymal stem cell (MSC) markers (CD29+, vimentin+, Sca-1+, nestin+) but did not express hematopoietic and endothelial stem cell markers. Moreover, renal capsule-derived cells also exhibited self-renewal, clonogenicity, and multipotency in differentiation conditions, all favoring stem cell characteristics and identifying them with MSC. In situ labeling of renal capsules with CM-DiI CellTracker demonstrated in vivo a directed migration of CM-DiI-labeled cells to the ischemic renal parenchyma, with the rate of migration averaging 30 µm/h. Decapsulation of the kidneys during ischemia resulted in a modest, but statistically significant, deceleration of recovery of plasma creatinine compared with ischemic kidneys with intact renal capsule. Comparison of these conditions allows the conclusion that renal capsular cells may contribute ∼25-30% of the recovery from ischemia. In conclusion, the data suggest that the renal capsule may function as a novel stem cell niche harboring MSC capable of participating in the repair of renal injury.

Regeneration and the kidney.

PURPOSE OF REVIEW: Following any injury, various intracellular and intercellular pathways must be activated and coordinated if tissue integrity and homeostasis need to be restored. In most injuries, repair results in once-functional tissue becoming a patch of cells and disorganized extracellular matrix that is referred to as a scar. However, most adult organs of the body, including the kidney, have the potential to regenerate functional tissues if appropriate conditions are restored. In this review, we highlight the burst of recent knowledge leading to discovery of regenerative mechanisms also in adult kidneys. RECENT FINDINGS: A large body of evidence has recently shown that the parietal epithelium of the Bowman's capsule represents a reservoir of renal progenitors in adult kidney. SUMMARY: The discovery of a hierarchical population of renal progenitors within the Bowman's capsule which can generate novel podocytes and also proximal tubular cells provides a new point of view for the understanding of renal physiology. In addition, the observation that renal progenitors can also generate hyperplastic glomerular lesions opens up a novel view of the pathogenesis of different types of glomerular disorders, which may at least in part result from abnormal regenerative responses to podocyte injury.

Fluid flow in the juxtaglomerular interstitium visualized in vivo.

Earlier electron microscopy studies demonstrated morphological signs of fluid flow in the juxtaglomerular apparatus (JGA), including fenestrations of the afferent arteriole (AA) endothelium facing renin granular cells. We aimed to directly visualize fluid flow in the JGA, the putative function of the fenestrated endothelium, using intravital multiphoton microscopy of Munich-Wistar rats and C57BL6 mice. Renin content of the AA correlated strongly with the length of the fenestrated, filtering AA segment. Fluorescence of the extracellular fluid marker lucifer yellow (LY) injected into the cannulated femoral vein in bolus was followed in the renal cortex by real-time imaging. LY was detected in the interstitium around the JG AA before the plasma LY filtered into Bowman's capsule and early proximal tubule. The fluorescence intensity of LY in the JGA interstitium was 17.9 +/- 3.5% of that in the AA plasma (n = 6). The JGA fluid flow was oscillatory, consisting of two components: a fast (one every 5-10 s) and a slow (one every 45-50 s) oscillation, most likely due to the rapid transmission of both the myogenic and tubuloglomerular feedback (TGF)-mediated hemodynamic changes. LY was also detected in the distal tubular lumen about 2-5 s later than in the AA, indicating the flow of JGA interstitial fluid through the macula densa. In the isolated microperfused JGA, blocking the early proximal tubule with a micropipette caused significant increases in MD cell volume by 62 +/- 4% (n = 4) and induced dilation of the intercellular lateral spaces. In summary, significant and dynamic fluid flow exists in the JGA which may help filter the released renin into the renal interstitium (endocrine function). It may also modulate TGF and renin signals in the JGA (hemodynamic function).