Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) is a serine protease that inhibits the degradation of glucagon-like peptide 1. DPP-4 inhibitors are used worldwide to treat type 2 diabetes mellitus and were recently shown to have pleiotropic effects such as anti-oxidant, anti-inflammatory, and anti-fibrotic actions. DPP-4 inhibitors improve albuminuria and renal injury including glomerular damage independent of its hypoglycemic effect. Although DPP-4 is mainly expressed in the kidney, the physiological function of DPP-4 remains unclear. METHODS: The localization of renal DPP-4 activity was determined in human renal biopsy specimens with glycyl-1-prolyl-4-methoxy-2-naphthylamide and the effects of a DPP-4 inhibitor were examined in human cultured podocyte. RESULTS: DPP-4 activity under normal conditions was observed in some Bowman's capsular epithelial cells and proximal tubules, but not in the glomerulus. DPP-4 activity was observed in crescent formation in anti-neutrophil myeloperoxidase cytoplasmic antigen antibody nephritis, nodular lesions in diabetic nephropathy, and some podocytes in focal segmental glomerulosclerosis. Notably, the DPP-4 inhibitor saxagliptin suppressed DPP-4 activity in podocytes and the proximal tubules. To assess the effect of DPP-4 inhibitor on podocytes, human cultured podocytes were injured by Adriamycin, which increased DPP-4 activity; this activity was dose-dependently suppressed by saxagliptin. Treatment with saxagliptin maintained the structure of synaptopodin and RhoA. Saxagliptin also improved the detachment of podocytes. CONCLUSIONS: DPP-4 activity induces degradation of synaptopodin and reduction of RhoA, resulting in destruction of the podocyte cytoskeleton. Saxagliptin may have pleiotropic effects to prevent podocyte injury.

Re-expression of Sall1 in podocytes protects against adriamycin-induced nephrosis.

The highly conserved spalt (sal) gene family members encode proteins characterized by multiple double zinc finger motifs of the C2H2 type. Humans and mice each have four known Sal-like genes (SALL1-4 in humans and Sall1-4 in mice). Sall1 is known to have a crucial role in kidney development. To explore the significance of Sall1 in differentiated podocytes, we investigated podocyte-specific Sall1-deficient mice (Sall1 KOp°d°/p°d°) using a podocin-Cre/loxP system and siRNA Sall1 knockdown (Sall1 KD) podocytes. Under physiological conditions, Sall1 KOp°d°/p°d° mice exhibited no proteinuria during their lifetime, but foot-process effacement was detected in some of the podocytes. To elucidate the role of Sall1 in injured podocytes, we used an adriamycin (ADR)-induced model of nephrosis and glomerulosclerosis. Surprisingly, the expression of Sall1 was elevated in control mice on day 14 after ADR injection. On day 28 after ADR injection, Sall1 KOp°d°/p°d° mice exhibited significantly higher levels of proteinuria and higher numbers of sclerotic glomeruli. Differentiated Sall1 KD podocytes showed a loss of synaptopodin, suppressed stress fiber formation, and, ultimately, impaired directed cell migration. In addition, the loss of Sall1 increased the number of apoptotic podocytes following ADR treatment. These results indicated that Sall1 has a protective role in podocytes; thus, we investigated the endoplasmic reticulum stress marker GRP78. GRP78 expression was higher in ADR-treated Sall1 KOp°d°/p°d° mice than in control mice. Sall1 appeared to influence the expression of GRP78 in injured podocytes. These results suggest that Sall1 is associated with actin reorganization, endoplasmic reticulum stress, and apoptosis in injured podocytes. These protective aspects of Sall1 re-expression in injured podocytes may have the potential to reduce apoptosis and possibly glomerulosclerosis.

Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD.

