Changes in awareness of cancer risk factors among adult New Zealanders (CAANZ): 2001 to 2015.

Behaviour change, specifically that which decreases cancer risk, is an essential element of cancer control. Little information is available about how awareness of risk factors may be changing over time. This study describes the awareness of cancer risk behaviours among adult New Zealanders in two cross-sectional studies conducted in 2001 and 2014/5.Telephone interviews were conducted in 2001 (n = 436) and 2014/5 (n = 1064). Participants were asked to recall things they can do to reduce their risk of cancer. They were then presented with a list of potential risk behaviours and asked if these could increase or decrease cancer risk.Most New Zealand adults could identify at least one action they could take to reduce their risk of cancer. However, when asked to provide specific examples, less than a third (in the 2014/5 sample) recalled key cancer risk reduction behaviours such as adequate sun protection, physical activity, healthy weight, limiting alcohol and a diet high in fruit. There had been some promising changes since the 2001 survey, however, with significant increases in awareness that adequate sun protection, avoiding sunbeds/solaria, healthy weight, limiting red meat and alcohol, and diets high in fruit and vegetables decrease the risk of developing cancer.

Inhibition of complement regulation is key to the pathogenesis of active Heymann nephritis.

Crry (complement receptor 1-related protein/gene y) is a key cellular complement regulator in rodents. It is also present in Fx1A, the renal tubular preparation used to immunize rats to induce active Heymann nephritis (HN), a model of membranous nephropathy. We hypothesized that rats immunized with anti-Fx1A develop autoantibodies (auto-Abs) to Crry as well as to the megalin-containing HN antigenic complex, and that anti-Crry Abs promote the development of injury in HN by neutralizing the complement regulatory activity of Crry. Rats immunized with Fx1A lacking Crry remained free of proteinuria and glomerular deposits of C3 during a 10-wk follow-up despite typical granular immunoglobulin (Ig)G deposits in glomeruli. Anti-Fx1A auto-Abs were present in their sera at levels that were not different from sera pooled from proteinuric rats with HN induced with nephritogenic Fx1A. Passive administration of sheep anti-Crry Abs to rats immunized with Crry-deficient Fx1A led to proteinuria and glomerular C3 deposition, which were not seen in such rats injected with preimmune IgG, nor in rats with collagen-induced arthritis injected with anti-Crry IgG. To directly examine the role of Crry in HN, rats were immunized with Crry-deficient Fx1A reconstituted with rCrry. This led to typical HN, with 8 out of 15 rats developing proteinuria within 14 wk. Moreover, the extent of glomerular C3 deposition correlated with proteinuria, and anti-Crry Abs were present in glomerular eluates. Thus, Crry is a key nephritogenic immunogen in Fx1A. Formation of neutralizing auto-Abs to Crry impairs its function, leading to unrestricted complement activation by Abs reactive with the HN antigenic complex on the epithelial cell surface.

Transgenic mice overexpressing the complement inhibitor crry as a soluble protein are protected from antibody-induced glomerular injury.

Complement receptor 1-related gene/protein y (Crry) is a potent murine membrane complement regulator that inhibits classical and alternative pathway C3 convertases. In nephrotoxic serum (NTS) nephritis, injected antibodies (Abs) bind to glomeruli, leading to complement activation and subsequent glomerular injury and albuminuria. To study the phenotypic effects of continuous complement pathway blockade, transgenic mice were created that express recombinant soluble (rs) Crry directed by the broadly active and heavy metal-inducible metallothionein-I promoter. One transgenic line expressing high levels of rsCrry was propagated. Serum rsCrry levels were 18.7 +/- 2.7 microg/ml (n = 5) at basal level and increased to 118.1 +/- 20.6 microg/ml 4 d after addition of zinc to the drinking water. By reverse transcription polymerase chain reaction (RT-PCR), transgene messenger (m)RNA was present in liver, kidney, brain, lung, and spleen, but not in heart. By in situ RT-PCR analysis of kidneys, transgene mRNA was widely expressed both in renal glomeruli and tubules. Urinary excretion of rsCrry was 113.4 +/- 22.4 microg/ml with a fractional excretion relative to creatinine of 13.2 +/- 2.7%, consistent with local renal production of rsCrry and secretion into urine. The founder and all transgene positive adult animals have remained healthy with no mortality or apparent phenotypic abnormalities, including infection or immune complex disease. To determine whether rsCrry blocked complement-mediated injury, NTS nephritis was induced by injection of NTS immunoglobulin (Ig)G, followed by an 18-h urine collection to quantitate the excretion of albumin as a measure of glomerular injury. In transgene-negative littermates (n = 15), transgene-positive animals (n = 10), and transgene-positive animals fed zinc (n = 10), albuminuria was 4,393 +/- 948, 1,783 +/- 454, and 1,057 +/- 277 microg/mg creatinine, respectively (P < 0.01 by ANOVA). Glomerular C3 was evident by immunofluorescence staining in 12/15 transgene-negative animals, but in none of the transgene-positive animals fed zinc. Thus, we have produced the first transgenic animals that overexpress a soluble C3 convertase inhibitor. rsCrry expression markedly ameliorates an Ab-induced disease model in vivo. These results support the hypothesis that continuous complement inhibition at the C3 convertase step is feasible and effective in complement-mediated injury states.

