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

Renin is largely expressed throughout the renal arteries in embryonic life. In contrast, the expression of renin in adulthood is restricted to the afferent arterioles where it is produced mainly by the juxtaglomerular cells. The constitutive inactivation by genomic targeting as well as null mutations of the renin gene cause developmental malformations in the kidney. These are manifested by glomerulosclerosis, arterial thickening and tubular dysgenesis, and consequently result in deterioration of renal function and early death. On the other hand, the causal role of renin for the maintenance of normal kidney function in adulthood when nephrogenesis is accomplished is still largely unknown. In addition, it has been suggested that the renin-producing cells themselves independent of renin may also be essential for the morphological and functional integrity of the kidney. The current studies in this research area are essentially hampered by the lack of an appropriate experimental model.In the proposed project we will address this issue by using transgenic mouse model for selective and inducible targeting of the renin-producing cells. We have already generated a mouse line (mRen-rtTAm2) expressing tetracycline transactivator under the control of the complete regulatory sequences of the renin gene. The mRen-rtTAm2 transgenic mice crossed with a tetracycline-inducible cre-recombinase expressing strain (LC1 mice) allow us to modulate the renin gene expression or to selectively ablate the renin-producing cells after the kidney development is completely finished.Using this transgenic model we will first study whether the inducible genomic inactivation of the renin gene leads to changes in the kidney phenotype. For this purpose we have already generated a transgenic mouse line with a floxed renin allele.In a second approach we will characterize the renal excretory function and morphology of mice in which the renin-producing cells are selectively destroyed. To this end, we will use animals with inducible expression of diphtheria toxin A chain in renin cells. Furthermore, we will examine the role of the orphan nuclear receptor COUP-TFII in renin cells. COUP-TFII regulates the renin gene expression by modulating the cAMP signaling, which in turn is the master switch of the renin production. Therefore we generated mice with inducible deficiency of COUP-TFII.We expect from these experiments to provide comprehensive insight into the renin-dependent and independent role of the renin-producing cells for the physiological integrity of the kidney beyond nephrogenesis. In a perspective our data could accelerate the development of novel therapeutic strategies based on the modulation of the renin-angiotensin-system, the renin production and/or the number of the renin-producing cells to beneficially influence the mechanisms of kidney repair during chronic kidney disease.

• DFG Programme: Research Grants