Regenerative and protective effects of renin cells on renal vasculature
Anatomy and Physiology
Final Report Abstract
Others and we found that the renin cells (or renin-producing cells, RPCs) are important for the functional and structural integrity of the kidney, independently of their role within Renin-Angiotensin-System (RAS). We developed a novel inducible triple-transgenic mouse model to study the RAS-unrelated functions of the renin cells. Using this model, we established that the renin cells serve as renewable stem-cell-like progenitors. We also found that RPC-specific Gs-alpha deficient mice develop chronic renal microvascular endothelial damage. Thus, Gs-alpha/cAMP signaling in renin cells confers vasoprotective properties. In this project, we aimed to study whether the protective effect of RPCs on renal microvascular endothelium could be modulated either by chronic alterations in renin production or by acute vascular injury. We also aimed to characterize the transcriptional landscape of the renin cells after Gs-alpha knockout. High-salt diet, which suppresses renin production, predisposed RPC-specific Gs-alpha-deficient mice to renal vascular damage by modulating the immune cell infiltration wherein cytotoxic CD8 cells persisted while protective FoxP3+ Tregs decreased in the kidney. Kidney immune cell infiltration after acute glomerular capillary damage was not dependent on Gs-alpha in RPCs. The Gs-alpha deficient mice seemed to be also very susceptible to organ damage induced by severe hypertension in a model combining salt and water loading with angiotensin II-induced vasoconstriction. However, decreased survival rate of the animals in this model limited a more detailed interpretation of the role of Gs-alpha/cAMP signaling in renin cells as a protective mechanism. Finally, yet importantly, we found that after Gs-alpha knockout, the RPCs persist as renin-negative progeny. Analysis of the global expression pattern of these renin cell descendants revealed that the inactivation of Gs-alpha/cAMP signaling changes the RPC phenotype from protective and secretory to damaging and profibrotic.
Publications
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New automatic quantification method of immunofluorescence and histochemistry in whole histological sections. Cellular Signalling, 62, 109335.
Kessel, Friederike; Steglich, Anne; Tschongov, Todor; Gembardt, Florian; Ruhnke, Leo; Stumpf, Julian; Behrendt, Rayk; Cohrs, Christian; Kopaliani, Irakli; Todorov, Vladimir; Gerlach, Michael & Hugo, Christian
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Renin cells with defective Gsα/cAMP signaling contribute to renal endothelial damage. Pflügers Archiv -European Journal of Physiology, 471(9), 1205-1217.
Steglich, Anne; Kessel, Friederike; Hickmann, Linda; Gerlach, Michael; Lachmann, Peter; Gembardt, Florian; Lesche, Mathias; Dahl, Andreas; Federlein, Anna; Schweda, Frank; Hugo, Christian P. M. & Todorov, Vladimir T.
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Beyond the Paradigm: Novel Functions of Renin-Producing Cells. Reviews of Physiology, Biochemistry and Pharmacology, 53-81. Springer International Publishing.
Steglich, Anne; Hickmann, Linda; Linkermann, Andreas; Bornstein, Stefan; Hugo, Christian & Todorov, Vladimir T.
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Patterns of differentiation of renin lineage cells during nephrogenesis. American Journal of Physiology-Renal Physiology, 321(3), F378-F388.
Kessel, Friederike; Steglich, Anne; Hickmann, Linda; Lira, Martinez Ricardo; Gerlach, Michael; Sequeira-Lopez, Maria Luisa S.; Gomez, R. Ariel; Hugo, Christian P. M. & Todorov, Vladimir T.
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Prolyl‐4‐hydroxylases 2 and 3 control erythropoietin production in renin‐expressing cells of mouse kidneys. The Journal of Physiology, 600(3), 671-694.
Broeker, Katharina A. E.; Fuchs, Michaela A. A.; Schrankl, Julia; Lehrmann, Claudia; Schley, Gunnar; Todorov, Vladimir T.; Hugo, Christian; Wagner, Charlotte & Kurtz, Armin
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Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation. Journal of Clinical Investigation, 132(6).
Failer, Theresa; Amponsah-Offeh, Michael; Neuwirth, Aleš; Kourtzelis, Ioannis; Subramanian, Pallavi; Mirtschink, Peter; Peitzsch, Mirko; Matschke, Klaus; Tugtekin, Sems M.; Kajikawa, Tetsuhiro; Li, Xiaofei; Steglich, Anne; Gembardt, Florian; Wegner, Annika C.; Hugo, Christian; Hajishengallis, George; Chavakis, Triantafyllos; Deussen, Andreas; Todorov, Vladimir & Kopaliani, Irakli
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Editorial: Recent advances on renoprotection and kidney regeneration. Frontiers in Physiology, 14.
Gimenez, Ignacio; Hugo, Christian & Todorov, Vladimir T.
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PLVAP as an Early Marker of Glomerular Endothelial Damage in Mice with Diabetic Kidney Disease. International Journal of Molecular Sciences, 24(2), 1094.
Wolf, Elena E.; Steglich, Anne; Kessel, Friederike; Kröger, Hannah; Sradnick, Jan; Reichelt-Wurm, Simone; Eidenschink, Kathrin; Banas, Miriam C.; Wolf, Eckhard; Wanke, Rüdiger; Gembardt, Florian & Todorov, Vladimir T.
