Lifetime exposure to unemployment and prior working conditions are associated with retiree's health: A retrospective study in a large population-based French cohort.

It is unclear whether unemployment exposure, as well as working conditions, can have sustained effects on the health of retirees who are no longer exposed. The aim of the present study is to investigate this issue in 29,281 French retirees from the CONSTANCES cohort in whom the prevalence of suboptimal self-rated health, disability for routine tasks, cardiovascular diseases and cancers is assessed according to lifetime exposure to unemployment and prior working conditions. The analyses are performed retrospectively using multivariable logistic regression models with adjustment for potential confounders such as sex, birth year, parental histories of cardiovascular disease and cancer, social position, retirement age and duration. High lifetime exposure to unemployment is associated with an increased prevalence of suboptimal self-rated health (adjusted odds ratio (95% CI), 1.39 (1.23-1.57)), disability for routine tasks (1.41 (1.26-1.57)) and several cardiovascular diseases including stroke (1.66 (1.19-2.31)), myocardial infarction (1.65 (1.18-2.31)) and peripheral arterial disease (2.38 (1.46-3.90)). Bad prior working conditions are associated with an increased prevalence of disability for routine tasks (1.17 (1.04-1.33)) and cancers (1.27 (1.04-1.54)), notably prostate cancer (1.60 (1.01-2.64)). These findings suggest that unemployment and working conditions have long-term health effects that may cumulate over lifetime, emphasizing that risk evaluation and preventive strategies in retirees, as in workers, should take into account the life-course of individuals in addition to traditional risk factors.

Changes in alcohol consumption according to the duration of unemployment: prospective findings from the French CONSTANCES cohort.

OBJECTIVES: To prospectively examine the association between the duration of unemployment among job seekers and changes in alcohol use in a year. DESIGN: A prospective study. SETTING: French population-based CONSTANCES cohort. PARTICIPANTS: We selected 84 943 participants from the CONSTANCES cohort included between 2012 and 2019 who, at baseline and 1-year follow-up, were either employed or job-seeking. OUTCOME MEASURES: Multinomial logistic regression models computed the odds of reporting continuous no alcohol use, at-risk alcohol use, increased or decreased alcohol use compared with being continuously at low risk and according to employment status. The duration of unemployment was self-reported at baseline; thus, the employment status at 1-year follow-up was categorised as follows: (1) employed, (2) return to employment since less than a year, (3) unemployed for less than 1 year, (4) unemployed for 1 to 3 years and (5) unemployed for 3 years or more. Analyses were adjusted for age, gender, education, household monthly income, marital status, self-rated health, smoking status and depressive state. RESULTS: Compared with being continuously at low risk (ie, ≤10 drinks per week), the unemployment categories were associated in a dose-dependent manner with an increased likelihood of reporting continuous no alcohol use (OR: 1.74-2.50), being continuously at-risk (OR: 1.21-1.83), experiencing an increase in alcohol use (OR: 1.21-1.51) and a decrease in alcohol use (OR: 1.17-1.84). CONCLUSION: Although our results suggested an association between the duration of unemployment and a decrease in alcohol use, they also revealed associations between at-risk and increased alcohol use. Thus, screening for alcohol use among unemployed job seekers must be reinforced, especially among those with long-term unemployment.

Cardiovascular burden and unemployment: A retrospective study in a large population-based French cohort.

The specific effect of unemployment on cardiovascular health relatively to the effects of social position and work environment is still unclear. To clarify this effect, the associations between current or past unemployment and the prevalence of common cardiovascular risk factor and events were tested using multiple logistic regression models with adjustment for both social position and prior work environment. The analyses were performed in a population-based French cohort (CONSTANCES) that included 131,186 adults enrolled between 2012 and 2021. Participants who were unemployed at inclusion (n = 8278) were overexposed to non-moderate alcohol consumption, smoking, leisure-time physical inactivity and depression (odds ratios (ORs) from 1.19 to 1.58) whereas those who have been unemployed at least once in the past (n = 19,015) were additionally overexposed not only to the previous risk factors but also to obesity, diabetes and sleep disorders (ORs from 1.10 to 1.35). These latter were also more exposed to non-fatal myocardial infarction and peripheral arterial disease (ORs of 1.44 and 1.47 respectively), overexposures that persisted after further adjustment for cardiovascular risk factors (ORs of 1.36 and 1.33). The overexposures to risk factors and cardiovascular events were both dependent on the duration of past unemployment. They were equally observed in participants with low social position or bad work environment. These results suggest that unemployment increases cardiovascular risk independently from social position and work environment with a cumulative effect over time. The effect of unemployment could add up to those of low social position and bad work environment during lifetime to further increase cardiovascular risk. They also suggest that long-term unemployment increases the prevalence of cardiovascular events through pathways including but not limited to overexposure to common risk factors.