Studies have revealed many analogies between podocytes and neurons, and these analogies may be key to elucidating the pathogenesis of podocyte injury. Cathepsin D (CD) is a representative aspartic proteinase in lysosomes. Central nervous system neurons in CD-deficient mice exhibit a form of lysosomal storage disease with a phenotype resembling neuronal ceroid lipofuscinoses. In the kidney, the role of CD in podocytes has not been fully explored. Herein, we generated podocyte-specific CD-knockout mice that developed proteinuria at 5 months of age and ESRD by 20-22 months of age. Immunohistochemical analysis of these mice showed apoptotic podocyte death followed by proteinuria and glomerulosclerosis with aging. Using electron microscopy, we identified, in podocytes, granular osmiophilic deposits (GRODs), autophagosome/autolysosome-like bodies, and fingerprint profiles, typical hallmarks of CD-deficient neurons. CD deficiency in podocytes also led to the cessation of autolysosomal degradation and accumulation of proteins indicative of autophagy impairment and the mitochondrial ATP synthase subunit c accumulation in the GRODs, again similar to changes reported in CD-deficient neurons. Furthermore, both podocin and nephrin, two essential components of the slit diaphragm, translocated to Rab7- and lysosome-associated membrane glycoprotein 1-positive amphisomes/autolysosomes that accumulated in podocyte cell bodies in podocyte-specific CD-knockout mice. We hypothesize that defective lysosomal activity resulting in foot process effacement caused this accumulation of podocin and nephrin. Overall, our results suggest that loss of CD in podocytes causes autophagy impairment, triggering the accumulation of toxic subunit c-positive lipofuscins as well as slit diaphragm proteins followed by apoptotic cell death.

Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ-induced diabetic mice.

Rac1, a GTPase of the Rho subfamily, has a crucial role in cytoskeletal architecture, as well as the regulation of cell migration and growth. However, renal injury in mice with podocyte-specific deletion of Rac1 has yet to be elucidated fully due to conflicting findings. Herein, we identified a possible role for Rac1 in podocytes of streptozotocin- (STZ) induced diabetic mice. The urinary albumin/creatinine ratio (ACR) in the knockout (KO) group was significantly higher than that in the wild type (WT) group at any week of age. A more marked ACR increase was observed in STZ/KO group than STZ/WT group, although ACR did increase with weeks of age in both diabetic groups. The kidney sections from diabetic mice revealed a glomerular hypertrophy with mesangial expansion, but there was no appreciable difference in glomerular findings under a light microscope between STZ/WT and STZ/KO mice. However, an electron microscopy analysis revealed that regardless of the presence or absence of diabetes, both KO (KO and STZ/KO) groups had a higher rate of foot process effacement compared with both WT (WT and STZ/WT) groups. The expression levels of the slit diaphragm protein, podocin, was reduced with the induction of diabetes, and the levels in the STZ/KO group experienced a further reduction compared with the STZ/WT group. The number of WT1-positive cells in the STZ/KO group was more significantly decreased than that in the other three groups. In contrast, the numbers of cleaved caspase 3- and TUNEL-positive cells in the glomeruli of the STZ/KO group were more increased than those in the STZ/WT group. Thus, this study provides evidence that podocyte-specific deletion of Rac1 results in morphological alteration in podocytes, and that the induction of apoptosis or decreased expression of the slit diaphragm proteins by hyperglycemic stimuli are associated with the progression of diabetic nephropathy.

Enhanced auto-antibody production and Mott cell formation in FcµR-deficient autoimmune mice.

The IgM-Fc receptor (FcµR) is involved in IgM homeostasis as evidenced by increased pre-immune serum IgM and natural auto-antibodies of both IgM and IgG isotypes in Fcmr-deficient C57BL/6 (B6) mice. To determine the impact of Fcmr-ablation on autoimmunity, we introduced the Fcmr null mutation onto the Fas-deficient autoimmune-prone B6.MRL Fas (lpr/lpr) mouse background (B6/lpr). Both IgM and IgG auto-antibodies against dsDNA or chromatin appeared earlier in FcµR(-) B6/lpr than FcµR(+) B6/lpr mice, but this difference became less pronounced with age. Splenic B2 cells, which were 2-fold elevated in FcµR(+) B6/lpr mice, were reduced to normal B6 levels in FcµR(-) B6/lpr mice, whereas splenic B1 cells were comparable in both groups of B6/lpr mice. By contrast, marginal zone (MZ) B cells were markedly reduced in FcµR(-) B6/lpr mice compared with either FcµR(+) B6/lpr or wild type (WT) B6 mice. This reduction appeared to result from rapid differentiation of MZ B cells into plasma cells in the absence of FcµR, as IgM antibody to a Smith (Sm) antigen, to which MZ B cells are known to preferentially respond, was greatly increased in both groups (B6/lpr and B6) of FcµR(-) mice compared with FcµR(+) B6/lpr or B6 mice. Mott cells, aberrant plasma cells with intra-cytoplasmic inclusions, were also increased in the absence of FcµR. Despite these abnormalities, the severity of renal pathology and function and survival were all indistinguishable between FcµR(-) and FcµR(+) B6/lpr mice. Collectively, these findings suggest that FcµR plays important roles in the regulation of auto-antibody production, Mott cell formation and the differentiation of MZ B cells into plasma cells in B6.MRL Fas (lpr/lpr) mice.