C3aR inhibition reduces neurodegeneration in experimental lupus.

Complement activation is an important aspect of systemic lupus erythematosus. In this study we investigated the role of C3a/C3a receptor (R) signaling in brains of the lupus model, MRL/lpr mice, by treating the mice with C3aR antagonist (a) from 13 to 19 weeks of age. C3aR mRNA (0.2 +/- 0.027 versus 0.56 +/- 0.19) and protein (0.16 +/- 0.09 versus 0.63 +/- 0.19) expression was increased in MRL/lpr brains compared with MRL+/+ controls. Apoptosis, a key feature in lupus brain, was significantly reduced by C3aRa treatment, as assessed by DNA laddering, TUNEL staining and caspase3 activity (48% of MRL/lpr mice). mRNA expression of proinflammatory molecules that cause apoptosis, TNFalpha (0.33 +/- 0.07 versus 0.15 +/- 0.1), MIP2 (3.8 +/- 1.3 versus 1.7 +/- 0.6), and INFgamma (4.8 +/- 1.0 versus 2.07 +/- 1.28) are reduced in MRL/lpr brains with C3aRa treatment. In line with these results, Western blotting demonstrates the significant increase in phosphorylation of survival molecules Akt and Erk, decrease in PTEN and reduced iNOS expression. INFgamma receptor (R) and AMPA-GluR1 co-localized, and concomitant with reduced INFgammaR expression, AMPAGluR1 expression was also decreased by C3aR antagonist. All of these variables that modulate neuronal excitability and regulate synaptic plasticity are C3aR dependent in the MRL/lpr brains and suggest a potential therapeutic role for C3aR inhibition in CNS lupus.

Inhibition of NF-kappaB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis.

Apoptosis and inflammation, important contributors to the progression of chronic kidney disease, can be influenced by clusterin (a secreted glycoprotein that regulates apoptosis) and nuclear factor-kappaB (NF-kappaB, a transcription factor modifying the expression of inflammatory genes). We studied proteinuria-induced renal disease and its influence on clusterin-mediated apoptosis. Exposure of cultured mouse proximal tubule epithelial cells to bovine serum albumin (BSA) resulted in activation of NF-kappaB and activator protein-1 (AP-1) within hours followed by a decline in their activation, decreased activation of extracellular signal-regulated kinases (ERK1/2), decreased cell-associated antiapoptotic Bcl-xL protein but increased apoptosis. Clusterin progressively increased in the media over a 3 day period. Clusterin siRNA blocked protein production, increased NF-kappaB activation, and significantly increased cellular Bcl-xL protein, thereby reducing spontaneous and BSA-induced apoptosis. An siRNA to the NF-kappaB inhibitor IkappaBalpha had similar results. BSA-stimulated NF-kappaB activation reciprocally decreased AP-1 activity by preventing ERK1/2 phosphorylation. These in vitro studies suggest that clusterin inhibits NF-kappaB-mediated antiapoptotic effects by the apparent stabilization of IkappaBalpha switching from promoting inflammation to apoptosis during proteinuria.

Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure. Dose-response relationships, correlation with circulating catecholamines, and effect of phosphodiesterase inhibition.

We infused dobutamine into the left main coronary artery of 24 patients with severe congestive heart failure (CHF) and 8 normal subjects without hemodynamic dysfunction. The maximal +dP/dt response to intracoronary (IC) dobutamine in CHF patients was only 37% of that in normals. This decrease in maximal response was not associated with a rightshift in the EC50 for dobutamine's effect on +dP/dt, or a decrease in the affinity of myocardial beta adrenergic receptors for dobutamine determined in vitro. In nine of the CHF patients, IC dobutamine infusion was followed by IC infusion of the phosphodiesterase inhibitor milrinone, and subsequently, by a second IC infusion of dobutamine. After IC milrinone, the increase in +dP/dt caused by IC dobutamine (74 +/- 10%) was significantly greater than that caused by the first infusion of dobutamine (52 +/- 11%; P less than 0.003) or milrinone (42 +/- 6%; P less than 0.001). Resting plasma norepinephrine was markedly elevated in CHF patients (837 +/- 208 ng/liter), but not in normal subjects (142 +/- 32 ng/liter); and the increase in +dP/dt caused by IC dobutamine was inversely related to resting plasma norepinephrine levels (r = -0.653; P less than 0.001). IC dobutamine caused a dose-related decrease in plasma norepinephrine (maximal effect, -160 +/- 31 ng/liter; P less than 0.001). Thus, (a) the maximal inotropic response to dobutamine is markedly depressed in patients with severe CHF, and is significantly greater after pretreatment with the phosphodiesterase inhibitor milrinone; (b) the impairment in inotropic response to dobutamine is inversely related to circulating norepinephrine levels; and (c) myocardial stimulation by dobutamine results in withdrawal of sympathetic tone.

Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes.

Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH(-/-) MRL-lpr mice, which exhibited higher levels of circulating nucleosomes and necrotic cells than their CFH(+/+) littermates. This unconventional function of FH broadens the established view of apoptotic cell clearance and appears particularly important considering the strong associations with genetic FH alterations and diseases such as systemic lupus erythematosus and age-related macular degeneration.

Relation of thallium uptake to morphologic features of chronic ischemic heart disease: evidence for myocardial remodeling in noninfarcted myocardium.

OBJECTIVES: The aim of this study was to investigate the disparity between the extent of myocardial injury as assessed by thallium and the severity of left ventricular (LV) dysfunction in chronic ischemic heart disease. BACKGROUND: Although it is believed that thallium differentiates between viable and nonviable myocardium, in some patients with chronic ischemic heart disease, viable regions by thallium may fail to improve function after revascularization. METHODS: Thirteen transplant candidates with chronic ischemic heart disease (LV ejection fraction = 14 +/- 6% at rest) were studied prospectively with stress-redistribution-reinjection thallium single-photon emission computed tomography. We examined pretransplantation quantitative thallium uptake and post-transplantation extent and the histological distribution of collagen replacement in infarcted and noninfarcted myocardium and in 13 age-matched control hearts. RESULTS: The volume fraction of collagen varied inversely with wall thickness (r = -0.70, p < 0.001) and was higher in irreversible (30.9 +/- 15.8%) compared with reversible (20.2 +/- 12.6%, p < 0.001) or normal thallium segments (15.0 +/- 8.7%, p < 0.001). The irreversible thallium segments had lower wall thickness and more severe coronary artery narrowing (9.7 +/- 2.8 mm and 95 +/- 8%) compared with reversible (11.7 +/- 2.7 mm and 87 +/- 13%, p < 0.001) and normal thallium segments (12.8 +/- 2.6 mm and 80 +/- 14%, p < 0.001). Mean volume fraction of collagen was significantly lower in noninfarcted than it was in infarcted segments (13 +/- 6% vs. 36 +/- 13%, p < 0.001) but exceeded that in the control hearts (4 +/- 2%, p < 0.001). Noninfarcted segments had predominantly interstitial fibrosis with either microscopic or patchy areas of replacement fibrosis. CONCLUSIONS: In chronic ischemic heart disease with severe LV dysfunction, patterns of normal, reversible and irreversible thallium uptake correlated with the magnitude of collagen replacement, segmental wall thickness and severity of coronary artery narrowing. The finding of scattered areas of replacement fibrosis in noninfarcted myocardium may explain the observed disparity between LV contractile dysfunction and the extent of myocardial injury assessed by thallium.

