Kork and kap7/2/2023 ![]() It was noteworthy that KAP provided a mechanistic insight into the higher prevalence of arterial hypertension in males. Our results in mice with transgenic overexpression of KAP in the proximal tubule demonstrated for the first time a key role for this protein in the induction and or activation of several extra renal pathways, including cardiovascular disease and arterial hypertension 11, 12. The function of KAP, which shares no significant homology with other known proteins in various databases, is almost unknown. Kidney-androgen regulated protein, which is one of the most abundant and specific genes expressed in proximal tubule epithelial cells 9, undergoes a strict and unique regulation by thyroid and sexual steroid hormones, mainly androgens, in the proximal tubules 10. Factors such as insulin resistance (IR), inflammation, renal endothelial dysfunction, oxidative stress, altered renal hemodynamics, activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) 8 may play a role. How the functional changes in the kidney affect MS pathophysiology remains speculative. Data from the NHANES III database, which includes more than 6000 adults, revealed that the multivariate-adjusted risk for both microalbuminuria and CKD was significantly raised in individuals with MS, and that this risk increased progressively with the number of the syndrome’s components detected in each patient 7. Recent epidemiologic studies have demonstrated that patients with MS are also at increased risk of microalbuminuria, an early marker of glomerular injury, endothelial dysfunction and/or CKD. Other obesity-related disorders associated with MS such as fatty liver disease, hyperuricemia and chronic kidney disease (CKD), defined as a glomerular filtration rate (GFR) below 60 ml/min per 1.73 m 2, are major causes of morbidity and mortality. The resulting hyperinsulinemia and hyperglycemia, as well as the release of adipocyte cytokines, play a critical role in vascular endothelial dysfunction, abnormal lipid profile, arterial hypertension (AHT), and vascular inflammation, which work in concert to enhance atherosclerosis 6. ![]() Accumulating evidence suggests that chronic inflammation in adipose tissue is instrumental in the development of obesity-related metabolic dysfunction 4, 5. One of the main underlying risk factors for MS is obesity 3. MS affects over 20% of adults in Western populations and is reaching an epidemic proportion globally 2. The metabolic syndrome (MS) is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increase the risk of atherosclerotic cardiovascular disease (ASCVD) and type 2 diabetes mellitus (T2DM) 1. We conclude that KAP, which might act as a hormone-like product in extra-renal tissues, protects Tg mice against hfd-induced MS by preventing inflammatory related events that are mediated, in part, through the IL-6 pathway. Moreover, KAP was localized in the secretory pathway of proximal tubule cells and it is released to the extracellular media, preventing IL-6 induction and STAT-3 activation upon TNFα stimulation. KAP transgenic were protected from hfd-induced insulin resistance, increased blood pressure and exhibited lower IL-6 serum levels and diminished expression of inflammatory markers in the adipose. KAP Tg mice showed diminished adipocyte hypertrophy and reduced hepatic steatosis, significantly correlating with expression of relevant molecular markers and lower lipid content in liver. Tg mice overexpressing KAP specifically in proximal tubule cells of the kidney exhibited reduced body weight and lower liver and adipose tissue weight compared to control littermates when fed a hfd. Since the molecular basis of MS remains poorly defined, we investigated the impact of KAP, a kidney specific androgen-regulated gene, in the development of high fat-diet (hfd)-induced MS. Metabolic Syndrome (MS) is reaching epidemic proportions with significant social and economical burden worldwide.
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