Successful treatment of acute tubulointerstitial nephritis probably due to Benikoji CholesteHelp®, a supplement containing red yeast rice.

Red yeast rice has been used to produce alcoholic beverages and various fermented foods especially in East Asia. Since around March 2024, there have been many cases of kidney dysfunction in people who have taken certain supplements containing red yeast rice in Japan. We experienced a case of acute kidney injuries induced after taking a supplement containing red yeast rice. A 58-year-old woman was admitted to our hospital due to renal dysfunction suspected to be caused by taking the supplement Benikoji CholesteHelp®, which contains red yeast rice. With elevations of urinary tubular injury markers such as urinary ß2-microglobulin and N-acetyl-ß-D-glucosaminidase, serum creatinine levels were elevated up to 2.75 mg/dL. A kidney biopsy revealed a diagnosis of tubulointerstitial nephritis with lymphocytic infiltration of the interstitium, tubular atrophy, and interstitial fibrotic changes. After discontinuation of the supplement and initiation of the prednisolone treatment, renal dysfunction rapidly improved. The course of this case suggests tubular damage caused by the supplements containing red yeast rice. For early diagnosis and treatment, it should be noted that even what are regarded as nutritional health supplements can cause renal dysfunction.

Translocation of dendrin to the podocyte nucleus in acute glomerular injury in patients with IgA nephropathy.

BACKGROUND: It has been reported that podocytopenia has been occurring with increasing disease severity in patients with IgA nephropathy (IgAN). Dendrin is localized at the slit diaphragm (SD) in podocytes. We showed that dendrin translocates to the nucleus of injured podocytes in experimental nephritis and the nuclear dendrin promotes podocyte apoptosis. It is still unknown whether dendrin translocates from the SD to podocyte nucleus in IgAN. We investigated the presence of nuclear dendrin in patients with IgAN and the association between the translocated dendrin to the podocyte nucleus and disease activity. METHODS: Fourteen adult patients with IgAN were enrolled. The pathological parameters were analyzed. Immunostaining of renal biopsy specimens and urinary sediments from IgAN or minimal change nephrotic syndrome (MCNS) as the control was performed. RESULTS: A positive correlation was observed between an acute extracapillary change and the number of dendrin-positive nuclei. The location of dendrin in the nuclei was found in urinary podocytes of IgAN. The number of dendrin-positive nuclei in urinary podocytes of IgAN was significantly higher than that of MCNS. Urinary podocytes, which expressed the apoptosis marker annexin V, were also detected in IgAN. The translocation of dendrin to the podocyte nucleus as well as strong cathepsin L staining were detected in the glomeruli of IgAN. CONCLUSION: An increasing number of dendrin-positive nuclei in the glomeruli suggest acute glomerular injury in IgAN. Apoptotic podocytes were detectable in the urine of IgAN. It appears that the translocation of dendrin to the podocyte nuclei enhances podocyte apoptosis in acute glomerular injury and leads to podocytopenia in patients with IgAN.

Predictive factors associated with change rates of LV hypertrophy and renal dysfunction in CKD patients.

