Regression and Renin Angiotensin Aldosterone System (RAAS) Inhibition
Re­gression of glomerulosclerosis has been achieved both in the ligation hypertensive remnant kidney model and in the nonhyper­tensive sclerosis associated with aging with high dose angiotensin type 1 receptor blocker (ARB) or angiotensin I converting enzyme inhibitor (ACEI) [1]. In our studies, sclerosis was induced by 5/6 nephrectomy, but intervention was not started until established sclerosis was present at 8 wks, and severity of sclerosis proven by renal biopsy. Rats were then treated for the next 4 weeks with high dose ARB or ACEI, beyond levels required for hemodynamic control, or an aldosterone antagonist [2]. At sacrifice, severity of sclerosis at autopsy was compared to biopsy in the same rats. Regression, defined as less severe sclerosis at sacrifice than at biopsy, was achieved in about 2/3 of rats [3]. The area of sclerosis was decreased from biopsy to autopsy by high dose ARB, accompanied by an increase in open capillary loop area. These data also support our hypothesis that decrease in ECM accumulation and increase in capillary growth contribute to regression. In additional experiments, we also showed re­gression could be achieved in the nonhyper­tensive sclerosis associated with aging with high dose ARB [4]. Regression has also been achieved with combination ACEI, ARB and statin therapy in a severe passive Heymann's nephritis model with sclerosis, and with ARB in the hypertensive nitric oxide–deficient rat model [5, 6] . Carefully detailed studies from the groups of Amann and Ritz have confirmed that regres­sion can occur in the surgical cautery remnant kidney model in the rat with high dose ACEI, with parallel regression of existing glomerular, tubular and vascular scarring, inferred by comparing sclerosis severity from sacrifice of different rats at varying time points after delayed intervention [7]. Additional studies by these investigators showed marked endothelial cell increase per glomerulus after injury, reversed by ACEI, with reduction of glomerular volume and capillary number [8]. Whether the same capillary remodeling mechanisms are involved in all models of sclerosis has not been established. Three-dimensional confocal images and theoretical mathematical modeling may become useful tools to analyze capillary branching in remodeling of sclerosis.

How then can new capillary loops evolve from the segmentally sclerotic glomeruli, and are there limits to the potential of regression? A proposed schema is shown in Fig. 1:

Figure 1: Schema of our hypotheses on mechanisms of regression of glomerulosclerosis: ECM degradation, contributed to by ARB-induced decreased PAI-1, decreases area of scar (gray). Capillary lengthening and branching (orange) occur by capillary growth, mediated by increased VEGF, Ang1 and Ang2, and migration of endothelial progenitor cells, EPC. Capillary growth is enhanced by decreased ECM and ARB, with key modulation by podocyte-derived factors.

Our previous data with mathematical modeling indicate a limit of the regression that can be achieved in individual glomeruli: if an individual tuft is sclerosed more than 50%, it is doomed to progression. Conversely, those glomeruli with less than 50% of the tuft sclerosed may grow new capillary loops [1, 3] . Detailed data are not yet available on specific capillary branching patterns when regression is achieved. However, elegant morphometric studies in chronic kidney disease in children and in rats have demonstrated that both capillary lengthening and branching contribute to such glomerular growth after injury [9, 10] . Confocal microscopy technology has now advanced such that Z-sections from confocal images spanning an entire glomerulus are achievable, and could greatly enhance understanding of the complex glomerular structure.

Proof of principle of regression has also been shown in human diabetic nephropathy, where cure of the underlying diabetes by pancreas transplant enabled regression of existing glomerulosclerosis and tubulointerstitial fibrosis over a 10-year follow-up period [11].

