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PubMed2005

Genetics of idiopathic nephrotic syndrome.

Nephrotic syndrome (NS) is a pathological entity characterized by massive proteinuria and has diverse etiology. Although it is one of the most common renal diseases in children, the etiological factors responsible for idiopathic NS/FSGS remain largely unknown. Previous studies had implicated a variety of factors including genetic factors, although NS is generally regarded as a sporadic disease. Familial cases of NS have however been reported periodically, and both autosomal dominant and recessive forms have been identified. Studies of familial NS/FSGS have led to the discovery of several genes that are expressed in podocytes and are associated with proteinuria. These discoveries have shifted the focus from glomerular basement membrane (GBM) to recognition of the central role of podocytes in maintaining glomerular perm selectivity and pathogenesis of NS/FSGS. Associations with various genes (NPHS1, ACTN4, NPHS2, WT-1) and linkage to several chromosomal regions (such as 19q13, 11q21, 11q24) have been reported in patients with familial NS/FSGS.

Child↗
PubMed2005

The effect of intrauterine environment and low glomerular number on the histological changes in diabetic glomerulosclerosis.

AIMS/HYPOTHESIS: We tested the hypothesis that diabetic glomerulosclerosis would develop more rapidly in animals with fewer glomeruli. METHODS: We studied the female offspring of Wistar rats that had been fed a low-protein diet (LPD) containing 6% protein or a normal-protein diet (NPD) containing 18% protein during pregnancy. Streptozotocin diabetes was induced at 12 weeks and animals were killed at 40 weeks. RESULTS: Non-diabetic LPD offspring were of lower birthweight than the NPD offspring (5.19+/-0.64 vs 6.45+/-0.67 g, p<0.001) and had fewer glomeruli (27,402+/-3,137 vs 34,203+/-6,471, p<0.05). Glomerular volume correlated inversely with glomerular number (r=-0.64, p=0.035), but total glomerular filtration surface area was reduced in the LPD animals (4,770+/-541 vs 5,779+/-1,302 mm(2), p=0.05). Other renal structural and functional parameters were similar. In LPD and NPD diabetic animals, glomerular volume and basement membrane width were significantly increased compared to their respective controls. Podocyte density was lowest in the LPD diabetic animals (not significant), and the area covered by each podocyte was greater in the LPD diabetic group (2.40+/-0.693 x10(-3) mm(2)) than in the LPD control group (1.68+/-0.374 x10(-3) mm(2), p<0.001) and in the NPD diabetic animals (1.71+/-0.291 x 10(-3) mm(2), p<0.05). There was no difference in any other structural or functional parameter between the LPD and NPD diabetic animals. CONCLUSIONS/INTERPRETATION: A decrease in glomerular number was not deleterious to renal structure and function over 40 weeks in this animal model. Further work in models with progressive renal impairment and hypertension is necessary to clarify the impact of glomerular number on the development of renal disease.

Animals↗
PubMed2006

Correlations of tissue macrophages and cytoskeletal protein expression with renal fibrosis in patients with diabetes mellitus.

BACKGROUND: In clinicopathological studies of cellular remodeling in the progression of diabetic nephropathy, it has not been well described whether tissue macrophage numbers and the expression of two cytoskeletal proteins--alpha-smooth muscle actin (alphaSMA) and vimentin--correlate with the disease severity. METHODS: Renal biopsy specimens from 23 patients with noninsulin-dependent diabetes mellitus (NIDDM) were examined by immunoperoxidase methods for CD68+ macrophages and alphaSMA and vimentin staining in paraffin-embedded samples. alphaSMA staining was evaluated in mesangial and interstitial myofibroblastic cells, and vimentin staining was evaluated in podocytes and mesangial and tubular cells. RESULTS: Glomerular macrophage numbers were not correlated with any clinicopathological scores. However, the interstitial macrophage score was significantly correlated with serum creatinine (sCr) and strongly correlated with the interstitial fibrosis score. Both alphaSMA and vimentin were detectable in the mesangium, without significant correlation with each other. A positive correlation was observed between mesangial alphaSMA and urinary (u-) protein levels. In contrast, an inverse correlation was observed between levels of mesangial vimentin and u-protein. Mesangial alphaSMA, but not vimentin, showed a significant correlation with glomerular sclerosis. Podocytic vimentin levels tended to decrease in patients with higher sCr levels. The severity of interstitial peritubular alphaSMA was correlated strongly with interstitial macrophage proliferation and significantly with the interstitial fibrosis score. CONCLUSIONS: The expression of mesangial alphaSMA may play a role in the progression of glomerular damage, while, on the other hand, newly acquired mesangial vimentin seems to be attenuated by heavy proteinuria. In addition, it was suggested that peritubular alphaSMA-positive myofibroblastic cells, in collaboration with interstitial macrophages, contribute to the progression of interstitial fibrosis in diabetic nephropathy.