BACKGROUND: This longitudinal study is the first report on the factors associated with change rates of the estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) using echocardiography in chronic kidney disease (CKD) patients. METHODS: Measurements of biochemical and physical values, and LVMI evaluated by echocardiography were performed twice (baseline and follow-up period) in pre-dialysis CKD patients. Blood and urine samples were collected at the time of the echocardiographic study. RESULTS: The change rates of hemoglobin (Hb) and transferrin saturation (TSAT: (serum iron/total iron binding capacity)) were identified as independent risk factors for changes in eGFR by multivariate regression analysis. In the LVMI improvement group, the change rate of systolic blood pressure (sBP) was identified as an independent factor for change in LVMI. In the LVMI worsening group, the change rates of sBP, proteinuria and Hb were identified as independent risk factors for changes in LVMI. CONCLUSIONS: It appears that treatment of renal and iron deficiency anemia might prevent progression of renal dysfunction. To prevent LV hypertrophy in CKD patients, renal anemia, hypertension and proteinuria should be treated.

A Case of Successful Pregnancy and Delivery in a Chronic Renal Failure Patient with Membranoproliferative Glomerulonephritis and Preeclampsia-related Nephrotic Syndrome.

A 37-year-old woman with chronic kidney disease stage (CKD) G4 with membranoproliferative glomerulonephritis was hospitalized for nephrotic syndrome and hypertension due to superimposed preeclampsia at 27 weeks into her third pregnancy. Proteinuria did not worsen significantly after pulse steroid therapy. Delivery was induced at 30 weeks' gestation due to the maternal renal function and fetal growth. No obvious fetal complications other than preterm delivery were observed. In this case, we successfully managed a high-risk patient with membranoproliferative glomerulonephritis complicated by advanced CKD, nephrotic syndrome, and hypertension, which are independent risk factors for pregnancy complications.

Effects of 22-oxa-calcitriol on podocyte injury in adriamycin-induced nephrosis.

BACKGROUND: In various animal studies, vitamin D has been shown to have a significant effect on reduction of proteinuria and the progression of kidney disease. However, little is known on its renoprotective effect in adriamycin (ADR)-induced nephrosis mice. The present study was intended to determine the therapeutic benefit of 22-oxa-calcitriol (OCT), a vitamin D analog, in reducing proteinuria and its renoprotective effect, i.e. preventing podocyte injury on ADR-induced nephrosis mice. METHODS: Three experimental groups were used as follows: (1) nephrosis mice, established by a single intravenous injection of ADR; (2) ADR+OCT mice, nephrosis mice treated with OCT, and (3) mice treated only with OCT as the control group. Podocyte injury was assessed by podocyte apoptosis using the TUNEL assay, podocyte counting, podocyte-specific expressed protein by immunofluorescence and Western blot analysis, and foot process effacement using electron microscopy. RESULTS: Lower proteinuria was observed in ADR+OCT mice. Improvement in glomerulosclerosis and interstitial fibrosis, and prevention of glomerular hyperfiltration were observed in ADR+OCT mice. Immunofluorescence and Western blot analyses showed restoration of downregulated expression of nephrin, CD2AP and podocin. Nevertheless, dendrin expression was not restored. An insignificant reduction in podocyte numbers was found in ADR+OCT mice. Complete foot process effacement was partially prevented in ADR+OCT mice. CONCLUSIONS: The results indicate that OCT reduces podocyte injury and has renoprotective effects in ADR nephrosis mice.

Significance of broad distribution of electron-dense deposits in patients with IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is characterized by mesangial cell proliferation and mesangial expansion with mesangial depositions of IgA. We have found that electron-dense deposits (EDD) are often observed in areas other than paramesangial areas in glomeruli. To compare electron microscopic findings with light microscopic findings and clinical data, we examined the biopsies from 178 patients with IgAN. Patients were divided into two groups: group A had only paramesangial deposits and group B had deposits not only in paramesangial areas but also in other areas. All patients examined in this study had EDD in glomerular paramesangial areas. Thirty-six patients were included in group B. Cellular crescent formation in glomeruli and urinary protein in group B were significantly higher than those in group A (P < 0.01). Serum albumin and estimated glomerular filtration rate (eGFR) in group B were significantly lower than those in group A (P < 0.05). Group B showed a significant positive correlation with histological severity, which is defined in the Japanese Clinical Guidelines on IgAN. In patients with broad distribution of EDD, urinary protein was significantly increased (P < 0.05). Detailed observation of EDD distribution has an impact on evaluation of the disease activity of IgAN.

