Pathological and Transcriptome Changes in the ReninAAV db/db uNx Model of Advanced Diabetic Kidney Disease Exhibit Features of Human Disease

Abstract

The ReninAAV db/db uNx model of diabetic kidney disease (DKD) exhibits hallmarks of advanced human disease, including progressive elevations in albuminuria and serum creatinine, loss of glomerular filtration rate, and pathological changes. Microarray analysis of renal transcriptome changes were more similar to human DKD when compared to db/db eNOS À/À model. The model responds to treatment with arterial pressure lowering (lisinopril) or glycemic control (rosiglitazone) at early stages of disease. We hypothesized the ReninAAV db/db uNx model with advanced disease would have residual disease after treatment with lisinopril, rosiglitazone, or combination of both. To test this, ReninAAV db/db uNx mice with advanced disease were treated with lisinopril, rosiglitazone, or combination of both for 10 weeks. All treatment groups showed significant lowering of urinary albumin to creatinine ratio compared to baseline; however, only combination group exhibited lowering of serum creatinine. Treatment improved renal pathological scores compared to baseline values with residual disease evident in all treatment groups when compared to db/m controls. Gene expression analysis by TaqMan supported pathological changes with increased fibrotic and inflammatory markers. The results further validate this model of DKD in which residual disease is present when treated with agents to lower arterial pressure and glycemic control.

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

“…Accordingly, ReninAAV administration induces persistent hypertension and has recently been shown to accelerate DKD progression in diabetic UNx mice (Harlan, Heinz-Taheny, Sullivan, et al, 2018;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, Heinz-Taheny, Overstreet, et al, 2018;Harlan, Heinz-Taheny, Sullivan, et al, 2018;Østergaard et al, 2021).…”

“…Although several transcriptomic studies have been reported in the db/db UNx and UNx-Renin mouse model, knowledge on disease-associated gene expression changes in these models is based on preselected gene sets Harlan, Heinz-Taheny, Overstreet, et al, 2018;Harlan, Heinz-Taheny, Sullivan, et al, 2018). Consequently, global gene expression profiling could help validating the clinical translatability of these models.…”

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

“…Our study corroborates and extends findings of robust nephroprotective effects of lisinopril in combination with antidiabetic treatment (rosiglitazone) in db/db UNx-ReninAAV mice (20,21).…”

“…Induction of persistent hypertension by adeno-associated virus (AAV)-mediated renin gene transfer has recently been reported to exacerbate kidney injury in uninephrectomized (UNx) db/db mice (20,21). Because the db/db UNx-ReninAAV mouse shows close resemblance to human DKD pathogenesis (21), we further validated the model for utility in preclinical drug discovery by characterizing renal disease and outcomes of long-term standard of care using an ACE inhibitor (lisinopril) and SGLT2 inhibitor (empagliflozin).…”

The kidney transcriptome, from single cells to whole organs and back

“…Transcriptome analysis provides the opportunity to survey changes resulting from genetic, physiological, or environmental interactions that may be involved in CKD pathogenesis [27][28][29]. While proteins show a closer relationship to function, methods analyzing protein quantity and modifications are relatively cumbersome.…”