Abstract MP07: Long-term Suppression Of The Renin-angiotensin System Leads To Concentric Arteriolar Hypertrophy By Activation Of Renin Cells.

Abstract

Hypertensive patients are frequently treated with inhibitors of the renin-angiotensin system (RASi). In renin knockout mice, cells programmed for the renin phenotype ( Renin null cells) stimulate the concentric hypertrophy of intrarenal arteries and arterioles. The Renin null cells invade the arteriolar walls and stimulate the concentric growth of smooth muscle cells (SMCs). EM exam showed disorganized glomerular arterioles, marked layering of SMCs and increased basement membrane, compared to a single organized SMC layer in WT mice. The hypertrophy leads to flow obstruction, ischemia, and renal failure.We hypothesize that Renin null cells or renin-expressing cells from animals treated with RASi possess a unique transcriptome that drives their own abnormal fate and the concentric accumulation of SMCs.To test this, we performed single-cell RNA-seq in WT and Renin null cells. We also tested genetically hypertensive mice and their normotensive controls treated with captopril for 6 months. Further, we examined renal biopsies from patients treated with RAS inhibitors for more than 5 years, age-matched controls without RAS inhibitors, and healthy control kidneys.The transcriptional profile of Renin null cells was markedly different from the profile of WT cells. Gene ontology indicated that Renin null cells possess a contractile rather than the endocrine phenotype of WT cells ( p <0.0001). The wall thickness of the afferent arterioles in both BPN/3 and BPH/2 mice treated with captopril was significantly increased when compared to the untreated controls (BPN/3: control; 5.54 ± 0.27 μm vs. captopril; 10.57 ± 0.61 μm, P <0.0001, BPH/2: control; 5.46 ± 0.26 μm vs. captopril; 10.44 ± 0.43 μm, P <0.0001), with arterioles positive for renin. Patients with long-term use of RASi had significantly thicker arterioles compared to the other groups (control; 6.55 ± 0.73 μm, without RAS; 8.54 ± 1.71 μm, vs. long-term RAS; 12.46 ± 1.86 μm, P <0.001). The renin-positive area was also increased in the kidneys with long-term use of RASi (control; 307.3 ± 74.7 μm 2 , without RAS; 677.8 ± 313.4 μm 2 , vs. long-term RAS; 1347 ± 529.9 μm 2 , P =0.003).In conclusion, renin cells stimulated by inhibition of RAS have specific molecular programs that contribute to arterial disease.