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Background: The glomerulus is a highly complex system, composed of different interdependent cell types that are subjected to various mechanical stimuli. These stimuli regulate multiple cellular functions, and changes in these functions may contribute to tissue damage and disease progression. To date, our understanding of the mechanobiology of glomerular cells is limited, with most research focused on the adaptive response of podocytes. However, it is crucial to recognize the interdependence between podocytes and parietal epithelial cells, in particular with the progenitor subset, as it plays a critical role in various manifestations of glomerular diseases. This highlights the necessity to implement the analysis of the effects of mechanical stress on renal progenitor cells., Methods: Microgravity, modeled by Rotary Cell Culture System, has been employed as a system to investigate how renal progenitor cells respond to alterations in the mechanical cues within their microenvironment. Changes in cell phenotype, cytoskeleton organization, cell proliferation, cell adhesion and cell capacity for differentiation into podocytes were analyzed., Results: In modeled microgravity conditions, renal progenitor cells showed altered cytoskeleton and focal adhesion organization associated with a reduction in cell proliferation, cell adhesion and spreading capacity. Moreover, mechanical forces appeared to be essential for renal progenitor differentiation into podocytes. Indeed, when renal progenitors were exposed to a differentiative agent in modeled microgravity conditions, it impaired the acquisition of a complex podocyte-like F-actin cytoskeleton and the expression of specific podocyte markers, such as nephrin and nestin. Importantly, the stabilization of the cytoskeleton with a calcineurin inhibitor, cyclosporine A, rescued the differentiation of renal progenitor cells into podocytes in modeled microgravity conditions., Conclusions: Alterations in the organization of the renal progenitor cytoskeleton due to unloading conditions negatively affect the regenerative capacity of these cells. These findings strengthen the concept that changes in mechanical cues can initiate a pathophysiological process in the glomerulus, not only altering podocyte actin cytoskeleton, but also extending the detrimental effect to the renal progenitor population. This underscores the significance of the cytoskeleton as a druggable target for kidney diseases., (© 2024. The Author(s).)

Podocyte depletion drives kidney disease and kidney failure progression, but podocyte complexity at the glomerular filtration barrier is difficult to model in vitro. In Nature Biomedical Engineering, Musah et al. (2017) developed a multifluidic device with iPS-derived podocytes mimicking a functional glomerular filtration barrier that elevates standards for modeling glomerular diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The critical role of genetic and epigenetic factors in the pathogenesis of kidney disorders is gradually becoming clear, and the need for disease models that recapitulate human kidney disorders in a personalized manner is paramount. In this study, we describe a method to select and amplify renal progenitor cultures from the urine of patients with kidney disorders. Urine-derived human renal progenitors exhibited phenotype and functional properties identical to those purified from kidney tissue, including the capacity to differentiate into tubular cells and podocytes, as demonstrated by confocal microscopy, Western blot analysis of podocyte-specific proteins, and scanning electron microscopy. Lineage tracing studies performed with conditional transgenic mice, in which podocytes are irreversibly tagged upon tamoxifen treatment (NPHS2.iCreER;mT/mG), that were subjected to doxorubicin nephropathy demonstrated that renal progenitors are the only urinary cell population that can be amplified in long-term culture. To validate the use of these cells for personalized modeling of kidney disorders, renal progenitors were obtained from (1) the urine of children with nephrotic syndrome and carrying potentially pathogenic mutations in genes encoding for podocyte proteins and (2) the urine of children without genetic alterations, as validated by next-generation sequencing. Renal progenitors obtained from patients carrying pathogenic mutations generated podocytes that exhibited an abnormal cytoskeleton structure and functional abnormalities compared with those obtained from patients with proteinuria but without genetic mutations. The results of this study demonstrate that urine-derived patient-specific renal progenitor cultures may be an innovative research tool for modeling of genetic kidney disorders., (Copyright © 2015 by the American Society of Nephrology.)

Introduction: Kidney diseases are a global public health problem whose incidence is rapidly growing due to a global rise in the aged population and the increasing prevalence of cardiovascular disease, hypertension and diabetes. With the emergence of stem cells as potential therapeutic agents, attempts in using them to significantly reduce the burden of these diseases have increased., Areas Covered: Several types of stem cells have been proven to be likely candidates for treating kidney diseases. We discuss in detail the potential use of mesenchymal stem cells in preclinical and clinical works, with additional populations that have been studied briefly described. Moreover, we discuss current knowledge on endogenous kidney regeneration ability and on the possibility to modulate it using chemical and biological agents., Expert Opinion: Stem cell therapy is a promising new treatment for kidney disease documented in many animal studies. Mesenchymal stem cells have emerged as a promising cell type, but their efficacy in clinical trials is still controversial. Identification of progenitor cells in the adult kidney is another step forward in regenerative medicine, suggesting the repair potential of the adult kidney and the possible modulation of renal progenitors in situ using pharmacological approaches.