Dendrin location in podocytes is associated with disease progression in animal and human glomerulopathy.

BACKGROUND: Adriamycin (ADR) nephrosis in mice has been extensively studied and has enabled a greater understanding of the processes underlying the progression of renal injury. Dendrin is a novel component of the slit diaphragm with proapoptotic signaling properties, and it accumulates in the podocyte nucleus in response to glomerular injury in mice. The present study re-evaluated chronic progressive nephropathy in ADR mice and the localization of dendrin in mice and in human glomerulopathy. METHODS: To investigate the localization of dendrin, a mouse model of nephrosis and glomerulosclerosis was used, in which ADR was injected once. WT-1-positive cells and apoptotic cells were counted in vivo and in vitro. To check the expression of dendrin in ADR mice, immunostaining and Western blot were performed. A survey of dendrin staining was performed on human kidney biopsy specimens. RESULTS: The injection of ADR induced proteinuria, podocyte loss and glomerulosclerosis. It also caused the relocation of dendrin from the slit diaphragm to the podocyte nucleus. We demonstrated the location of dendrin to podocyte nuclei in several cases of human glomerulopathy. The mean occurrence of dendrin-positive nucleus per glomerulus increased in several cases of human glomerulopathy. CONCLUSIONS: These findings suggest that the relocation of dendrin to the podocyte nuclei is useful as a novel marker of podocyte injury in human glomerulopathy.

Mindin: a novel marker for podocyte injury in diabetic nephropathy.

BACKGROUND: GeneChip Expression Analysis was employed to survey the glomerular gene expression profile in a type 2 diabetes (T2D) model of KK/Ta mice fed with a high-calorie diet (HC), and we focused on the role of mindin (also called spondin 2), whose expression is upregulated by HC. METHODS: Isolated glomeruli from three 20-week-old KK/Ta mice fed with HC or a standard diet (SD) were dissected. Total RNA was extracted and labelled for hybridization using the Affymetrix GeneChip Mouse Genome 430 2.0 Array. The gene expression profile was compared between the HC and SD groups using GeneSpring 7.3.1 software. Mindin expression was examined using real-time PCR, western blot analysis and immunohistochemical staining in the glomeruli, cultured podocytes and urine samples of both mice and humans. RESULTS: Podocyte foot process effacement was observed in mice fed with HC. The mindin protein expression levels in mice were localized in the podocytes, and their levels in the glomeruli were increased in the HC group compared with the SD group. The levels of urinary mindin in the HC group at 16 weeks of age were also significantly higher than those in the SD group although albumin/creatinine ratio (ACR) did not differ between the groups. Furthermore, the levels in patients with T2D were higher than those in healthy individuals and increased gradually with increases in ACR. CONCLUSIONS: Mindin could be related to podocyte injury and appears to be an early biomarker of the progression of diabetic nephropathy.

Expression of Cathepsin L and Its Intrinsic Inhibitors in Glomeruli of Rats With Puromycin Aminonucleoside Nephrosis.

Cathepsin L, a lysosomal cysteine proteinase, may have a key role in various biological and disease processes by intracellular and extracellular degradation of proteins. We examined the levels of cathepsin L and its intrinsic inhibitors in glomeruli of rats with puromycin aminonucleoside (PAN) nephrosis. In contrast to the weak levels of cathepsin L in normal glomeruli, on days 4 and 8, strong immunostaining was detected in almost all podocytes when proteinuria and pathological changes of the podocytes developed. Cathepsin L was reduced after day 28, but remained in a focal and segmental manner. Cystatin ß, an intracellular inhibitor, was not detected in podocytes. However, cystatin C, an extracellular inhibitor, was detected in podocytes after day 4, coincident with cathepsin L. Cystatin C levels were gradually reduced but sustained in many podocytes on day 28, while cystatin C was not detected in podocytes sustained cathepsin L. These results demonstrated that cathepsin L levels are not always accompanied by the levels of its inhibitors in podocytes of PAN nephrosis, suggesting a potential role of cathepsin L in podocyte injury, which is a critical process for the development and progression of tuft adhesion and sclerosis.

