Mice are the most commonly used mammalian species for in vivo experiments24. Almost all murine genes share their functions with those of humans25, but mice have a short generation time, in the order of 10 weeks from birth to parenthood26. Additionally, mice are small and require little space for breeding. Finally, they are genetically tractable and well characterized; therefore, they are frequently used for genetic modification studies. However, compared with other species such as rats, dogs, and cats, mice are relatively resistant to kidney damage. For example, the C57BL/6 mouse strain, which is often used in experiments, does not develop glomerular or tubulointerstitial injury and is resistant to hypertension when used to create a remnant kidney model16.
Long-term dietary HPD loading causes renal glomerular hyperfiltration and sclerosis in rats21. The loading of an HPD to rats increases sodium-dependent amino acid reabsorption in their proximal tubules, resulting in tubuloglomerular feedback, which causes dilation of the afferent arterioles and constriction of the efferent arterioles. This leads to higher intraglomerular pressure and excessive filtration, resulting in glomerulosclerosis27. Independently of this tubuloglomerular feedback mechanism, vascular endothelial growth factor (VEGF) is also involved in the pathogenesis of HPD-induced glomerular hyperfiltration28,29. Additionally, HPD also increases renal sterol-regulatory element binding protein 1 (SREBP-1) expression, which promotes renal lipogenesis and triglyceride accumulation in obese Zuckerfa/fa rats30. Such renal triglyceride accumulation promotes renal interstitial fibrosis via the transforming growth factor-β (TGF-β) signaling pathway31. However, in the present study, 129/Sv mice fed an HPD alone for 12 weeks did not develop any renal histological lesions, such as glomerulosclerosis or tubulointerstitial fibrosis. Furthermore, the systolic BP of the 129/Sv mice was not affected by the consumption of HPD alone. Thus, even in the 129/Sv strain, which is susceptible to renal damage, HPD loading does not cause hypertension or renal histopathology to develop, and so the feeding of mice with an HPD is probably insufficient to cause kidney disease on its own.
Remnant kidney models are characterized by low GFR, and therefore they have been widely used in research into CKD. The mechanism of renal parenchymal injury in the remnant kidney model is thought to involve an increase in single-nephron GFR in the remaining glomeruli to compensate for nephron loss32; this increase in intraglomerular pressure leads to intraglomerular hypertension, and the resulting barotrauma induces glomerulosclerosis, proteinuria, and lower filtration. In Sprague-Dawley rats, 5/6 Nx results in albuminuria, glomerulomegaly, glomerulosclerosis, mild interstitial fibrosis, and tubular atrophy within 8 weeks, and more extensive glomerulosclerosis and interstitial fibrosis within 12 weeks15. In the present study, the 129/Sv mice underwent 5/6 Nx, followed by HPD loading for 12 weeks. The combination of HPD loading and 5/6 Nx significantly increased BP and albumin excretion, and caused cardiac hypertrophy. However, histological analysis showed that the glomerulosclerosis induced was very mild and there was only modest tubulointerstitial inflammation and fibrosis. A previous study showed that angiotensin II-infused C57BL/6 mice are resistant to kidney injury, possibly because of higher expression of renal cortical angiotensin type II receptor and anti-oxidative factors such as heme oxygenase-133. In the present study, the factor responsible for the renal protection in the remnant kidney model remains to be identified. Therefore, further studies should aim to elucidate the molecular mechanisms of the renal protection in mice.
The present study had some limitations. We did not include a control group that was fed a normal diet and relatively few animals were studied. Nevertheless, the findings of the present study provide important information that mice are resistant to renal parenchymal damage induced by glomerular hyperfiltration via a combination of 5/6 Nx and HPD loading. Therefore, to determine the protective effects of drugs against the development of CKD in vivo, long-term studies of mouse 5/6 Nx models are required. Alternatively, a rat 5/6 Nx model may be more suitable because renal pathology develops more rapidly in this species. For the same reason, the genetic modification of rats, combined with 5/6 Nx, may facilitate the investigation of candidate genetic mediators of CKD, although the genetic modification of rats is more difficult than that of mice34. Therefore, researchers should consider the advantages and disadvantages of using both mice and rats when designing studies of the mechanisms of, and potential therapies for, CKD.