Regression and ECM Modulation
What then are the mechanisms allowing regression of a moderately sclerotic glomerulus? Our results point to increased degradation of matrix by high-dose RAAS inhibition, contributed to by decreased plasminogen activator inhibitor-1 (PAI-1) PAI-1. PAI-1 is the major inhibitor of tissue-type plasminogen activator and urokinase-type plasminogen activator [12, 13] . PAI-1 not only inhibits fibrinolysis, but also proteolysis (Fig. 2) [12, 13] . The plasmin/plasminogen activator system is comprised of the plasminogen activators and their inhibitors, which together modulate the production of plasmin. Plasmin can cleave many ECM proteins including laminin, fibronectin and collagen IV. Both t-PA and u-PA play important roles in vascular remodeling, angiogenesis and tumor metastasis [13]. t-PA primarily effects fibrinolysis, whereas u-PA has less affinity for fibrin but avidly degrades matrix [13]. Plasmin also activates latent matrix metalloproteases (MMPs).

Angiotensin induces PAI-1 in vitro, and in vivo via the AT1 receptor [14]. Aldosterone enhances this in vitro angiotensin-induced increase in PAI-1, possibly through effects on a GRE element in the PAI-1 promoter [14, 15, 16, 17] . Of note, combined ARB and aldosterone inhibition in humans suppressed the enhanced plasma PAI-1 levels that occurred in response to a diuretic, whereas monotherapy with either alone was without effect. These data support interactions of angiotensin and aldosterone on PAI-1 induction [18]. We have linked high local levels of PAI-1 expression to sclerosis [19, 20] . Our recent data further indicate that PAI-1 and tissue inhibitor of metalloprotease-1 (TIMP-1) were decreased when regression was achieved by high dose ARB, thus promoting increased ECM proteolysis [2].

Podocyte Contribution to Sclerosis
Podocyte injury in intricately linked to progressive sclerosis, and interventions that ameliorate sclerosis also attenuate podocyte injury [21]. However, these observations do not per se prove causality of the podocyte injury in progressive sclerosis. The first attempt to investigate the potential causal role of podocyte injury in sclerosis was made by injecting saponin directly into the Bowman's space by micropuncture, a maneuver that in fact resulted in sclerosis in the saponin-injected glomeruli [22]. However, the injected saponin could potentially have affected not only podocytes, but also parietal epithelial, as well as endothelial and mesangial cells.

Recent studies of familial FSGS/nephrotic syndrome have demonstrated the importance of key podocyte genes in these disease processes, including nephrin, podocin, α-actinin-4, CD2AP and other molecules, as discussed elsewhere in this symposium. In addition, podocyte-specific gene manipulations in transgenic mice have resulted in progressive glomerular sclerosis [23, 24, 25, 26, 27, 28, 29, 30, 31] .

The group of Ichikawa et al has recently genetically engineered a mouse model to specifically explore the impact of podocyte-specific injury on sclerosis [32]. The model is a transgenic mouse strain (called NEP25) that carries a transgene which is selectively transcribed in podocytes to produce foreign receptors for a recombinant Pseudomonas immunotoxin designed to only bind to the foreign receptor. After toxin injection, mice develop massive and non-selective proteinuria within 2-3 days. Podocyte injury was apparent by electron microscopy within 12 hours, followed by endothelial cell swelling, mesangiolysis, expansion of mesangial matrix, and damage and proliferation of parietal epithelial cells; and later development of glomerulosclerosis. We next modulated the immunotoxin injury model by performing unilateral ureteral obstruction (UUO) after toxin delivery, a maneuver that markedly decreases GFR and protein flux across the GBM in the ligated kidney [33]. This superimposed UUO lead to remarkable complete of the podocyte from the secondary injury, thereby preserving the podocyte structure and preventing the development of sclerosis.

In a recent study, we next examined whether damage of the podocyte can spread to other podocytes, using the NEP25 toxin model [34]. Chimeric mice made up of either NEP25 receptor-expressing or wild type cells were used. After injection of the recombinant immunotoxin, both NEP25 and wild type podocytes showed injury, although only the former could be directly affected by the toxin, implicating that damage can spread from podocyte to podocyte. Similar findings were also documented in chimeric mice made up with cells with or without heterozygous Wt1^tmT396 mutation, which causes Denys-Drash syndrome [35]. Possible mechanisms for such podocyte-to-podocyte transmission of injury include, but are not limited to increased toxic substance(s) secreted in an autocrine or paracrine fashion, such as basic FGF, TGFβ, angiotensin II, MIF, decrease of podocyte-specific survival factors, such as VEGF-A and interferon-inducible protein-10 (IP-10), loss of cell-cell interactions, such as signaling via nephrin, and/or transmission of death signals through gap junctions [36, 37, 38, 39, 40, 41, 42, 43, 44] .