Neurofilament heavy polypeptide protects against reduction in synaptopodin expression and prevents podocyte detachment.

Podocytes are highly specialized cells that line the glomerulus of the kidney and play a role in filtration. Podocyte injury plays a critical role in the development of many kidney diseases, but the underlying mechanisms remain unclear. In this study, we identified that neurofilament heavy polypeptide (NEFH), an intermediate filament component, protects podocyte from injury. We observed that NEFH was upregulated after ADRIAMYCIN(ADR)-induced podocyte injury in both mice and cultured murine podocytes. Immunofluorescence and co-immunoprecipitation analyses revealed that NEFH was colocalized with synaptopodin, a podocyte-specific marker. High NEFH expression in podocytes prevented the Adriamycin-induced reduction in synaptopodin expression. The siRNA-mediated knockdown of NEFH in podocytes reduced the number of vinculin-containing focal contacts, thereby reducing adhesion to the extracellular matrix and increasing podocyte detachment. In addition, NEFH expression was significantly increased in renal biopsy specimens from patients with focal segmental glomerulosclerosis and membranous nephropathy, but in those with minimal change disease. These findings indicate that NEFH is expressed in podocytes during the disease course and that it prevents the reduction in synaptopodin expression and detachment of podocytes.

Rac1 in podocytes promotes glomerular repair and limits the formation of sclerosis.

Rac1, a Rho family member, is ubiquitously expressed and participates in various biological processes. Rac1 expression is induced early in podocyte injury, but its role in repair is unclear. To investigate the role of Rac1 expression in podocytes under pathological conditions, we used podocyte-specific Rac1 conditional knock-out (cKO) mice administered adriamycin (ADR), which causes nephrosis and glomerulosclerosis. Larger areas of detached podocytes, more adhesion of the GBM to Bowman's capsule, and a higher ratio of sclerotic glomeruli were observed in Rac1 cKO mice than in control mice, whereas no differences were observed in glomerular podocyte numbers in both groups after ADR treatment. The mammalian target of rapamycin (mTOR) pathway, which regulates the cell size, was more strongly suppressed in the podocytes of Rac1 cKO mice than in those of control mice under pathological conditions. In accordance with this result, the volumes of podocytes in Rac1 cKO mice were significantly reduced compared with those of control mice. Experiments using in vitro ADR-administered Rac1 knockdown podocytes also supported that a reduction in Rac1 suppressed mTOR activity in injured podocytes. Taken together, these data indicate that Rac1-associated mTOR activation in podocytes plays an important role in preventing the kidneys from developing glomerulosclerosis.

Sorting Nexin 9 facilitates podocin endocytosis in the injured podocyte.

The irreversibility of glomerulosclerotic changes depends on the degree of podocyte injury. We have previously demonstrated the endocytic translocation of podocin to the subcellular area in severely injured podocytes and found that this process is the primary disease trigger. Here we identified the protein sorting nexin 9 (SNX9) as a novel facilitator of podocin endocytosis in a yeast two-hybrid analysis. SNX9 is involved in clathrin-mediated endocytosis, actin rearrangement and vesicle transport regulation. Our results revealed and confirmed that SNX9 interacts with podocin exclusively through the Bin-Amphiphysin-Rvs (BAR) domain of SNX9. Immunofluorescence staining revealed the expression of SNX9 in response to podocyte adriamycin-induced injury both in vitro and in vivo. Finally, an analysis of human glomerular disease biopsy samples demonstrated strong SNX9 expression and co-localization with podocin in samples representative of severe podocyte injury, such as IgA nephropathy with poor prognosis, membranous nephropathy and focal segmental glomerulosclerosis. In conclusion, we identified SNX9 as a facilitator of podocin endocytosis in severe podocyte injury and demonstrated the expression of SNX9 in the podocytes of both nephropathy model mice and human patients with irreversible glomerular disease.

The influence of incontinence on the characteristic properties of the skin in bedridden elderly subjects.

