Hypoxia and vasa recta function
Nephrology
Final Report Abstract
The project tested the main hypothesis that hypxia/reoxygenation impairs renal microvessel function. The focus was on medullary descending vasa recta (DVR). We assumed that the adenosine may play a protective role by dilating vasa recta during hypoxia/reoxygenation and that EETs released from the renal medulla influence DVR diameter. We found relative stronger angiotensin II-induced constrictions of DVR after 90 min hypoxia/ and 10 min reoxygenation compared to control conditions in living kidney slices. This suggests a shift of the balance of vasoactive substances in favour of constriction. Nitric oxide synthases were less expressed in hypoxia/reoxygenation compared to control, supporting the idea of a reduced vasodilator capacity under these conditions. Adenosine application combined with selective inhibition of adenosine receptor subtypes failed to affect reactivity and the basal diameter of microvessels in living kidney slices. Therefore, we created alternative protocols and tested if hypoxia/reoxygenation facilitates preglomerular cortical microvessel constriction in living kidney slices. Data were compared with those of isolated perfused arterioles of mice. Interestingly, the angiotensin II response was similarly increased in both experimental models, which indicates a negligible influence of surrounding tissue on the cortical arteriolar function in hypoxia/reoxygenation in this. We also showed that hypoxia/reoxygenation goes along with a reduced vasodilatory capacity in bigger renal arteries and obtained a reduced cGMP concentration along with impaired soluble guanylyl cyclase function in vascular smooth muscle cells, which may be an important mechanism of reduced dilatation after hypoxia/reoxygenation. In the same model, we saw increased responses to angiotensin II after hypoxia/reoxygenation. Here, the activation of the p38 MAPK, resulting in increased calcium sensitivity, seems to be causative for the effect of hypoxia/reoxygenation on the angiotensin II response. A comprehensive series of experiments, we analysed the effect of adenosine A2 receptor activation in kidney slices in cooperation with Dr. Schunk’s group. Surprisingly, treatment with adenosine did not affect the concentration of EET and enzymes of the EET system at all. These results agree with the lack of vascular reaction to adenosine and to adenosine receptor manipulation in kidney slices. In cooperation with the group of E.Y. Lai (who now has received a Mercator Fellowship by the German Research Foundation to follow up on our studies), we studied the microvascular function ex vivo after renal ischemia/reperfusion. Angiotensin II reactivity of afferent arterioles was reduced 24 hours after ischemia/reperfusion. The catalase activity was low, and the increased hydrogen peroxide explain impaired contractility. When comparing these results with those of the acute studies in kidney slices and isolated vessels, it seems that cortical microvascular function change from an increased to a reduced angiotensin II response after ischemia/reperfusion injury over 24 hours. By using the same ischemia/reperfusion model, we found also a reduced dilatation of afferent arterioles to acetylcholine. This study suggests ADAMTS13 as an important player in the pathogenesis of the renal ischemia/reperfusion injury, because treatment with recombinant ADAMTS13 ameliorated renal ischemia/reperfusion injury and improved microvascular endothelial dysfunction.
Publications
- Norepinephrine enhances angiotensin II responses via p38 MAPK activation after hypoxia/re-oxygenation in renal interlobar arteries. Acta Physiol (Oxf) 213(4): 920-32, 2015
Kaufmann J, Martinka P, Moede O, Sendeski M, Steege A, Fähling M, Hultström M, Gaestel M, Moraes-Silva IC, Nikitina T, Liu ZZ, Zavaritskaya O, Patzak A
(See online at https://doi.org/10.1111/apha.12457) - Increased hydrogen peroxide impairs angiotensin II contractions of afferent arterioles in mice after renal ischemia-reperfusion injury. Acta Physiol (Oxf) 218(2): 136-45, 2016
Huang Q, Wang Q, Zhang S, Jiang S, Zhao L, Yu L, Hultström M, Patzak A, Li L, Wilcox CS, Lai EY
(See online at https://doi.org/10.1111/apha.12745) - Myoglobin facilitates angiotensin II induced constriction of renal afferent arterioles. Am J Physiol Renal Physiol 312: F908-F916, 2017
Liu ZZ, Mathia S, Pahlitzsch T, Wennysia IC, Persson PB, Lai EY, Högner A, Xu MZ, Schubert R, Rosenberger C, Patzak A
(See online at https://doi.org/10.1152/ajprenal.00394.2016) - Short-term hypoxia and vasa recta function in kidney slices. Clinical Hemorheology and Microcirculation 67: 475-484, 2017
Braun D, Dietze S, Pahlitzsch TMJ, Wennysia IC, Persson PB, Ludwig M, Patzak A
(See online at https://doi.org/10.3233/CH-179230) - Understanding and preventing contrast-induced acute kidney injury. Nat Rev Nephrol. 13(3): 169-180, 2017
Fähling M, Seeliger E, Patzak A, Persson PB
(See online at https://doi.org/10.1038/nrneph.2016.196) - Enhanced Renal Afferent Arteriolar Reactive Oxygen Species and Contractility to Endothelin-1 Are Associated with Canonical Wnt Signaling in Diabetic Mice. Kidney Blood Press Res 43: 860-871, 2018
Zhang S, Huang Q, Wang Q, Wang Q, Cao X, Zhao L, Xu N, Zhuge Z, Mao J, Fu X, Liu R, Wilcox CS, Patzak A, L. Li L, Lai EY
(See online at https://doi.org/10.1159/000490334) - Hypoxia/re-oxygenation enhances murine afferent arteriolar vasoconstriction by angiotensin II. Am J Physiol Renal Physiol 314(3): F430-F438, 2018
Pahlitzsch T, Liu ZZ, Al-Masri A, Braun D, Dietze S, Persson PB, Schunck WH, Blum M, Kupsch E, Ludwig M, Patzak A
(See online at https://doi.org/10.1152/ajprenal.00252.2017) - Hypoxia/Reoxygenation of Rat Renal Arteries Impairs Vasorelaxation via Modulation of Endothelium-Independent sGC/cGMP/PKG Signaling. Front Physio. 9: 480, 2018
Braun D, Zollbrecht C, Dietze S, Schubert R, Golz S, Summer H, Persson PB, Carlström M, Ludwig M, Patzak A
(See online at https://doi.org/10.3389/fphys.2018.00480) - ADAMTS13 protects mice against renal ischemia/reperfusion injury by reducing inflammation and improving endothelial function. Am J Physiol Renal Physiol 316: F134-F145, 2019
Zhou S, Jiang S, Guo J, Xu N, Wang Q, Zhang G, Zhao L, Zhou Q, Fu X, Li L, Patzak A, Hultström M, Lai EY
(See online at https://doi.org/10.1152/ajprenal.00405.2018)
