Role of renin and the renin-producing cells for the functional and structural integrity of the kidney

• Applicant: Professor Dr. Vladimir Todorov
• Subject Area: Nephrology ; Endocrinology, Diabetology, Metabolism
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258497933

• Final Report Year: 2019

Final Report Abstract

Increasing evidence demonstrates that next to their classical role in renin-angiotensin-system (RAS) and blood pressure control, renin-producing juxtaglomerular (JG) cells might be decisive for the functional and structural integrity of the adult kidney in health and disease. This proposal aimed to characterize the RAS-independent roles of the renin-producing cells in the control of renal function in adulthood. To this end, three transgenic mouse models for selective and inducible targeting of the renin-producing cells were used: I. Mice with cell-specific renin knockout. II. Mice with cell-specific ablation of renin cells. III. Mice with cell-specific COUP-TFII transcription factor knockout. We could confirm the high specificity and efficiency of our transgenic model for targeting the reninproducing cells. We also found that the renin-producing cells are continuously repopulated by regulated neogenesis (de novo differentiation) from unrelated progenitor cells. Further studies revealed some functional changes, but to some extent surprisingly no major adverse renal phenotype in any of the three transgenic strains characterized. Recruitment of renin cells upstream in the afferent arterioles provided mechanistic explanation for these findings in the strains with renin and renin cell deficiency. For the COUP-TFII deficient mice it could not be excluded that the floxed strain supplied by the cooperation partners did not recombine as originally described. Altogether, it appeared that not renin or the renin-producing cells themselves but the intracellular cAMP signaling is the main factor necessary for the physiological maintenance of the adult kidney. Transcriptome analyses showed that the JG cells are source not only for renin, but also for angiogenic and tissue remodeling factors. The data generated in the frames of this proposal demonstrated unequivocally that the renin-producing cells do have renin- and RAS-independent functions. These exciting findings are an excellent background for further studies on the unconventional role of the renin-producing cells in the kidney under conditions where homeostasis is disturbed by aberrant salt loading, hypertensive stress or primary renal injury.

Publications

• Inducible glomerular erythropoietin production in the adult kidney. Kidney Int 88:1345-1355, 2015
  Gerl K, Miquerol L, Todorov V, Hugo C, Adams R, Kurtz A, Kurt B
  
• Extrarenal progenitor cells do not contribute to endothelial repair in the mouse kidney. J Am Soc Nephrol 27:1714-1726, 2016
  Sradnick J, Rong S, Lüdemann A, Parmentier SP, Bartaun C, Todorov V, Gueler F, Hugo CP, Hohenstein B
  
• Interference with Gsα-coupled receptor signaling in renin-producing cells leads to renal endothelial damage. J Am Soc Nephrol 28:3479-3489, 2017
  Lachmann P, Hickmann L, Steglich A, Al-Mekhlafi M, Gerlach M, Jetschin N, Jahn S, Hamann B, Wnuk M, Madsen K, Djonov V, Chen M, Weinstein LS, Hohenstein B, Hugo C, Todorov VT
  
• Persisting and inducible neogenesis repopulates renin lineage cells in the kidney. Kidney Int 92:1419-1432, 2017
  Hickmann L, Gerlach M, Al-Mekhlafi M, Sradnick J, Lachmann P, Steglich A, Sequeira- Lopez ML, Gomez RA, Hohenstein B. Hugo CP, Todorov VT
  
• The PPAR- gamma-binding sequence Pal3 is necessary for basal but dispensable for high-fat diet regulated human renin expression in the kidney. Pflugers Arch 469:1349-1357, 2017
  Lachmann P, Selbmann J, Hickmann L, Hohenstein B, Hugo C, Todorov VT
  
• COX-2 derived PGE2 triggers hyperplastic renin expression and hyperreninemia in aldosterone synthase deficient mice. Pflugers Arch, 470: 1127-1137, 2018
  Karger C, Machura K, Schneider A, Hugo C, Todorov VT, Kurtz A
  
• Progenitor Renin Lineage Cells are not involved in the regeneration of glomerular endothelial cells during experimental renal thrombotic microangiopathy. Plos One 13:e0196752, 2018
  Ruhnke L, Sradnick J, Al-Mekhlafi M, Gerlach M, Gembardt F, Hohenstein B, Todorov VT, Hugo C
  
• New automatic quantification method of immunofluorescence and histochemistry in whole histological sections. Cell Signal 62:109335, 2019
  Kessel F, Steglich A, Tschongov T, Gembardt F, Ruhnke L, Stumpf J, Behrendt R, Cohrs C, Kopaliani I, Todorov V, Gerlach M, Hugo C
  
• Renin cells with defective Gsα/cAMP-signaling contribute to renal endothelial damage. Pflugers Arch 471:1205- 1217, 2019
  Steglich A, Kessel F, Hickmann L, Gerlach M, Lachmann P, Gembardt F, Lesche M, Dahl A, Federlein A, Schweda F, Hugo C, Todorov VT