Podocyte Response in Injury
As discussed above, podocyte injury is the primary event in many diseases that ultimately progress to glomerulosclerosis. We investigated the role in sclerosis of a transcription factor upregulated in podocytes after injury, namely peroxisome proliferator-activated receptor γ (PPARγ). PPARγ is not normally detected in vivo in podocytes by immunostaining or in situ hybridization, but by real time PCR we found low levels of PPARγ expression in cultured mouse podocytes at baseline. PPARγ expression was increased after injury in podocytes both in vitro and in vivo. PPARγ expression was augmented, especially in sclerotic glomeruli in podocytes adjacent to areas of injury in the rat 5/6 nephrectomy and puromycin aminonucleoside (PAN) models of FSGS, and in human diseases in hypertensive nephrosclerosis, diabetic nephropathy and chronic transplant nephropathy [45, 46] .

What effects could this increased PPARγ have on the podocyte in these settings? In contrast to the positive potential of mesangial and endothelial cells to contribute to remodeling, the glomerular podocyte cell is terminally differentiated and growth-challenged. Importantly, PPARγ has effects on cell differentiation and growth. Activation of PPARγ inhibits cell growth and promotes differentiation in a broad spectrum of epithelial derived-tumor cell lines. Our in vitro studies of cultured podocytes exposed to PAN showed that the PPARγ agonist pioglitazone promoted podocyte differentiation with increased synaptopodin expression both at baseline and after injury. PPARγ effects were mediated by PPARγ activation, as demonstrated by a PPRE3-TK-luciferase reporter construct in these cells [47].

PPARγ also modulates apoptosis, a process may be involved in the control of podocyte number in FSGS. Deficiency of podocyte number is one mechanism whereby progressive sclerosis may develop in FSGS. Apoptosis may in some settings be a beneficial response to injury, removing cells with minimal induction of profibrotic/proinflammatory mediators. However, in cells with limited replicative capacity to replace those injured cells deleted by apoptosis, this response may be counterproductive. A recent study indicated that pioglitazone reduced urinary podocyte excretion and podocyte injury in early-stage type 2 diabetes patients, suggesting that PPARγ could ameliorate diabetic injury not only by its metabolic effects, but by direct podocyte actions [48]. We found that PPARγ also protected against PAN-induced apoptosis and necrosis of podocytes in vitro, with decreased TUNEL staining, annexin V binding and DNA laddering in PAN-injured podocytes treated with PPARγ . In vivo in the PAN model of FSGS, the PPARγ agonist pioglitazone ameliorated development of sclerosis, when intervention was started at a time point of early injury [49]. PPARγ agonist was also protective in the 5/6 Nx model of FSGS, despite lack of significant antihypertensive effects [45]. This beneficial protective effect was linked to decreased macrophage infiltration, altered cell turnover and decreased PAI-1 and TGFβ expressions. Taken together, the above results support that PPARγ activation in injured podocytes exerts counterregulatory, beneficial roles in renal injury.