Nephropathies arise from conditions that alter nephron development or trigger nephron damage during neonatal, juvenile, and adult stages of life. Much evidence suggests that a key role in maintaining kidney integrity, homeostasis, and regenerative capacity is played by a population of progenitor cells resident in the organ. Although the primary goals in the field of renal progenitor cells are understanding their ability to regenerate nephrons and to restore damaged kidney function, the discovery of these cells could also be used to elucidate the molecular and pathophysiological basis of kidney diseases. As a result, once the identification of a subset of progenitor cells capable of kidney regeneration has been obtained, the increasing knowledge about their characteristics and about the mechanisms of renal development had pointed out the possibility of understanding the molecular basis of kidney diseases, so that, nowadays, some renal disorders could also be related to renal progenitor dysfunction. In this review, we summarize the evidence on the existence of renal progenitors in fetal and adult kidneys and discuss their role in physiology as well as in the pathogenesis of renal disorders with a particular focus on childhood age.

Recent evidence suggests that injury to the renal vasculature may play an important role in the pathogenesis of both chronic and acute ischemic kidney injury. Early alterations in peritubular capillary blood flow during reperfusion have been documented and associated with loss of normal endothelial cell function. In addition, ischemia induces alterations in endothelial cells that may promote inflammation and procoagulant activity, thus contributing to vascular congestion. Reduction of the microvasculature density increases hypoxia-mediated fibrosis and alters proper hemodynamics, which may lead to hypertension. This may play a critical role in the progression of chronic kidney disease following initial recovery from ischemia/reperfusion-induced acute kidney injury. The turnover and replacement of endothelial cells is therefore an important mechanism in the maintenance of vascular integrity also in the kidney. It is becoming clear that impaired vascular repair mechanisms as a result of a reduced number and/or impaired function of endothelial progenitor cells may contribute to renal disease. Moreover, investigators have begun to identify potential mechanisms responsible for the loss of function of endothelial progenitors in renal disease. In allografts, persistent injury results in excessive turnover of graft vascular endothelial cells. Moreover, chronic damage elicits a response that is associated with the recruitment of both leukocytes and endothelial progenitors, facilitating an overlapping process of inflammation and angiogenesis. In conclusion, angiogenesis and endothelial cell turnover play a pivotal role in renal disease and allograft rejection. Manipulation of these processes might have important implications for the development of novel therapeutic strategies in the near future.

Cytokines are soluble factors that are critical for the pathophysiology of the immune system and exhibit other important functions. Cytokines produced by type 1 helper T (Th1) lymphocytes, such as interferon (IFN)-g, play a pathogenic role in proliferative glomerulonephrites (GN), as well as in the acute rejection of kidney allografts. Cytokines produced by type 2 Th (Th2) lymphocytes, such as interleukin (IL)-4, IL-5, and IL-13), predominate in membranous GN and in minimal change disease. More recently, the pathogenic role of some members of the family of chemotactic cytokines (chemokines) in different nephropathies and in the acute and chronic rejection of kidney allografts has also been demonstrated. In particular, the chemokine MCP1/CCL2 has been found to be expressed in the kidneys of subjects with tubulo-interstitial nephritis and seems to play an important role in the sclerotic evolution of both inflammatory and metabolic nephropathies. Interactions between IP-10/CXCL10, Mig/CXCL9 and I-TAC/CXCL11 and their shared receptor, CXCR3, seem to be responsible not only for Th1 cell infiltration in acute allograft rejection and in proliferative GN, but also for mesangial cell proliferation typical of the latter condition. In proliferative GN, mesangial cells indeed express both these chemokines and their receptor. Moreover, in the kidneys of subjects suffering from chronic allograft nephropathy, IP-10/CXCL10, Mig/CXCL9 and I-TAC/CXCL11 have been found to be produced by and to act on the proxymal tubular epithelial cells, endothelial cells and smooth muscle vessel cells, suggesting their possible role in both the genesis of tubular atrophy and allograft artheriosclerosis.

High levels of expression of mRNA and protein for the chemokines interferon-gamma (IFN-gamma)-inducible protein of 10 kD (IP-10) (CXCL10) and the monokine induced by IFN-gamma (Mig) (CXCL9) were observed, by using in situ hybridization and immunohistochemical analyses, in kidney biopsy specimens from patients with glomerulonephritis (GN), particularly those with membranoproliferative or crescentic GN, but not in normal kidneys. Double-immunostaining or combined in situ hybridization and immunohistochemical analyses for IP-10, Mig, and proliferating cell nuclear antigen (PCNA) or alpha-smooth muscle actin (alpha-SMA) revealed that IP-10 and Mig production by resident glomerular cells was a selective property of glomeruli in which mesangial cells demonstrated active proliferation. IP-10 and Mig mRNA and protein were also expressed by primary cultures of human mesangial cells and human visceral epithelial cells after stimulation with IFN- gamma or with IFN-gamma plus tumor necrosis factor-alpha (TNF-alpha) (which produced greater stimulation). The induction of IP-10 and Mig mRNA and protein expression by IFN-gamma plus TNF-alpha was strongly inhibited by nitric oxide (NO) donors, such as sodium nitroprusside or S-nitroso-N-acetylpenicillamine, but not by cGMP analogues. Electrophoretic mobility shift assays demonstrated that NO donors repressed IP-10 gene transcription induced by IFN-gamma plus TNF-alpha through the inhibition of NF-kappaB activation. These data demonstrate that resident glomerular cells in kidneys of patients with proliferative GN produce large amounts of IP-10 and Mig, which may play important pathogenic roles in this disease. These data also indicate that the production of IP-10 and Mig by human mesangial cells can be downregulated by NO donors through cGMP-independent inhibition of NF-kappaB activation.