BACKGROUND: The mechanisms of skin breakdown induced by incontinence have been proposed from a variety of experimental studies. However, studies on the influence of skin properties caused by incontinence of bedridden subjects are very limited. OBJECTIVE: This work was conducted to reveal how incontinence influences skin properties by comparing bedridden incontinent elderly subjects with age-matched healthy continent elderly and middle-aged subjects. METHODS: Bedridden incontinent elderly subjects (n = 35, 83.5 ± 9.7 years, mean age ± SD), healthy continent elderly (n = 41, 75.9 ± 5.6 years), and middle-aged (n = 20, 41.3 ± 2.8 years) were recruited for this study. Skin surface pH, capacitance/hydration, transepidermal water loss, and bacteria on forearm and buttock skin were measured. RESULTS: Hydration and transepidermal water loss values between healthy elderly subjects and incontinent elderly subjects were significantly different on buttock skin. Significant differences between those two groups were also observed regarding pH and total bacteria levels on buttock skin. The forearm skin showed no significant difference in these parameters. No significant influence was observed between with and without urination at the measurement time except for the pH of buttock skin. No significant correlation was observed except between pH and bacteria levels on buttock skin of incontinent elderly subjects. CONCLUSION: In this study, we clarified the characteristic features of skin induced by incontinence. Our results indicate that these parameters are adequate not only to evaluate the characteristic skin features of bedridden incontinent subjects but also to develop new diapers to avoid the diaper dermatitis caused by incontinence.

Combination therapy with telmisartan and oxacalcitriol suppresses the progression of murine adriamycin nephropathy.

BACKGROUND: Blockade of the renin-angiotensin system plays a key role in suppressing the progression of renal diseases. It has not been well established whether this therapy provides additional effects when combined with vitamin D or its analog in a model of adriamycin (ADR)-induced nephropathy. METHODS: We evaluated the effect of an angiotensin II subtype 1 receptor blocker (telmisartan) combined with a vitamin D analog (oxacalcitriol) on mice ADR-induced nephropathy (9.5 mg/kg single intravenous injection). We also tested immortalized murine podocytes to examine the effects on podocyte apoptosis. RESULTS: Mice with ADR-induced nephropathy developed progressive albuminuria and glomerulosclerosis within 30 days accompanied by decreased expression of slit diaphragm (SD)-associated proteins (nephrin and podocin), reduced numbers of podocytes, and increased systolic blood pressure. Treatment with telmisartan or oxacalcitriol alone moderately ameliorated kidney injury. The combined treatment most effectively reduced the albuminuria and glomerulosclerosis. These effects were accompanied by the restoration of SD-associated proteins, reduction of podocyte apoptosis, and prevention of podocyte depletion in the glomeruli. Treatment with telmisartan, oxacalcitriol, and the combination therapy resulted in similar reductions in systolic blood pressure. In cultured murine podocytes, ADR stimulated the expression of Bax/Bcl-2 and apoptosis as determined by Hoechst 33342 staining. These changes were effectively inhibited by telmisartan or oxacalcitriol, but the combination treatment most effectively reduced these effects. CONCLUSIONS: These data demonstrated that application of a renin-angiotensin system blocker plus a vitamin D analog effectively prevented renal injury in ADR-induced nephropathy. The observed amelioration of renal injury may be partly attributable to antiapoptotic effects in podocytes.

Notch2 activation ameliorates nephrosis.

Activation of Notch1 and Notch2 has been recently implicated in human glomerular diseases. Here we show that Notch2 prevents podocyte loss and nephrosis. Administration of a Notch2 agonistic monoclonal antibody ameliorates proteinuria and glomerulosclerosis in a mouse model of nephrosis and focal segmental glomerulosclerosis. In vitro, the specific knockdown of Notch2 increases apoptosis in damaged podocytes, while Notch2 agonistic antibodies enhance activation of Akt and protect damaged podocytes from apoptosis. Treatment with triciribine, an inhibitor of Akt pathway, abolishes the protective effect of the Notch2 agonistic antibody. We find a positive linear correlation between the number of podocytes expressing activated Notch2 and the number of residual podocytes in human nephrotic specimens. Hence, specific activation of Notch2 rescues damaged podocytes and activating Notch2 may represent a novel clinical strategy for the amelioration of nephrosis and glomerulosclerosis.