Mechanism of the attenuated peak heart rate response to exercise after orthotopic cardiac transplantation.

The mechanism responsible for attenuation of the peak heart rate response to exercise in patients after cardiac transplantation was studied. Because the donor heart is believed to be surgically denervated, the peak heart rate response to exercise is dependent primarily on 1) an increase in the circulating levels of the catecholamines norepinephrine and epinephrine at peak exercise, and 2) the end-organ responsiveness of the sinoatrial (SA) node to beta-adrenergic stimulation. To assess the former mechanism, the levels of plasma nonepinephrine and epinephrine were measured at rest and at peak exercise on a cycle ergometer in 23 transplant recipients an average of 7 +/- 1 months after transplantation and in 23 normal subjects matched for age. To assess the latter mechanism, the heart rate response to a graded infusion of isoproterenol was determined in six normal subjects with and without atropine pretreatment and in eight transplant recipients. In transplant recipients, both the absolute plasma levels of nonepinephrine and epinephrine at peak exercise and the increments from baseline to peak exercise were comparable with or greater than those in normal subjects. In transplant recipients, the isoproterenol dose that increased heart rate by 25 beats/min over baseline was not different from that in atropine-treated normal subjects (normal subjects 9 +/- 2 ng/kg per min; transplant recipients 11 +/- 1 ng/kg per min; p = NS). These data show that after cardiac transplantation, there is a normal or slight elevation of circulating catecholamines at peak exercise, and that the responsiveness of the SA node to beta-adrenergic stimulation is normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness and safety of diltiazem or lisinopril in treatment of hypertension after heart transplantation. Results of a prospective, randomized multicenter trail.

OBJECTIVES: The purpose of this study was to determine the effectiveness and safety of diltiazem or lisinopril for treatment of hypertension after heart transplantation. BACKGROUND: Systemic hypertension is common after heart transplantation, and to date there are no randomized, prospective multicenter treatment trials. METHODS: Members of the Cardiac Transplant Research Database Group developed and implemented a prospective, randomized multicenter trial of the effectiveness and safety of diltiazem or lisinopril in the treatment of hypertension in cyclosporine-treated patients after heart transplantation. RESULTS: One hundred sixteen patients with hypertension (blood pressure > or = 140/90 mm Hg) after heart transplantation were randomized for > or = 3 months of treatment. Of 55 diltiazem-treated patients, 21 (38%) were responders (diastolic blood pressure < 90 mm Hg), 23 (42%) were nonresponders (diastolic blood pressure > or = 90 mm Hg), and 11 (20%) were withdrawn from the study. Of 61 lisinopril-treated patients, 28 (46%) were responders, 22 (36%) were nonresponders, and 11 (18%) were withdrawn. There was no difference in baseline characteristics or percent responders between the two groups. Systolic pressure decreased from 157 +/- 2.3 to 130 +/- 2.0 mm Hg (mean +/- 1 SEM) in the diltiazem-treated responders and from 153 +/- 2.1 to 127 +/- 2.7 mm Hg in the lisinopril-treated responders (p < 0.0001). Diastolic pressure decreased from 100 +/- 0.9 to 85 +/- 1.6 mm Hg in the diltiazem-treated responders and from 100 +/- 1.0 to 84 +/- 2.0 mm Hg in the lisinopril-treated responders (p < 0.0001). There were a total of 35 reported adverse events, 22 of which led to withdrawal of the patient from the study. All drug-related side effects were considered minor and resolved with discontinuation of the drug. CONCLUSIONS: These results indicate that both diltiazem and lisinopril are safe for treatment of hypertension after heart transplantation, although titrated monotherapy with either drug controlled the condition in < 50% of patients.

Local steroids in dialysis-associated pericardial effusion. A single intrapericardial administration of triamcinolone.

