Mazagova M, Buikema H, Landheer SW, Vavrinec P, van Buiten A, Henning RH, Deelman LE. Growth differentiation factor 15 impairs aortic contractile and relaxing function through altered caveolar signaling of the endothelium. Am J Physiol Heart Circ Physiol 304: H709 -H718, 2013. First published December 21, 2012 doi:10.1152/ajpheart.00543.2012.-Growth differentiation factor 15 (GDF15) is an independent predictor of cardiovascular disease, and increased GDF15 levels have been associated with endothelial dysfunction in selected patients. We therefore investigated whether GDF15 modulates endothelial function in aortas of wild-type (WT) and GDF15 knockout (KO) mice. Vascular contractions to phenylephrine and relaxation to ACh were assessed in aortas obtained from healthy WT and GDF15 KO mice. The effects of GDF15 pretreatment and the involvement of ROS or caveolae were determined. Phenylephrine-induced contractions and ACh-mediated relaxations were similar in WT and GDF15 KO mice. Pretreatment with GDF15 inhibited contraction and relaxation in both groups. Inhibition of contraction by GDF15 was absent in denuded vessels or after blockade of nitric oxide (NO) synthase. Relaxation in WT mice was mediated mainly through NO and an unidentified endothelium-derived hyperpolarizin factor (EDHF), whereas GDF15 KO mice mainly used prostaglandins and EDHF. Pretreatment with GDF15 impaired relaxation in WT mice by decreasing NO; in GDF15 KO mice, this was mediated by decreased action of prostaglandins. Disruption of caveolae resulted in a similar inhibition of vascular responses as GDF15. ROS inhibition did not affect vascular function. In cultured endothelial cells, GDF15 pretreatment caused a dissociation between caveolin-1 and endothelial NO synthase. In conclusion, GDF15 impairs aortic contractile and relaxing function through an endotheliumdependent mechanism involving altered caveolar endothelial NO synthase signaling. growth differentiation factor 15; aorta; endothelium; mice; caveolae; caveolin-1 GROWTH DIFFERENTIATION FACTOR 15 (GDF15), also called macrophage inhibitory cytokine (MIC)-1, is a distant member of the transforming growth factor (TGF)-␤ family and the result of posttranslational modification of the product of an early response gene (4). Upregulation of GDF15 has been demonstrated after chemical and hyperoxic injury of the lung, by surgical, chemical, and heat-induced injury of the liver (19), and after ischemia-reperfusion injury of the heart (15), indicating that GDF15 is a general mediator of the organ injury response. Furthermore, GDF15 is emerging as an independent predictor of cardiovascular disease (CVD) in the elderly and a predictor of prognosis in patients with established CVD (17,20,21). An association between GDF15 levels and endothelial dysfunction was found in an elderly population (21). Hence, endothelial dysfunction is considered the first step in the chain of events leading to atherosclerosis and CVD. It comprises an imbalanced production of vasodilating and vasoconstricting substances by th...

Type 2 diabetes mellitus (T2DM) is associated with risk for chronic kidney disease (CKD), which is associated with a decrease in renal myogenic tone - part of renal autoregulatory mechanisms. Novel class of drugs used for the treatment of T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitors, have protective effects on the cardiovascular system. A Zucker Diabetic Fatty (ZDF) rat is an animal model of T2DM that displays progressive nephropathy in which inflammation leads to initiation of renal fibrosis and CKD. We hypothesized that CKD in the ZDF rat is related to decrease in myogenic constriction (MC) of intrarenal arteries and that treatment with the DPP-4 inhibitor, vildagliptin, prevents such changes. Renal arteries isolated from 25 weeks old lean, ZDF and ZDF treated with vildagliptin (n=7 in each group) were transferred to an arteriograph to assess agonist and pressure induced contractile responses. Furthermore, blood glucose, proteinuria, focal glomerulosclerosis (FGS) and p22phox mRNA expression of renal tissue were measured. Compared to lean controls, ZDF had significantly increased plasma glucose and cholesterol levels, focal glomerulosclerosis and interstitial α-SMA expression, and urinary protein excretion. ZDF rats also had impaired MC of renal arteries and increased renal p22phox expression. Vildagliptin did not affect plasma glucose levels or proteinuria, but effectively decreased glomerulosclerosis and restored MC and p22phox expression to the levels found in lean rats. Based on these data, it can be suggested that vildagliptin treatment protects diabetic rats from the loss of renal vascular reactivity and the development of glomerulosclerosis perhaps secondary to a reduction in oxidative stress.

Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4- in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/ 6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

Uremic encephalopathy is a severe complication of renal failure. The underlying pathogenesis is unknown although several mechanisms have been suggested. Renal failure causes oxidative stress leading to cardiovascular complications. It has been suggested as the potential mediator of uremic encephalopathy as well, but it is largely unknown whether brain tissue itself undergoes oxidative damage in uremia. The aim of our experiment was to analyze oxidative stress markers in different brain regions in an animal model of acute kidney injury (AKI). AKI was induced by ischemia-reperfusion injury in male Wistar rats. Urine was collected in metabolic cages after 24 h. Samples of plasma and several brain regions were collected after 48 h. Markers of lipid peroxidation, protein oxidation and total antioxidant capacity were assessed. Renal failure was confirmed by high plasma creatinine, urea and urinary albumin to creatinine ratio. Our data confirmed increased systemic oxidative stress in the AKI group with plasma concentrations of markers of oxidative damage being twice as high compared to the sham-operated control group. No effect was seen in the urine. In the hippocampus, lipid and protein oxidation was higher, while antioxidant capacity was lower in the rats with AKI. Lipid oxidation markers in the frontal cortex were higher by 33%. No differences to controls were found in the cerebellum and hypothalamus. In conclusion, our results indicate that AKI leads to oxidative stress in the brain, especially in the hippocampus and in the frontal cortex. This kidney-brain crosstalk mediated by increased oxidative stress might explain some of the symptoms of uremic encephalopathy. The causes and consequences of oxidative damage observed in the brain during AKI remain to be elucidated.