Distinct cardiovascular and cancer burdens associated with social position, work environment and unemployment: a cross-sectional and retrospective study in a large population-based French cohort.

OBJECTIVES: Distinguish the respective effects of social position, work environment and unemployment on cardiovascular and cancer risks. DESIGN: A cross-sectional and retrospective observational study. SETTING: A population-based French cohort (CONSTANCES). PARTICIPANTS: 130 197 adults enrolled between 2012 and 2021 without missing values. PRIMARY OUTCOME MEASURES: The associations of social position, work environment and unemployment exposure with the prevalence of cardiovascular events and cancers simultaneously tested using logistic regression models adjusting for common risk factors. RESULTS: While social position, work environment and unemployment exposure are strongly inter-related with each other, they are not linked to the same cardiovascular and cancer outcomes. Low social position and long unemployment duration are significantly associated with an increased prevalence of angina pectoris, myocardial infarction and peripheral arterial disease (OR=1.22 to 1.90, p<0.04 to p<0.0001) but not of stroke. In contrast, a bad work environment is associated with an increased prevalence of stroke (OR=1.29, p<0.01) but not of angina pectoris, myocardial infarction and peripheral arterial disease. Low social position is associated with an increased prevalence of cervical and lung cancers (OR=1.73 and 1.95, p<0.002 and p<0.03) and a decreased prevalence of skin cancer (OR=0.70, p<0.0001) while a bad work environment is associated with an increased prevalence of breast, skin, prostate and colon cancers (OR=1.31 to 2.91, p<0.0002 to p<0.0001). Unemployment exposure is not associated with the prevalence of any type of cancers. CONCLUSIONS: Social position, work environment and unemployment are associated with distinct cardiovascular and cancerous diseases that could add up during lifetime, they should therefore be considered all together in any preventive strategy.

Identification of risk loci for primary aldosteronism in genome-wide association studies.

Primary aldosteronism affects up to 10% of hypertensive patients and is responsible for treatment resistance and increased cardiovascular risk. Here we perform a genome-wide association study in a discovery cohort of 562 cases and 950 controls and identify three main loci on chromosomes 1, 13 and X; associations on chromosome 1 and 13 are replicated in a second cohort and confirmed by a meta-analysis involving 1162 cases and 3296 controls. The association on chromosome 13 is specific to men and stronger in bilateral adrenal hyperplasia than aldosterone producing adenoma. Candidate genes located within the two loci, CASZ1 and RXFP2, are expressed in human and mouse adrenals in different cell clusters. Their overexpression in adrenocortical cells suppresses mineralocorticoid output under basal and stimulated conditions, without affecting cortisol biosynthesis. Our study identifies the first risk loci for primary aldosteronism and highlights new mechanisms for the development of aldosterone excess.

Respective Mediating Effects of Social Position and Work Environment on the Incidence of Common Cardiovascular Risk Factors.

Background Social position and work environment are highly interrelated and their respective contribution to cardiovascular risk is still debated. Methods and Results In a cohort of 20 625 French workers followed for 25 years, discrete-time survival analysis with reciprocal mediating effects, adjusted for sex, age, and parental history of early coronary heart disease, was performed using Bayesian structural equation modeling to simultaneously investigate the extent to which social position mediates the effect of work environment and, inversely, the extent to which work environment mediates the effect of social position on the incidence of common cardiovascular risk factors. Depending on the factor, social position mediates 2% to 53% of the effect of work environment and work environment mediates 9% to 87% of the effect of social position. The mediation by work environment is larger than that by social position for the incidence of obesity, hypertension, dyslipidemia, diabetes, sleep complaints, and depression (mediation ratios 1.32-41.5, 6.67 when modeling the 6 factors together). In contrast, the mediation by social position is larger than that by work environment for the incidence of nonmoderate alcohol consumption, smoking, and leisure-time physical inactivity (mediation ratios 0.16-0.69, 0.26 when modeling the 3 factors together). Conclusions The incidence of behavioral risk factors seems strongly dependent on social position whereas that of clinical risk factors seems closely related to work environment, suggesting that preventive strategies should be based on education and general practice for the former and on work organization and occupational medicine for the latter.