Five patients receiving maintenance hemodialysis for end-stage renal disease underwent therapeutic pericardiocentesis for pericarditis manifested by either cardiac tamponade or effusion unresponsive to conservative therapy. Pericardiocentesis was followed by a one-time instillation of triamcinolone hexacetonide, a nonabsorbable corticosteroid, into the pericardial space with subsequent needle withdrawal. All patients had prompt hemodynamic and symptomatic improvement. Serial echocardiograms showed resolution of the pericardial effusion in all patients. Follow-up evaluation for six months to six years has shown no clinical or postmortem evidence of recurrence. This procedure appears safe and effective and potentially can obviate the need for prolonged catheter drainage or more invasive surgical procedures as therapy for these patients.

Effects of intravenous milrinone followed by titration of high-dose oral vasodilator therapy on clinical outcome and rehospitalization rates in patients with severe heart failure.

This study evaluated the efficacy of intravenous milrinone in improving hemodynamics and facilitating the titration of high-dose oral vasodilator therapy to improve clinical status. Fourteen patients (mean age 52 +/- 12 years) with severe heart failure and a left ventricular ejection fraction of 18 +/- 6% underwent right-side heart catheterization and an intravenous milrinone infusion followed by titration of oral vasodilator and diuretic therapy. Milrinone significantly (p <0.05) improved right atrial pressure (12 +/- 5 to 8 +/- 5 mm Hg), pulmonary capillary wedge pressure (23 +/- 7 to 15 +/- 7 mm Hg), cardiac index (1.9 +/- 0.4 to 3.4 +/- 0.5 L/min/m2), systemic vascular resistance (1,809 +/- 526 to 891 +/- 144 dynes/s/cm(-5)), and pulmonary vascular resistance (285 +/- 151 to 163 +/- 68 dynes/s/cm(-5)), which was maintained in 10 patients with titration of high-dose oral vasodilator therapy. Oral angiotensin-converting enzyme inhibitor and diuretic doses were increased 318% and 89%, respectively. Four patients also received hydralazine to optimize hemodynamics. New York Heart Association functional class improved from 3.8 +/- 0.4 to 2.6 +/- 0.6 following therapy. Ten patients who responded to therapy had fewer hospitalized days during the subsequent year compared with the year before treatment (4 +/- 17 vs 17 +/- 15), and no patient died. In contrast, the 3 patients who responded poorly to therapy tended to have more hospitalized days at 12 months compared with pretreatment (31 +/- 11 vs 20 +/- 18; NS); 1 patient died. We conclude that intravenous milrinone followed by optimization of oral medical therapy may be used as a therapeutic trial to identify patients in need of cardiac transplantation.

Reversal of severe cardiac systolic dysfunction caused by pheochromocytoma in a heart transplant candidate.

Whenever a patient is evaluated as a possible candidate for heart transplantation, potential causes of reversible cardiomyopathy must always be considered. Although rate, it is well-known that pheochromocytoma can result in a dilated cardiomyopathy, which can be partially or completely reversible. We report a case of a 33-year-old woman with heart failure that was caused by a severe dilated cardiomyopathy who was referred for urgent heart transplant evaluation. The diagnosis of bilateral adrenal pheochromocytomas was made, and within 3 weeks of medical therapy, left ventricular systolic dysfunction completely reversed, avoiding the need for heart transplantation. The patient later underwent successful adrenalectomy. Unique features of this case of pheochromocytoma-induced cardiomyopathy include (1) serial norepinephine measurements over 3 weeks documenting the efficacy of medical therapy, (2) unique cutaneous manifestations that resolved with medical therapy, and (3) familial multiple endocrine neoplasia syndrome with medullary carcinoma of the thyroid in three generations of this patient's family.

Modulation of the QT interval: effects of graded exercise and reflex cardiovascular stimulation.

