Progressive Renal Disease Established by Renin-Coding Adeno-Associated Virus–Driven Hypertension in Diverse Diabetic Models

Harlan, Shannon M.; Heinz-Taheny, Kathleen; Sullivan, John M.; Wei, Tao; Baker, Hana E.; Jaqua, Dianna L.; Qi, Zhonghua; Cramer, Martin S.; Shiyanova, Tatiyana; Breyer, Matthew D.; Heuer, Josef G.

doi:10.1681/asn.2017040385

Cited by 24 publications

(58 citation statements)

References 43 publications

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“…The C57BLKS db/db mouse is one of the most widely used animal models of diabetes with renal complications (Tesch & Lim, 2010), as substantiated by albuminuria and mesangial matrix expansion (Harlan et al, 2018;Heuer et al, 2017;Tang et al, 2017). In agreement with the literature, the present study demonstrated albuminuria and glomerular hypertrophy in the UNx db/db model.…”

Section: Discussionsupporting

confidence: 92%

“…In accordance to previous reports (Ninomiya, Inomata, & Ogihara, 1999;Springer et al, 2014), we observed several cases of hydronephrosis in male mice exclusively. The susceptibility to hydronephrosis and pyelonephritis (Harlan et al, 2018;Springer et al, 2014) in male db/db mice may pose an argument for selecting female over male mice to further refine the db/db model of DN. However, all together, data do not support a biological rationale for using male or female mice F I G U R E 4 Transcriptional changes in the cortical kidney between male and female UNx db/db mice.…”

Section: Discussionmentioning

confidence: 99%

“…This may mainly be driven by the absence of hypertension during late stage DN, which is the main risk factor associated with progression of DN to ESRD (Betz & Conway, 2014;Conway et al, 2011;Heerspink & Zeeuw, 2011). The use of an adeno associated virus vector to overexpress the renin gene in the db/db UNx mouse model offers an intriguing means of adding this hypertensive component to both accelerate and progress the disease phenotype to an advanced stage of DN (Harlan et al, 2018).…”

Section: Male Femalementioning

confidence: 99%

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Impact of sex on diabetic nephropathy and the renal transcriptome in UNx db/db C57BLKS mice

et al. 2019

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Diabetic nephropathy (DN) is associated with albuminuria and loss of kidney function and is the leading cause of end-stage renal disease. Despite evidence of sexassociated differences in the progression of DN in human patients, male mice are predominantly being used in preclinical DN research and drug development. Here, we compared renal changes in male and female uninephrectomized (UNx) db/db C57BLKS mice using immunohistochemistry and RNA sequencing. Male and female UNx db/db mice showed similar progression of type 2 diabetes, as assessed by obesity, hyperglycemia, and HbA1c. Progression of DN was also similar between sexes as assessed by kidney and glomerular hypertrophy as well as urine albuminto-creatinine ratio being increased in UNx db/db compared with control mice. In contrast, kidney collagen III and glomerular collagen IV were increased only in female UNx db/db as compared with respective control mice but showed a similar tendency in male UNx db/db mice. Comparison of renal cortex transcriptomes by RNA sequencing revealed 66 genes differentially expressed (p < .01) in male versus female UNx db/db mice, of which 9 genes were located on the sex chromosomes. In conclusion, male and female UNx db/db mice developed similar hallmarks of DN pathology, suggesting no or weak sex differences in the functional and structural changes during DN progression. K E Y W O R D S albuminuria, animal model, diabetic nephropathy, mesangial expansion, uninephrectomy How to cite this article: Sembach FE, Fink LN, Johansen T, et al. Impact of sex on diabetic nephropathy and the renal transcriptome in UNx db/ db C57BLKS mice. Physiol Rep. 2019;7:e14333.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Male Femalementioning

confidence: 99%

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Impact of sex on diabetic nephropathy and the renal transcriptome in UNx db/db C57BLKS mice

et al. 2019

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“…Fibrotic renal injury in patients can result from diverse insults. Experiments with animal models across different species (mouse, rat, and carp) have found an association between IL-11 and the varied renal insults, including ischaemia (Grgic et al, 2014;Lemay et al, 2000), drug or chemical toxicity (Mitazaki et al, 2009;Schafer et al, 2017), hypertension (Harlan et al, 2018;Menendez-Castro et al, 2019), diabetes (Harlan et al, 2018), infection (Xu et al, 2014), and physical obstruction of the urinary tract (Grgic et al, 2014). These studies are summarized in Table 1.…”

Section: Il-11 Is Associated With Renal Injury In Diverse Animal Momentioning

confidence: 99%

IL‐11 in cardiac and renal fibrosis: Late to the party but a central player

Corden

Adami

Sweeney

et al. 2020

British J Pharmacology

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Fibrosis is a pathophysiological hallmark of cardiorenal disease. In the heart, fibrosis leads to contractile dysfunction and arrhythmias; in the kidney, it is the final common pathway for many diseases and predicts end‐stage renal failure. Despite this, there are currently no specific anti‐fibrotic treatments available for cardiac or renal disease. Recently and unexpectedly, IL‐11 was found to be of major importance for cardiorenal fibroblast activation and fibrosis. In mouse models, IL‐11 overexpression caused fibrosis of the heart and kidney while genetic deletion of Il11ra1 protected against fibrosis and preserved organ function. Neutralizing antibodies against IL‐11 or IL‐11RA have been developed that have anti‐fibrotic activity in human fibroblasts and protect against fibrosis in murine models of disease. While IL‐11 biology has been little studied and, we suggest, largely misunderstood, its autocrine activity in myofibroblasts appears non‐redundant for fibrosis, which offers new opportunities to better understand and potentially target cardiorenal fibrosis.

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“…Recently, a novel murine model of progressive DKD was generated by inducing hypertension via ReninAAV in db/db uNx mice (Harlan et al 2018). The ReninAAV db/db uNx model has many physiological features of advanced human DKD including robust proteinuria, decline in glomerular filtration rate (GFR), and increased serum creatinine and blood urea nitrogen (Harlan et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Progressive Renal Disease Established by Renin-Coding Adeno-Associated Virus–Driven Hypertension in Diverse Diabetic Models

Cited by 24 publications

References 43 publications

Impact of sex on diabetic nephropathy and the renal transcriptome in UNx db/db C57BLKS mice

Impact of sex on diabetic nephropathy and the renal transcriptome in UNx db/db C57BLKS mice

IL‐11 in cardiac and renal fibrosis: Late to the party but a central player

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

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