Actins↗
PubMed2006

Glomerular expression of neuronal activity-regulated pentraxin precedes the development of anti-Thy-1-induced progressive glomerulosclerosis.

Although it is clear that genetic predispositions play a role in progressive glomerulosclerosis, identification of specific genes is difficult because of natural genetic heterogeneity among individuals. We have reported a differential susceptibility to progressive glomerulosclerosis after induction of experimental glomerulonephritis anti-Thy-1 nephritis in Lewis rat substrains. Glomerular lesions in Lewis/Møllegard rats resolve spontaneously, whereas Lewis/Maastricht (Lew/Maa) rats develop progressive glomerulosclerosis. This predisposition for progressive glomerulosclerosis is governed by unknown genes that are expressed by renal cells. Here, differential gene expression analysis using a rat complementary DNA micro array revealed neuronal activity-regulated pentraxin (Narp) as a candidate gene involved in the remodeling or progression of damaged glomeruli. Glomerular Narp mRNA expression was monitored during disease in both Lewis sub strains. Immunohistochemistry revealed that Narp protein is exclusively expressed in Lew/Maa glomeruli 7 and 14 days after induction of anti-Thy-1 nephritis. Double-immunofluorescent staining showed that proliferating mesangial cells and parietal epithelial cells (PECs) at sites of adhesion to podocytes are partially Narp-positive, whereas podocytes fail to express Narp. Immunohistochemistry in nephritic Wistar, unilaterally nephrectomized Wistar and Sprague-Dawley rats showed that Narp protein is present only in strains that develop progressive glomerulosclerosis but never in strains that show remodeling. We conclude that Narp is a predictor for anti-Thy-1 nephritis-induced glomerulosclerosis and its expression by PECs may be involved in the progression to glomerulosclerosis.

Animals↗
PubMed2002

Effects of antihypertensive drugs in experimental type 2 diabetes-related nephropathy.

BACKGROUND: It has been extensively reported that antihypertensive drugs reduce proteinuria and glomerulosclerosis (GS) in many experimental nephropathies and in humans. However, the role of calcium channel blockers (CCBs) in the prevention of proteinuria and GS remains controversial and in most cases only dihidropyridine-CCBs are studied. Few studies have reported whether the time at which drug administration is initiated plays a role in the reduction of proteinuria and GS. METHODS: Fifty-six male Obese Zucker rats (OZR) were used as a model of spontaneous type 2 diabetes-related nephropathy. Biochemical and histological analysis were performed to compare the efficacy of a non-dihydropyridine-CCB diltiazem [DZM; 100 mg/kg body weight (BW)/day], an ACEI quinapril (10 mg/kg BW/day), or both in diminishing proteinuria and GS, and to determine their role in effective prevention and treatment. RESULTS: Only quinapril was able to diminish proteinuria. As far as histological lesions, both treatments were effective, although only quinapril prevented GS. The combination of quinapril plus DZM did not demonstrate any beneficial effects. Surprisingly, quinapril ameliorated the damage of podocytes whereas DZM did not, thus leading to doubt concerning the efficiency of DZM in long-term studies. Nonetheless, the combination of quinapril plus DZM demonstrated a greater reduction in podocyte damage than treatment with DZM alone, which shows an interesting association in the prevention of longer-term glomerular damage. Few differences were found between prevention and treatment. CONCLUSIONS: Quinapril, but not DZM, was able to diminish proteinuria in OZR. Both treatments were effective in diminishing GS, although only quinapril totally prevented it. The combination of both drugs prevented long-term glomerular damage, which is intriguing.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease.