Podocytes and Capillary Growth- Potential Impact on Regression
The podocyte is a key regulator of capillary growth, a potential key component of remodeling in glomerulosclerosis. The processes that govern capillary growth include angiogenesis and vasculogenesis. Angiogenesis is defined as blood vessel growth from existing differentiated endothelial cells, and has previously been thought to be the only mechanism of vascular growth in the adult. Vasculogenesis occurs in the embryo, where endothelial progenitor cells (EPCs) organize loosely to form a primordial endothelial tube. Recently, EPCs have been recognized to also contribute to capillary repair/regeneration in the adult after injury [50]. Vascular endothelial-derived growth factor–A (VEGF-A) and the angiopoietins (Ang1, Ang2) are key factors for vessel growth and normal glomerular and vascular development (reviewed in 51). Both VEGF-A and Ang1 are expressed in podocytes, and affect the endothelium, where their receptors, Flt-1 and Flk-1, and Tie-1 and –2, respectively, are expressed [11]. Increased VEGF-A stimulates endothelial cell mitogenesis, migration and morphogenesis of EPCs. VEGF-A is induced by various cytokines and growth factors, and induces the expression of proteinases, in particular MMP-1 and MMP-2, which may facilitate cell migration. VEGF-A has also been implicated in glomerular diseases. VEGF-A treatment resulted in less injury and enhanced endothelial cell proliferation and capillary repair in models of acute glomerulonephritis or thrombotic microangiopathy [51]. Conversely, when VEGF-A was antagonized in the spontaneously resolving mesangioproliferative model of anti-Thy-1 model, endothelial cell regeneration was inhibited [52]. Glomerular VEGF-A was markedly decreased, as was capillary density, in a model of glomerulosclerosis [53]. Conversely, VEGF-A treatment ameliorated development of glomerulosclerosis and tubulointerstitial fibrosis [54]. Thus, VEGF-A has been shown in various models to have a protective role in ameliorating the development of glomerular injury. Ang1 is key for stabilization of vessels, and Ang2 has differential effects depending on the presence or absence of VEGF-A [51]. When VEGF-A is absent, Ang2 induces vessel regression. In contrast, in pathological situations where VEGF-A is increased, Ang2 promotes vessel sprouting, and may function as a Tie-2 agonist.

Many additional molecules have key roles in vascular growth control, including some linked to increased fibrosis. Platelet-derived growth factor (PDGF)-B is secreted by vessels and attracts mesenchymal cells, which activate transforming growth factor-β (TGFβ ) once they come in contact with the endothelial cells. TGFβ then suppresses endothelial cell proliferation and migration, inducing mural cell differentiation and vessel maturation. Decreased ECM facilitates capillary growth at least in part by augmenting cell migration. How these coordinated capillary growth responses are modulated in the sclerotic glomerulus is not known. The interaction of podocytes and endothelial cells in these complex coordinated processes is of interest.

Capillary Growth- Interactions of Podocytes and Endothelial Cells
Podocyte VEGF-A is crucial for normal development of the glomerulus: podocyte-specific knockout of VEGF-A resulted in abnormal development, the heterozygote showed an abnormal endothelial phenotype reminiscent of the endotheliosis lesion of pre-eclampsia, and the podocyte VEGF-A over-expressing mice showed a phenotype resembling collapsing glomerulopathy [31]. Ang1 is synthesized by many cells, including podocytes and pericytes, whereas Ang2 is principally secreted from endothelial cells. The similarities in Ang1/Tie-2 sites of expression with that of VEGF-A and its receptor suggest possible interactions in their functions, and point to the key role of the podocyte in regulating endothelial cell growth responses.

Importantly, both podocytes and glomerular endothelial cells are postulated to play important roles in the progression and potential regression of glomerulosclerosis. Inhibition of angiotensin is crucial in treatment of chronic kidney disease, presumed via effects on blood pressure and extracellular matrix [1]. Our recent studies indicate that ARB may also influence podocyte modulation of glomerular endothelial cell growth. Our results show that media from podocytes injured by puromycin aminonucleoside was ineffective in mediating endothelial sprouting, proliferation and migration, linked to decreased VEGF-A and Ang1 produced from the podocytes. These endothelial cell responses could be restored by ARB treatment of the injured podocytes, which normalized podocyte VEGF-A and Ang1, and was associated with endothelial cell activation of p38 MAPK, ERK and AKT. These data support that ARB effects on podocytes may contribute to mediate capillary remodeling in vivo [55].

Summary
In summary, regression of glomerulosclerosis has been demonstrated both in experimental models and in humans. Regression of sclerosis encompasses breakdown of existing matrix, and optimally restoration of open capillary loops. Podocyte responses to injury and intervention are key in mediating these processes. These data further support that antagonism of the renin angiotensin aldosterone system may mediate regression of sclerosis in vivo, not only by effects on blood pressure and ECM modulation, but in part also by effects on podocytes that promote capillary growth.

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