Therapeutic effects of lisinopril and empagliflozin in a mouse model of hypertension-accelerated diabetic kidney disease

Abstract

Hypertension is a critical comorbidity for progression of diabetic kidney disease (DKD). To facilitate development of novel therapeutic interventions with the potential to control disease progression, there is a need to establish translational animal models that predict treatment effects in human DKD. The present study aimed to characterize renal disease and outcomes of standard of medical care in a mouse model of advanced DKD facilitated by adeno-associated virus (AAV)-mediated renin overexpression in uninephrectomized (UNx) db/db mice. Five weeks after single AAV administration and four weeks after UNx, female db/db UNx-ReninAAV mice received (PO, QD) vehicle, lisinopril (40 mg/kg), empagliflozin (20 mg/kg) or combination treatment for 12 weeks (n=17 per group). Untreated db/+ mice (n=8) and vehicle-dosed db/db UNx-LacZAAV mice (n=17) served as controls. Endpoints included plasma, urine and histomorphometric markers of kidney disease. Total glomerular numbers and individual glomerular volume was evaluated by whole-kidney 3D imaging analysis. db/db UNx-ReninAAV mice developed hallmarks of progressive DKD characterized by severe albuminuria, advanced glomerulosclerosis and glomerular hypertrophy. Lisinopril significantly improved albuminuria, glomerulosclerosis, tubulointerstitial injury and inflammation. While empagliflozin alone had no therapeutic effect on renal endpoints, lisinopril and empagliflozin exerted synergistic effects on renal outcomes. In conclusion, the db/db UNx-ReninAAV mouse demonstrates good clinical translatability with respect to the physiological and histological hallmarks of progressive DKD. Efficacy of standard of care to control hypertension and hyperglycemia provides proof-of-concept for testing novel drug therapies in the model.

Recent Advances in Diabetic Kidney Diseases: From Kidney Injury to Kidney Fibrosis

“…RAAS regulates blood pressure, salt balance, and fluid homeostasis [ 32 ], and RAAS blockade with ACE inhibitors (ACEI) or angiotensin receptor blockers (ARB) is often used to modify hyperfiltration states and delay progression of renal disease [ 33 ]. Drugs that control hypertension (lisinopril) and hyperglycemia (empagliflozin) were also shown to improve the physiological and histopathological features of kidney disease in a mouse model of hypertension-accelerated progressive DKD [ 34 ]. Moreover, treatment with N-acetyl-seryl-aspartyl-proline (Ac-SDKP), a naturally occurring immunomodulatory and angiogenic peptide mainly produced through enzymatic hydrolysis involving meprin-α and prolyl oligopeptidase, has been shown to partially improve end-organ damage by reducing inflammation and fibrosis, and promoting angiogenesis [ 35 ].…”

ScoMorphoFISH: A deep learning enabled toolbox for single‐cell single‐mRNA quantification and correlative (ultra‐)morphometry

“…Typically, tissue segmentation tasks are demanding in heterogeneous sample sets (like kidney biopsies) and therefore traditional bottlenecks in image analysis workflows. DL has great potential to accelerate segmentation tasks and has already been applied to classify glomerulosclerosis 27 or immunofluorescence‐based glomerular morphometry. 14 We custom‐trained two DL networks for the virtual microdissection of glomeruli, all cells by DAPI‐fluorescence, and podocytes using nuclear IF‐markers.…”

Integrative transcriptomic profiling of a mouse model of hypertension-accelerated diabetic kidney disease

“…The UNx-Renin mouse represents a promising model of progressive DKD ( Harlan et al, 2018b ). Accordingly, ReninAAV administration induces persistent hypertension and has recently been shown to accelerate DKD progression in diabetic UNx mice ( Harlan et al, 2018b ; Østergaard et al, 2021 ). Our study corroborates previous findings in the UNx-Renin model, demonstrating biochemical and histological features of progressive DKD, notably severe albuminuria and advanced glomerulosclerosis ( Harlan et al, 2018a ; 2018b ; Østergaard et al, 2021 ).…”

“…Accordingly, ReninAAV administration induces persistent hypertension and has recently been shown to accelerate DKD progression in diabetic UNx mice ( Harlan et al, 2018b ; Østergaard et al, 2021 ). Our study corroborates previous findings in the UNx-Renin model, demonstrating biochemical and histological features of progressive DKD, notably severe albuminuria and advanced glomerulosclerosis ( Harlan et al, 2018a ; 2018b ; Østergaard et al, 2021 ). Although several transcriptomic studies have been reported in the db/db UNx and UNx-Renin mouse models, knowledge on disease-associated gene expression changes in these models is based on preselected gene sets ( Ninichuk et al, 2007 ; Harlan et al, 2018a , b ).…”