Association between unemployment and the co-occurrence and clustering of common risky health behaviors: Findings from the Constances cohort.

BACKGROUND: Unemployment is associated with a high prevalence of risky health behaviors. Mortality increases with the number of co-occurring risky behaviors but whether these behaviors co-occur with a greater than expected frequency (clustering) among unemployed people is not known. METHODS: Differences according to unemployment status in co-occurrence and clustering of smoking, alcohol abuse, low leisure-time physical activity and unhealthy diet (marked by low fruit and vegetable intake) were assessed in 65,630 salaried workers, aged 18 to 65, who were participants in Constances, a French population-based cohort. Among them, 4573 (7.0%) were unemployed without (n = 3160, 4.8%) or with (n = 1413, 2.1%) past experience of unemployment. RESULTS: Compared to the employed, unemployed participants without or with past experience of unemployment were similarly overexposed to each risky behavior (sex and age adjusted odds-ratios ranging from 1.38 to 2.19) except for low physical activity, resulting in higher rates of co-occurrence of two, three and four behaviors (relative risk ratios, RRR 1.20 to 3.74). Association between behavior co-occurrence and unemployment did not vary across gender, partnership status or income category. Risky behavior clustering, i.e., higher than expected co-occurrence rates based on the prevalence of each behavior, was similar across unemployment status. The same observations can be made in employed participants with past experience of unemployment, although overexposure to risky behaviors (ORs 1.15 to 1.38) and increased rates of co-occurrence (ORs 1.19 to 1.58) were not as pronounced as in the unemployed. CONCLUSIONS: Co-occurrence of risky behaviors in currently and/or formerly unemployed workers is not worsened by behavior clustering. Engagement in each of these behaviors should be considered an engagement in distinct social practices, with consequences for preventive policies.

Hostility, depression and incident cardiac events in the GAZEL cohort.

BACKGROUND: Psychological factors such as hostility and depression have been associated with cardiovascular disease. However, their role in predicting incident cardiac events independently one of another is not clear. METHODS: Among 10,304 GAZEL middle-aged workers free of cardiovascular diseases in 1993, 581 incident cardiac events were validated from 1994-2014. Hostile traits (cognitive hostility, behavioral hostility, irritability and negativism) were assessed with the Buss and Durkee Hostility Inventory at baseline. Depressive symptoms were assessed at baseline and every three years with the Center for Epidemiological Studies Depression scale. We used Cox proportional hazards models to calculate hazard ratios (HR) of hostile traits for incident cardiac events adjusting for baseline self-reported socio-demographics and family history of coronary heart diseases (model 1), then additionally for time-dependent depressive symptoms (either as a binary or continuous variable) (model 2) and for yearly self-reported modifiable cardiovascular risk factors (physical activity, smoking, body mass index, diabetes, dyslipidemia and hypertension) (model 3). RESULTS: In Model 1, the only hostile trait associated with incident cardiac events was irritability (HR for one interquartile range: 1.16, 95% confidence interval: 1.02-1.32). This association was no longer statistically significant when further adjusting for depressive symptoms. Depressive symptoms, in turn, remained significant predictors of cardiac events with HRs ranging from 1.40-1.49 (binary). LIMITATIONS: Hostility traits were measured only once. CONCLUSIONS: Depressive symptoms might explain the association between irritability and cardiac events and should therefore be prioritized in interventions aiming to prevent cardiovascular disease. Further research is needed to identify the mechanisms underlying this association.

Alcohol, tobacco and cannabis use are associated with job loss at follow-up: Findings from the CONSTANCES cohort.