During exercise, as heart rate (HR) increases, the QT interval of the electrocardiogram shortens. The mechanism(s) involved in this QT shortening has not been clearly defined. To distinguish the influence of increased circulating catecholamines from myocardial efferent stimulation, the relationship between HR and QT interval was investigated during exercise and cardiovascular reflex stimulation in cardiac transplant patients and normal control subjects. Because of cardiac denervation, increases in HR in these patients are solely due to circulating catecholamines and thus allow isolation of their effect on the QT interval. Twenty-one cardiac transplant patients were studied and compared with 16 normal control subjects. The QT-HR relationship was determined according to an exponential model during treadmill exercise in both groups [QT = 0.12 + 0.492e(-0.008.HR) and QT = 0.12 + 0.459e(-0.007.HR) in normal subjects and transplant patients, respectively] and was statistically similar between groups, suggesting similar QT interval shortening in both groups. During cold pressor and Valsalva maneuvers, HR increased significantly in normal subjects only, whereas QT interval changed minimally in both groups. These results suggest that during exercise the QT interval is influenced predominantly by increases in circulating catecholamines rather than by neurally mediated reflex autonomic changes.

Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain.

The cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 proapoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIP(L)) is required for proliferation and effector T-cell development. However, the role of c-FLIP(L) in triggering autoimmunity has not been carefully analyzed. We now report that c-FLIP(L) transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multiorgan infiltration, high titers of auto-antibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent manner. The development of autoimmunity requires CD4(+) T cells and may result from impaired thymic selection. At the molecular level, c-FLIP(L) overexpression inhibits the zeta chain-associated protein tyrosine kinase of 70 kDa (ZAP-70) activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIP(L) as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.

Renoprotective role of the vitamin D receptor in diabetic nephropathy.

1,25-Dihydroxyvitamin D3 negatively regulates the renin-angiotensin system (RAS), which plays a critical role in the development of diabetic nephropathy. We tested if mice lacking the vitamin D receptor (VDR) are more susceptible to hyperglycemia-induced renal injury. Diabetic VDR knockout mice developed more severe albuminuria and glomerulosclerosis due to increased glomerular basement membrane thickening and podocyte effacement. More fibronectin (FN) and less nephrin were expressed in the VDR knockout mice compared to diabetic wild-type mice. In receptor knockout mice, increased renin, angiotensinogen, transforming growth factor-beta (TGF-beta), and connective tissue growth factor accompanied the more severe renal injury. 1,25-Dihydroxyvitmain D3 inhibited high glucose (HG)-induced FN production in cultured mesangial cells and increased nephrin expression in cultured podocytes. 1,25-Dihydroxyvitmain D3 also suppressed HG-induced activation of the RAS and TGF-beta in mesangial and juxtaglomerular cells. Our study suggests that receptor-mediated vitamin D actions are renoprotective in diabetic nephropathy.

Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy.

The db/db mouse develops features of type II diabetes mellitus as the result of impaired signaling through its abnormal leptin receptor. In spite of accurate metabolic features of diabetes, renal disease manifestations in these mice are not as severe as in humans suggesting the presence of protective genes. There is a growing body of evidence in humans for the relevance of vitamin D in diabetes. Here we followed a large cohort of db/db mice and their non-diabetic db/+ littermates. Transcriptional profiling revealed significant upregulation of 23 genes involved in Ca2+ homeostasis and vitamin D metabolism in db/db glomeruli relative to db/+ glomeruli. Increased glomerular expression of vitamin D3 1alpha-hydroxylase, vitamin D binding protein, calbindins D9K and D28K, and calcyclin mRNA was confirmed by quantitative reverse transcription-polymerase chain reaction in 20-, 36-, and 52-week-old db/db glomeruli. Although vitamin D3 1alpha-hydroxylase protein was primarily expressed and upregulated in db/db renal tubules, it was also expressed in glomerular podocytes in vivo. Serum 1,25-dihydroxyvitamin D3 and urinary Ca2+ excretion were increased >3-fold in db/db mice compared to db/+ mice. Cultured glomerular podocytes had mRNA for vitamin D3 1alpha-hydroxylase, vitamin D receptor, and calbindin D28K, each of which was increased in high glucose conditions. High glucose also led to enhanced production of fibronectin and collagen IV protein, which was blocked by 1,25-dihydroxyvitamin D3. These results show that vitamin D metabolism is altered in db/db mice leading to metabolic and transcriptional effects. The podocyte is affected by paracrine and potentially autocrine effects of vitamin D, which may explain why db/db mice are resistant to progressive diabetic nephropathy.