Type IV collagen is a predominant component of basement membranes, and glomeruli of a kidney filter approximately 70-90 liters of plasma every day through a specialized glomerular basement membrane (GBM). In Alport syndrome, a progressive disease primarily affecting kidneys, mutations in GBM-associated type IV collagen genes (COL4A3, COL4A4, or COL4A5) lead to basement membrane structural defects, proteinuria, renal failure, and an absence of all three GBM collagen triple helical chains because of obligatory posttranslational assembly requirements. Here, we demonstrate that transplantation of wild-type bone marrow (BM) into irradiated COL4A3(-/-) mice results in a possible recruitment of BM-derived progenitor cells as epithelial cells (podocytes) and mesangial cells within the damaged glomerulus, leading to a partial restoration of expression of the type IV collagen alpha3 chain with concomitant emergence of alpha4 and alpha5 chain expression, improved glomerular architecture associated with a significant reduction in proteinuria, and improvement in overall kidney histology compared with untreated COL4A3(-/-) mice or irradiated COL4A3(-/-) mice with BM from adult COL4A3(-/-) mice. The alpha3(IV) collagen produced by BM-derived podocytes integrates into the GBM and associates with other alpha-chains to form type IV collagen triple helical networks. This study demonstrates that BM-derived stem cells can offer a viable strategy for repairing basement membrane defects and conferring therapeutic benefit for patients with Alport syndrome.

Animals↗
PubMed2006

Kidney failure in mice lacking the tetraspanin CD151.

The tetraspanin CD151 is a cell-surface molecule known for its strong lateral interaction with the laminin-binding integrin alpha3beta1. Patients with a nonsense mutation in CD151 display end-stage kidney failure associated with regional skin blistering and sensorineural deafness, and mice lacking the integrin alpha3 subunit die neonatally because of severe abnormalities in the lung and kidney epithelia. We report the generation of Cd151-null mice that recapitulate the renal pathology of human patients, i.e., with age they develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation. However, neither skin integrity nor hearing ability are impaired in the Cd151-null mice. Furthermore, we generated podocyte-specific conditional knockout mice for the integrin alpha3 subunit that show renal defects similar to those in the Cd151 knockout mice. Our results support the hypothesis that CD151 plays a key role in strengthening alpha3beta1-mediated adhesion in podocytes.

Animals↗
PubMed2006

Cells differentiated from mouse embryonic stem cells via embryoid bodies express renal marker molecules.

Differentiation of mouse embryonic stem (ES) cells via embryoid bodies (EB) is established as a suitable model to study cellular processes of development in vitro. ES cells are known to be pluripotent because of their capability to differentiate into cell types of all three germ layers including germ cells. Here, we show that ES cells differentiate into renal cell types in vitro. We found that genes were expressed during EB cultivation, which have been previously described to be involved in renal development. Marker molecules characteristic for terminally differentiated renal cell types were found to be expressed predominantly during late stages of EB cultivation, while marker molecules involved in the initiation of nephrogenesis were already expressed during early steps of EB development. On the cellular level--using immunostaining--we detected cells expressing podocin, nephrin and wt-1, characteristic for differentiated podocytes and other cells, which expressed Tamm-Horsfall protein, a marker for distal tubule epithelial cells of kidney tissue. Furthermore, the proximal tubule marker molecules renal-specific oxido reductase, kidney androgen-related protein and 25-hydroxyvitamin D3alpha-hydroxylase were found to be expressed in EBs. In particular, we could demonstrate that cells expressing podocyte marker molecules assemble to distinct ring-like structures within the EBs. Because the differentiation efficiency into these cell types is still relatively low, application of fibroblast growth factor (FGF)-2 in combination with leukaemia inhibitory factor was tested for induction, but did not enhance ES cell-derived renal differentiation in vitro.

Animals↗
PubMed2006

High glucose and advanced glycosylated end-products affect the expression of alpha-actinin-4 in glomerular epithelial cells.

