Abstract
ABSTRACTThe current understanding of molecular mechanisms driving diabetic kidney disease (DKD) is limited, partly due to the complex structure of the kidney. To identify genes and signalling pathways involved in the progression of DKD, we compared kidney cortical versus glomerular transcriptome profiles in uninephrectomized (UNx) db/db mouse models of early-stage (UNx only) and advanced [UNxplus adeno-associated virus-mediated renin-1 overexpression (UNx-Renin)] DKD using RNAseq. Compared to normoglycemic db/m mice, db/db UNx and db/db UNx-Renin mice showed marked changes in their kidney cortical and glomerular gene expression profiles. UNx-Renin mice displayed more marked perturbations in gene components associated with the activation of the immune system and enhanced extracellular matrix remodelling, supporting histological hallmarks of progressive DKD in this model. Single-nucleus RNAseq enabled the linking of transcriptome profiles to specific kidney cell types. In conclusion, integration of RNAseq at the cortical, glomerular and single-nucleus level provides an enhanced resolution of molecular signalling pathways associated with disease progression in preclinical models of DKD, and may thus be advantageous for identifying novel therapeutic targets in DKD.
Highlights
Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the most common cause of chronic kidney disease worldwide, accounting for approximately 50% and 25% of patients with kidney failure in the USA and EU, respectively (United States Renal Data System, 2018; Kramer et al, 2019)
ReninAAV administration was evaluated for renal effects and transcriptome changes in the diabetic UNx mouse model of DKD, while UNx mice injected with LacZAAV and healthy db/m mice served as controls (Fig. 1A-B)
Measurements indicate that a single injection with ReninAAV exacerbates kidney injury, notably albuminuria and glomerulosclerosis, in UNx-renin mice compared with UNx mice, but does not affect body weight or blood glucose levels
Summary
Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the most common cause of chronic kidney disease worldwide, accounting for approximately 50% and 25% of patients with kidney failure in the USA and EU, respectively (United States Renal Data System, 2018; Kramer et al, 2019). Despite drug therapeutic advances in hyperglycemia and hypertension management (Lewis et al, 1993; Brenner et al, 2001; Wanner et al, 2016; Mann et al, 2017; Perkovic et al, 2019; Heerspink et al, 2020), the combination of increased diabetes prevalence and life expectancy in diabetes patients have led to an increase in patients with DKD progressing to kidney failure (McCullough et al, 2019). Hypertension, a common comorbidity in diabetes and a driving factor of DKD progression, is absent in most rodent models commonly used in preclinical DKD research, including the uninephrectomized (UNx) db/db mouse model of early-stage DKD (Levine, Iacovitti and Robertson, 2008). The db/db UNx-Renin mouse presents with hallmarks of late-stage DKD including markedly increased urine albumin-to-creatinine ratio (ACR), advanced glomerulosclerosis, and elevated serum creatinine levels
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