Research Report 2010 - MDC

Daumke (both MDC) on studying the (pro)renin receptor,a transmembrane protein that binds either renin orprorenin. Prorenin is activated by this binding to allowthe cleavage of angiotensinogen to Ang I (and then toAng II through the angiotensin converting enzyme).Independent of that process, the (pro)renin receptoralso signals via extracellular-regulated kinase (ERK1/2)and can activate the transforming growth factor (TGF)pathway. Others claim that by blocking the (pro)reninreceptor, by means of a decoy peptide sequence termedthe handle-region peptide (HRP), the vascular damagecaused by diabetes mellitus can be completely ameliorated.The Müller laboratory has worked intensively onthis important problem. Sandra Feldt was primarilyresponsible for this project. The group tested whetherhuman prorenin and renin induce ERK1/2 activationand whether the direct renin inhibitor aliskiren or theHRP inhibits the receptor. The (pro)renin receptormRNA and protein was detected in isolated humanmonocytes and in U937 monocytes. In U937 cells, thegroup found that both human renin and prorenininduced a long-lasting ERK1/2 phosphorylation despiteAng II type 1 and 2 receptor blockade. A mitogen-activatedprotein kinase kinase 1/2 inhibitor inhibited bothrenin and prorenin-induced ERK 1/2 phosphorylation.Neither aliskiren nor HRP inhibited binding of (125)Ireninor (125)I-prorenin to the (pro)renin receptor.Fluorescence-activated cell sorter analysis showed that,although fluorescein isothiocyanate-labeled HRPbound to U937 cells, HRP did not inhibit renin orprorenin-induced ERK1/2 activation. Thus, prorenin andrenin-induced ERK 1/2 activation are independent ofAng II. The signal transduction is different from thatevoked by Ang II. Aliskiren has no (pro)renin receptorblocking effect and did not inhibit ERK1/2 phosphorylationor kinase activity. There was no evidence that HRPaffects renin or prorenin binding and signaling. TheCouncil for High Blood Pressure Research of theAmerican Heart Association voted this work as the“best basic paper of the year”, published in the journalHypertension.Renin and metabolismRenin initiates Ang II formation and (aside from the(pro)renin receptor) has no other known functions.Petra Gratze and the Muller group observed that transgenicrats (TGR) overexpressing the human renin gene(hREN) developed moderate obesity with increasedbody fat mass and glucose intolerance compared withnontransgenic Sprague-Dawley (SD) rats. The metabolicchanges were not reversed by an angiotensin-convertingenzyme inhibitor, a direct renin inhibitor, or by(pro)renin receptor blocker treatment. The obese phenotypein TGR(hREN) originated from higher foodintake, which was partly compensated by increases inRenal Id2 deficiency does not the genesis of hypertension andrenal damage.resting energy expenditure, total thermogenesis (postprandialand exercise activity), and lipid oxidation duringthe first 8 weeks of life. Once established, the differencein body weight between TGR(hREN) and SD ratsremained constant over time. The group observed nochanges in the cocaine and amphetamine-regulatedtranscript, pro-opiomelanocortin, both anorexigenic, orneuropeptide Y, orexigenic, mRNA levels in TGR(hREN)versus SD controls. However, the mRNA level of theagouti-related peptide, orexigenic, was significantlyreduced in TGR(hREN) versus SD controls at the end ofthe study, which indicates a compensatory mechanism.The group suggested that the human renin transgeneinitiates a process leading to increased and earlyappetite, obesity, and metabolic changes not related toAng II. The mechanisms are independent of any currentlyknown renin-related effects. The novelty here is theintroduction of renin as an obesity-related enzyme. Thegroup is busy exploring mechanisms further.Selected PublicationsGratze, P, Dechend, R, Stocker, C, Park, J-K, Feldt, S, Shagdarsuren, E, Wellner,M, Gueler, F, Rong, S, Gross, V, Obst, M, Plehm, R, Alenina, N, Zenclussen, A,Titze, J, Small, K, Yokota, Y, Zenke, M, Luft, FC, Muller, DN. (2008) Novel rolefor inhibitor of differentiation 2 in the genesis of angiotensin II-inducedhypertension. Circulation. 117, 2645-2656.Kvakan, H, Kleinewietfeld, M, Qadri, F, Park, JK, Fischer, R, Schwarz, I, Rahn,HP, Plehm, R, Wellner, M, Elitok, S, Gratze, P, Dechend, R, Luft, FC, Muller, DN.(2009) Regulatory T cells ameliorate angiotensin II-induced cardiacdamage. Circulation. 119, 2904-2912Feldt, S, Maschke, U, Dechend, R, Luft, FC, Muller, DN. (2008) The putative(pro)renin receptor blocker HRP fails to prevent (pro)renin signaling. J AmSoc Nephrol. 19, 743-748.Feldt, S, Batenburg, WW, Mazak, I, Maschke, U, Wellner, M, Kvakan, H,Dechend, R, Fiebeler, A, Burckle, C, Contrepas, A, Danser, JAH, Bader, M,Nguyen, G, Luft, FC, Muller, DN. (2008) Prorenin and renin-inducedextracellular signal-regulated kinase 1/2 activation in monocytes is notblocked by aliskiren or the handle-region peptide. Hypertension. 51,682-688.Gratze, P, Boschmann, M, Dechend, R, Qadri, F, Malchow, J, Graeske, S, Engeli,S, Janke, J, Springer, J, Contrepas, A, Plehm, R, Klaus, S, Nguyen, G, Luft, FC,Muller, DN. (2009) Energy metabolism in human renin-gene transgenicrats: does renin contribute to obesity? Hypertension. 53, 516-523.Cardiovascular and Metabolic Disease Research 37