AIM: To investigate the molecular basis for the phenotypic alterations of glomerular epithelial cells (GEpC, podocytes), involving cytoskeletal changes especially on alpha-actinin-4 as a candidate regulating the barrier to protein filtration and the podocyte actin cytoskeleton. METHODS: To examine the effects of glucose and advanced glycosylated end-products (AGE) on alpha-actinin-4, the author cultured rat GEpC on AGE- or BSA-coated plates under normal (5 mmol) and high glucose (30 mmol) conditions and examined the distribution of alpha-actinin by confocal microscope and measured the change in alpha-actinin-4 production by western blotting and reverse transcription-polymerase chain reaction. RESULTS: Confocal microscopy indicated that alpha-actinin-4 moved from the peripheral cytoplasm to inner actin filament complexes in the presence of AGE and high glucose. These changes might be related to the fusion of microvilli of cell surface examined by electron microscopy. In western blot analysis, AGE significantly decreased the amount of alpha-actinin by 28.1%. Furthermore, the combination of high glucose and AGE decreased the amount of alpha-actinin more significantly by 53.6% compared with that of the control. The mRNA expression for alpha-actinin-4 was not changed with high glucose or AGE-coated surfaces; however, when added, the combination of high glucose and AGE significantly decreased the expression of alpha-actinin-4 mRNA by 15.7% compared with that of the control. CONCLUSION: The author suggests that both high glucose and AGE (either individually or in combination) induce the cytoplasmic translocation and the combination suppresses the production of alpha-actinin-4 at the transcriptional level with post-translational modification and these in vitro changes may explain the cytoskeletal changes of GEpC in diabetic conditions.

Actin Cytoskeleton↗
PubMed2005

Redox dependence of glomerular epithelial cell hypertrophy in response to glucose.

Podocytes or glomerular epithelial cells (GECs) are important targets of the diabetic microenvironment. Podocyte foot process effacement and widening, loss of GECs and hypertrophy are pathological features of this disease. ANG II and oxidative stress are key mediators of renal hypertrophy in diabetes. The cellular mechanisms responsible for GEC hypertrophy in diabetes are incompletely characterized. We investigated the effect of high glucose on protein synthesis and GEC hypertrophy. Exposure of GECs to high glucose dose dependently stimulated [(3)H]leucine incorporation, but not [(3)H]thymidine incorporation. High glucose resulted in the activation of ERK1/2 and Akt/PKB. ERK1/2 pathway inhibitor or the dominant negative mutant of Akt/PKB inhibited high glucose-induced protein synthesis. High glucose elicited a rapid generation of reactive oxygen species (ROS). The stimulatory effect of high glucose on ROS production, ERK1/2, and Akt/PKB activation was prevented by the antioxidants catalase, diphenylene iodonium, and N-acetylcysteine. Exposure of the cells to hydrogen peroxide mimicked the effects of high glucose. In addition, ANG II resulted in the activation of ERK1/2 and Akt/PKB and GEC hypertrophy. Moreover, high glucose and ANG II exhibited additive effects on ERK1/2 and Akt/PKB activation as well as protein synthesis. These additive responses were abolished by treatment of the cells with the antioxidants. These data demonstrate that high glucose stimulates GEC hypertrophy through a ROS-dependent activation of ERK1/2 and Akt/PKB. Enhanced ROS generation accounts for the additive effects of high glucose and ANG II, suggesting that this signaling cascade contributes to GEC injury in diabetes.

Animals↗
PubMed2003

A molecular look at the glomerular barrier.

The glomerular barrier is the kidney's physical block to the unrestricted flow of molecules from the plasma into the urinary space. Its exquisite selectivity allows solutes and water in the glomerular capillaries to pass through, but it prevents the bulk of plasma proteins, most notably albumin, from crossing. Classically, the barrier consists of three distinct components: glomerular endothelium, glomerular basement membrane, and glomerular epithelium (podocytes). In this review, I discuss these three components, with particular emphasis on the barrier presumed to be imparted by a specialized podocyte cell-cell junction, the glomerular slit diaphragm.

Animals↗
PubMed2005

Cell cycle and glomerular disease: a minireview.