BACKGROUND: Substance use is more prevalent among unemployed subjects compared to employed ones. However, quantifying the risk subsequent of job loss at short-term according to substance use remains underexplored as well as examining if this association persist across various sociodemographic and occupational positions previously linked to job loss. We examined this issue prospectively for alcohol, tobacco, cannabis use and their combination, among a large population-based sample of men and women, while taking into account age, gender, overall health status and depressive symptoms. METHODS: From the French population-based CONSTANCES cohort, 18,879 working participants were included between 2012 and 2016. At baseline, alcohol use disorder risk according to the Alcohol Use Disorders Identification Test (mild, dangerous, problematic or dependence), tobacco (non-smoker, former smoker, 1-9, 10-19, >19 cigarettes/day) and cannabis use (never, not in past year, less than once a month, once a month or more) were assessed. Employment status at one-year (working versus not working) was the dependent variable. Logistic regressions provided Odds Ratios(OR(95%CI)) of job loss at one-year, adjusting for age, gender, self-reported health and depressive state (measured with the Center of Epidemiologic Studies Depression scale). Stratified analyses were performed for education, occupational grade, household income, job stress (measured with the Effort-Reward Imbalance), type of job contract, type of work time and history of unemployment. In sensitivity analyses, employment status over a three-year follow-up was used as dependent variable. RESULTS: Alcohol, tobacco and cannabis use were associated with job loss, from the second to the highest category: 1.46(95%CI:1.23-1.73) to 1.92(95%CI:1.34-2.75), 1.26(95%CI:1.09-1.46) to 1.78(95%CI:1.26-2.54) and 1.45(95%CI:1.27-1.66) to 2.68(95%CI:2.10-3.42), respectively, and with dose-dependent relationships (all p for trend <0.001). When introduced simultaneously, associations remained significant for the three substances without any between-substance interactions. Associations remained significant across almost all stratifications and over a three-year follow-up as well as after adjustment for all the sociodemographic and occupational factors. CONCLUSIONS: Alcohol, tobacco and cannabis use were independently associated with job loss at short-term, with dose-dependent relationships. This knowledge will help refining information and prevention strategies. Importantly, even moderate levels of alcohol, tobacco or cannabis use are associated with job loss at short-term and all sociodemographic and occupational positions are potentially concerned.

Work environment mediates a large part of social inequalities in the incidence of several common cardiovascular risk factors: Findings from the Gazel cohort.

Whether working conditions contribute to social inequalities in cardiovascular disease is still a matter of debate. The present study investigates the extent to which the social gradient in the incidence of common behavioral and clinical risk factors is explained by work environment. In a well-characterized cohort of 20,625 middle-aged French civil servants followed for 25 years, social status and work environment were globally measured at baseline by combining respectively four socioeconomic indicators (education, wealth, income, occupational grade) and 25 physical, biomechanical, organizational and psychosocial occupational exposures. These 2 global measures are strongly correlated with each other (p < 0.0001), lower is social status, worse is work environment. In proportional hazard regression models adjusted for sex, age and parental cardiovascular disease, low social status increases the incidence of 9 risk factors with hazard ratios ranging from 1.12 to 1.72 while bad work environment increases the incidence of 7 risk factors with hazard ratios ranging from 1.15 to 2.02. Structural equation models to discrete-time survival analysis with moderated mediation show that bad work environment explains nearly 50% of the global effect of low social status on the incidence of the 9 risk factors (p < 0.01). This mediating effect varies substantially from one risk factor to another, explaining 32-39% of social gradients in the risk of physical inactivity, obesity, diabetes, dyslipidemia and 64-90% of gradients in the risk of hypertension, sleep complaints and depression (all p < 0.01). No significant mediating effect of work environment is found for social gradients in the incidence of non-moderate alcohol consumption and smoking. These results suggest that work environment mediates a large part of the social gradient in the incidence of several common cardiovascular risk factors, emphasizing the necessity to include working conditions in policies aimed to reduce social inequalities in health.

A Global View of the Relationships between the Main Behavioural and Clinical Cardiovascular Risk Factors in the GAZEL Prospective Cohort.

Although it has been recognized for a long time that the predisposition to cardiovascular diseases (CVD) is determined by many risk factors and despite the common use of algorithms incorporating several of these factors to predict the overall risk, there has yet been no global description of the complex way in which CVD risk factors interact with each other. This is the aim of the present study which investigated all existing relationships between the main CVD risk factors in a well-characterized occupational cohort. Prospective associations between 12 behavioural and clinical risk factors (gender, age, parental history of CVD, non-moderate alcohol consumption, smoking, physical inactivity, obesity, hypertension, dyslipidemia, diabetes, sleep disorder, depression) were systematically tested using Cox regression in 10,736 middle-aged individuals free of CVD at baseline and followed over 20 years. In addition to independently predicting CVD risk (HRs from 1.18 to 1.97 in multivariable models), these factors form a vast network of associations where each factor predicts, and/or is predicted by, several other factors (n = 47 with p<0.05, n = 37 with p<0.01, n = 28 with p<0.001, n = 22 with p<0.0001). Both the number of factors associated with a given factor (1 to 9) and the strength of the associations (HRs from 1.10 to 6.12 in multivariable models) are very variable, suggesting that all the factors do not have the same influence within this network. These results show that there is a remarkably extensive network of relationships between the main CVD risk factors which may have not been sufficiently taken into account, notably in preventive strategies aiming to lower CVD risk.

Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes.

BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is critical for regulation of blood pressure and fluid balance and influences cardiovascular remodeling. Dysregulation of the RAAS contributes to cardiovascular and renal morbidity. The genetic architecture of circulating RAAS components is incompletely understood. METHODS AND RESULTS: We meta-analyzed genome-wide association data for plasma renin activity (n=5275), plasma renin concentrations (n=8014), and circulating aldosterone (n=13289) from ≤4 population-based cohorts of European and European-American ancestry, and assessed replication of the top results in an independent sample (n=6487). Single-nucleotide polymorphisms (SNPs) in 2 independent loci displayed associations with plasma renin activity at genome-wide significance (P<5×10(-8)). A third locus was close to this threshold (rs4253311 in kallikrein B [KLKB1], P=5.5×10(-8)). Two of these loci replicated in an independent sample for both plasma renin and aldosterone concentrations (SNP rs5030062 in kininogen 1 [KNG1]: P=0.001 for plasma renin, P=0.024 for plasma aldosterone concentration; and rs4253311 with P<0.001 for both plasma renin and aldosterone concentration). SNPs in the NEBL gene reached genome-wide significance for plasma renin concentration in the discovery sample (top SNP rs3915911; P=8.81×10(-9)), but did not replicate (P=0.81). No locus reached genome-wide significance for aldosterone. SNPs rs5030062 and rs4253311 were not related to blood pressure or renal traits; in a companion study, variants in the kallikrein B locus were associated with B-type natriuretic peptide concentrations in blacks. CONCLUSIONS: We identified 2 genetic loci (kininogen 1 and kallikrein B) influencing key components of the RAAS, consistent with the close interrelation between the kallikrein-kinin system and the RAAS.

Chronic potassium depletion increases adrenal progesterone production that is necessary for efficient renal retention of potassium.

Modern dietary habits are characterized by high-sodium and low-potassium intakes, each of which was correlated with a higher risk for hypertension. In this study, we examined whether long-term variations in the intake of sodium and potassium induce lasting changes in the plasma concentration of circulating steroids by developing a mathematical model of steroidogenesis in mice. One finding of this model was that mice increase their plasma progesterone levels specifically in response to potassium depletion. This prediction was confirmed by measurements in both male mice and men. Further investigation showed that progesterone regulates renal potassium handling both in males and females under potassium restriction, independent of its role in reproduction. The increase in progesterone production by male mice was time dependent and correlated with decreased urinary potassium content. The progesterone-dependent ability to efficiently retain potassium was because of an RU486 (a progesterone receptor antagonist)-sensitive stimulation of the colonic hydrogen, potassium-ATPase (known as the non-gastric or hydrogen, potassium-ATPase type 2) in the kidney. Thus, in males, a specific progesterone concentration profile induced by chronic potassium restriction regulates potassium balance.

Tissue kallikrein permits early renal adaptation to potassium load.

Tissue kallikrein (TK) is a serine protease synthetized in renal tubular cells located upstream from the collecting duct where renal potassium balance is regulated. Because secretion of TK is promoted by K+ intake, we hypothesized that this enzyme might regulate plasma K+ concentration ([K+]). We showed in wild-type mice that renal K+ and TK excretion increase in parallel after a single meal, representing an acute K+ load, whereas aldosterone secretion is not modified. Using aldosterone synthase-deficient mice, we confirmed that the control of TK secretion is aldosterone-independent. Mice with TK gene disruption (TK-/-) were used to assess the impact of the enzyme on plasma [K+]. A single large feeding did not lead to any significant change in plasma [K+] in TK+/+, whereas TK-/- mice became hyperkalemic. We next examined the impact of TK disruption on K+ transport in isolated cortical collecting ducts (CCDs) microperfused in vitro. We found that CCDs isolated from TK-/- mice exhibit net transepithelial K+ absorption because of abnormal activation of the colonic H+,K+-ATPase in the intercalated cells. Finally, in CCDs isolated from TK-/- mice and microperfused in vitro, the addition of TK to the perfusate but not to the peritubular bath caused a 70% inhibition of H+,K+-ATPase activity. In conclusion, we have identified the serine protease TK as a unique kalliuretic factor that protects against hyperkalemia after a dietary K+ load.

A second expressed kininogen gene in mice.

