Kidney Week

Abstract: SA-PO109

Anti-Proteinuric Actions of Angiotensin II Receptor Blockade in a Mouse Model of Diabetic Nephropathy

Session Information

• Diabetic Kidney Disease: Basic - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Azushima, Kengo, Duke-NUS Medical School, Singapore, Singapore

Kengo Azushima,

• Gurley, Susan B., Oregon Health and Science University, Portland, Oregon, United States

Susan B. Gurley,

• Coffman, Thomas M., Duke-NUS Medical School, Singapore, Singapore

Thomas M. Coffman,

Background

The progress in the research field of Diabetic nephropathy (DN) has been disturbed by the lack of reliable animal models. We have developed a mouse model exhibiting cardinal characteristics of human DN including high-grade albuminuria, glomerulosclerosis and genetic susceptibility to kidney damage. Because responsiveness to blockade of the renin-angiotensin system (RAS) is a key feature of human DN, we examined the impact of an angiotensin II receptor blocker (ARB) in our mouse model.

Methods

We generated mice with heterozygous for the Ins2^C96Y (Akita) allele combined with a single-copy renin transgene (ReninTg), with renin expression under control of the albumin promoter. Akita-ReninTg mice on a 129/SvEv inbred background, which tends to exhibit exaggerated susceptibility to kidney disease, were generated through back-crossing. In the Acute protocol, losartan (10mg/kg/day) was given to 16-week old 129 Akita-ReninTg for 10 days, whereas in the Chronic protocol, losartan was administered daily from 12-24 weeks of age. Urine samples were collected over a 24-hour period using metabolic cages and albumin levels were measured with immunoassay.

Results

By 24 weeks of age, 129 Akita-ReninTg mice develop substantial albuminuria with severe renal pathological changes including mesangial expansion, nodular glomerulosclerosis and renal interstitial inflammatory cells accumulation. In 16-week old 129 Akita-ReninTg mice, Acute ARB administration caused an abrupt and significant reduction of albuminuria from 1049±325 to 308±156 µg/day (p=0.004). In the Chronic protocol, baseline levels of albumin excretion were similar between treated and untreated groups (767±154 vs 905±169 µg/day). ARB treatment prevented the progressive increase of albuminuria compared to untreated controls at 18 (721±136 vs 142±27 µg/day; p=0.001) and 24 (1480±562 vs 193±42 µg/day; p=0.045) weeks of age.

Conclusion

129 Akita-ReninTg mice replicate key features of human DN, including responsiveness to RAS blockade. As in humans, the anti-proteinuric actions of ARB can be seen early after initiating treatment, likely representing acute reversal of abnormal glomerular hemodynamics and/or permeability. Chronic ARB administration causes a significant reduction in albuminuria that is sustained during the entire treatment period, likely due to protection against Ang II-dependent kidney injury.

Funding

• Government Support - Non-U.S.