Globally, glomerular diseases are a leading cause of chronic and end-stage renal disease. In the mature glomerulus, under normal conditions, glomerular cells have a low turnover rate. However, in disease, a variety of pathophysiological stimuli can lead to disturbances in glomerular cell biology, including toxins, immune-mediated stresses, metabolic derangements, drugs, infections, hemodynamic changes, growth factors, and cytokines. Not only does the form of injury govern the histologic and clinical manifestations of disease, but also the nature of the response to injury. This response to injury is largely cell-type specific, and the glomerulus represents a rare microcosm of the larger organism in which one can study the cellular responses of three very distinct cell types: mesangial cells, visceral epithelial cells or podocytes, and endothelial cells. These cells can undergo several cell fates in response to injury, including proliferation, de-differentiation, hypertrophy, senescence, apoptosis, or necrosis. The regulation of these responses occurs at the level of the cell cycle, coordinated by positive regulators, cyclins and cyclin-dependent kinases, and negative regulators, cyclin-dependent kinase inhibitors. There is now a large body of literature confirming the importance of cell cycle regulatory proteins in the glomerular cellular response to injury. The recent advances in cell cycle biology in diseases of the mesangial cell and the podocyte are the focus of this minireview.

Animals↗
PubMed2006

Beneficial effect of TGFbeta antagonism in treating diabetic nephropathy depends on when treatment is started.

BACKGROUND: In diabetic rats with maximal activation of RAS induced by uninephrectomy, late treatment with anti-TGFbeta antibody limited renal injury only when combined with ACE inhibitor. We investigated whether in a two-kidney diabetic model the time at which treatment started predicted the response to TGFbeta antagonist. METHODS: 27 weeks after streptozotocin injection, animals had mild proteinuria and were randomized to receive irrelevant antibody, anti-TGFbeta antibody (1D11) or enalapril till 52 weeks (early treatment). The effect of agents alone or combined was also evaluated at the time of overt proteinuria (late treatment, 52-61 weeks). RESULTS: When given early, 1D11 displayed marked antihypertensive and antiproteinuric effects. Glomerulosclerosis was reduced to the extent that a remarkable percentage of glomeruli without sclerosis appeared after treatment. Podocyte number was normalized. Renoprotection of 1D11 was comparable to enalapril. Despite control of blood pressure, in late treatment single agents did not reduce proteinuria significantly. Glomerulosclerosis and podocyte loss were partially limited by 1D11 or enalapril, but full protection was achieved by combination. CONCLUSIONS: Renoprotective effect of TGFbeta antagonism crucially depends on the time at which treatment started. Effectiveness of early treatment with 1D11 would indicate that TGFbeta is a major mediator of damage in early diabetes. To tackle the renal damage in the phase of advanced disease, a combined treatment with ACE inhibitor is needed.

Albuminuria↗
PubMed2006

Association of glomerular podocytopathy and nephrotic proteinuria in mesangial lupus nephritis.

We investigated a series of patients with systemic lupus erythematosus (SLE), who had sparse subepithelial and mesangial immune deposits. Our goal was to determine structure: function correlation. We examined whether proteinuria correlated with either capillary wall immune aggregate formation or abnormal podocyte morphology. Renal biopsies from patients with sparse (two or fewer subepithelial or intramembranous electron dense deposits per glomerular capillary loop) immune deposits and podocyte effacement were studied. Patients fulfilled criteria for the diagnosis of SLE. Cases were excluded if the biopsy showed endocapillary proliferation or necrosis. Eighteen biopsies were studied, five from patients with nephrotic range proteinuria (> or =3 g/day) and 13 from patients with non-nephrotic proteinuria (<3 g/day). The five nephrotic patients had a mean foot process effacement of 48% +/- 39% (range 10-100%). Thirteen non-nephrotic patients had a mean foot process effacement of 11.7% +/- 8% (range 0-20%). The only distinguishing morphologic finding associated with nephrotic range proteinuria was diffuse foot process effacement. No correlation between subepithelial deposits and proteinuria was observed. There were no other histologic differences between the nephrotic and non-nephrotic patients. Among these patients, the nephrotic syndrome appears best correlated with podocytopathy rather than subepithelial electron dense deposits, mesangial deposits, or mesangial hypercellularity.

Adult↗
PubMed2005

Expression and effect of inhibition of aminopeptidase-A during nephrogenesis.