We isolated PCR, RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE-PCR)-, and RT-PCR-generated clones from mouse kininogen family transcripts. DNA sequencing indicated that the clones were from two distinct genes. One set (K1) is from the previously reported mouse kininogen gene. The second set (K2) has an open reading frame, is 93% identical to K1 in the overlapping nucleotide sequence, and, unlike T-kininogens in the rat, encodes a bradykinin motif identical to K1. We discovered that K2 exists with two different 5' ends. We used RT-PCR to determine the distribution and relative abundance of K1 and K2 mRNA in mouse tissues. K2 is transcribed and K1 and K2 are generally both expressed in the same tissues; however, they differ in their regulation of the alternative splicing event that yields either low-molecular-weight kininogen (LMWK) or high-molecular-weight kininogen (HMWK). For example, in the liver K1 is expressed as both HMWK and LMWK, whereas K2 is only expressed as LMWK. Conversely, in the kidney K2 is strongly expressed as both HMWK and LMWK, whereas K1 is not expressed as HMWK and expressed only very weakly as LMWK.

Molecular identification of Sch28080-sensitive K-ATPase activities in the mouse kidney.

Rat collecting ducts display either an ouabain-insensitive or an ouabain-sensitive K-ATPase activity inhibited by Sch28080 according as animals are fed a normal or a potassium-depleted diet (types I and III K-ATPase, respectively). Two isoforms of H,K-ATPase have been cloned from rat gastric mucosa and colon, respectively. Gastric and colonic H,K-ATPase are expressed in the kidney, suggesting that they might account for types I and III K-ATPases. However, this hypothesis is not fully supported by segmental expression of gastric and colonic H,K-ATPase along the rat collecting duct, as well as by comparison of the pharmacological properties of gastric and colonic H,K-ATPase expressed in Xenopus ovocyte and types I and III K-ATPases in rat collecting ducts. The aim of the present work is to address directly the molecular origin of types I and III K-ATPases in the mouse collecting duct by measuring K-ATPase activities in collecting ducts of wild-type mice and mice genetically deficient in either gastric or colonic H,K-ATPase fed either a regular or a potassium-depleted diet. Like the rat, mouse collecting ducts display type I or III K-ATPase activity when fed a regular or a potassium-depleted diet, respectively. Type I K-ATPase activity is detected in colonic H,K-ATPase-deficient mice but not in gastric H,K-ATPase-deficient animals. Conversely, type III K-ATPase activity disappears in colonic H,K-ATPase-deficient but not in gastric H,K-ATPase-deficient mice. In conclusion, types I and III K-ATPases measured in collecting ducts of normal and potassium-depleted mice reflect the functional expression of gastric and colonic H,K-ATPase, respectively.

Structure and expression of two kininogen genes in mice.

Kininogens serve dual functions by forming a scaffold for the assembly of the protein complex initiating the surface-activated blood coagulation cascade and as precursors for the kinin hormones. While rats have three kininogen genes, for mice, cattle, and humans only one gene has been described. Here, we present sequence and expression data of a second mouse kininogen gene. The two genes, kininogen-I and kininogen-II, are located in close proximity on chromosome 16 in a head-to-head arrangement. In liver and kidney, both genes are expressed and for each gene three alternative splice variants are synthesized. Two of them are the expected high and low molecular weight isoforms known from all mammalian kininogens. However, for both genes also a third, hitherto unknown splice variant was detected which lacks part of the high molecular weight mRNA due to splicing from the low molecular weight donor site to alternative splice acceptor sites in exon 10. The physiological functions of the six kininogen isoforms predicted by these findings need to be determined.

Altered renin synthesis and secretion in the kidneys of heterozygous mice with a null mutation in the TGF-beta(2) gene.

Transforming growth factors beta (TGF-betas) are peptides involved in autocrine and paracrine control of cell growth and differentiation. In the kidneys, TGF-beta(2) has been shown to localize specifically in renin-producing cells in various conditions stimulating the renin response. To test in vivo the functional role of TGF-beta(2), the renin response was investigated in mice heterozygous for a null mutation of the TGF-beta(2) gene, which had a twofold reduction in the amount of TGF-beta(2) mRNA. Although the increase in plasma renin concentration triggered by dehydration was not different from wild-type mice, renal renin mRNA and protein levels were higher in mutant mice under hydrated or dehydrated conditions. These data suggest that TGF-beta(2) exerts an inhibitory effect on renin synthesis and release from the juxtaglomerular apparatuses.