Aminopeptidase-A (APA) is a metalloprotease that cleaves N-terminal aspartyl and glutamyl residues from peptides. Its best-known substrate is angiotensin II (Ang II), the most active compound of the renin-angiotensin system (RAS). The RAS is involved in renal development. Most components of the RAS system are expressed in the developing kidney. Thus far, APA has not been studied in detail. In the present study we have evaluated the expression of APA at the protein, mRNA, and enzyme activity (EA) level in the kidney during nephrogenesis. Furthermore, we have studied the effect of inhibiting APA EA by injection of anti-APA antibodies into 1-day-old mice. APA expression was observed from the comma stage onwards, predominantly in the developing podocytes and brush borders of proximal tubular cells. Notably, APA was absent in the medulla or the renal arterioles. Inhibition of APA EA caused temporary podocyte foot-process effacement, suggesting a minimum role for APA during nephrogenesis.

Animals↗
PubMed2005

T-cell activation and immunologic synapse.

The focus of my laboratory is in three areas. The first area is our long-standing interest in the mechanics of T-cell activation. In addition to our interest in protein phosphorylation mediated by T-cell receptor engagement, we have been interested in defining the function of the immunologic synapse. The second area of focus is on the pathogenesis of glomerular disease. Here we are interested in the function of the podocyte and trying to understand how genetic deficiency of CD2AP in podocytes leads to kidney failure. The third area is the effect of modifiers of protein kinase cascades. Here we are focused on scaffold proteins, namely KSR and its role in controlling the activation of mitogen-activated protein kinase.

14-3-3 Proteins↗
PubMed2005

Treatment of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is not a disease, but a lesion affecting the podocyte. Secondary FSGS may be due to a host of various factors, and patients are rarely nephrotic, requiring symptomatic treatment only. The best prognostic feature of nephrotic FSGS is its response to corticosteroids. Some forms are most likely of immunological origin, relapse in a renal transplant and justify immunosuppressive treatment. In a growing number of cases, genetic profiling of molecules that contribute to the podocyte slit diaphragm permselectivity to albumin has identified defects that do not represent indications for immunosuppression. In the other forms, corticosteroids and cyclosporin A (CsA) remain the mainstay of treatment, with better efficacy when CsA is associated with steroids. The renal tolerability of CsA is reasonably good when the dosage is low. CsA dependency is not constant. Alkylating agents are reluctantly indicated in steroid-sensitive forms, which are rare. They are mostly ineffective in steroid-resistant forms. Tacrolimus seems a promising therapy with low toxicity, but it is usual for dependency on the drug to occur. Sirolimus seems to be ineffective. Azathioprine is not considered indicated, despite rare reports with favourable results, which would deserve further controlled trials. Recent publications indicate that mycophenolate mofetil might usefully find a place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the elusive substance that causes the nephrotic syndrome and its relapse on a transplant has not led to practical treatment options.

Alkylating Agents↗
PubMed2005

Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms.

Galectins are beta-galactoside-binding lectins that are involved in various biologic processes, such as apoptosis, cell proliferation, and cell-cycle regulation. Galectin-9 (Gal-9) was identified previously and demonstrated to have apoptotic potential to thymocytes in mice and activated CD8(+) T cells in nephrotoxic serum nephritis model. In this study, the effect of Gal-9 on G1-phase cell-cycle arrest, one of the hallmark pathologic changes in early diabetic nephropathy, was investigated. Eight-week-old male db/db mice received injections of recombinant Gal-9 or vehicle for 8 wk. The injection of Gal-9 into db/db mice significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion. Gal-9 reduced glomerular expression of TGF-beta1 and the number of p27(Kip1)- and p21(Cip1)-positive cells in glomeruli. Double staining with nephrin and type IV collagen revealed that podocytes were mainly positive for p27(Kip1). For further confirming the cell-cycle regulation by Gal-9, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mM d-glucose supplemented with Gal-9. Cell-cycle distribution analyses revealed that Gal-9 maintained further progression of cell cycle from the G1 phase. Gal-9 reversed the high-glucose-mediated upregulation of p27(Kip1) and p21(Cip1) and inhibited cell-cycle-dependent hypertrophy, i.e., reduced [(3)H]proline incorporation. The data suggest that Gal-9 plays a central role in inducing their successful progression from G1 to G2 phase by suppressing glomerular expression of TGF-beta1 and inhibition of cyclin-dependent kinase inhibitors. Gal-9 may give an impetus to develop new therapeutic tools targeted toward diabetic nephropathy.

Animals↗