A phosphate and calcium-enriched diet promotes progression of 5/6-nephrectomy-induced chronic kidney disease in C57BL/6 mice

Abstract

C57BL/6 mice are known to be rather resistant to the induction of experimental chronic kidney disease (CKD) by 5/6-nephrectomy (5/6-Nx). Here, we sought to characterize the development of CKD and its cardiac and skeletal sequelae during the first three months after 5/6-Nx in C57BL/6 mice fed a calcium- and phosphate enriched diet (CPD) with a balanced calcium/phosphate ratio. 5/6-NX mice on CPD showed increased renal fibrosis and a more pronounced decrease in glomerular filtration rate when compared to 5/6-Nx mice on normal diet (ND). Interestingly, despite comparable levels of serum calcium, phosphate, and parathyroid hormone (PTH), circulating intact fibroblast growth factor-23 (FGF23) was 5 times higher in 5/6-Nx mice on CPD, relative to 5/6-Nx mice on ND. A time course experiment revealed that 5/6-Nx mice on CPD developed progressive renal functional decline, renal fibrosis, cortical bone loss, impaired bone mineralization as well as hypertension, but not left ventricular hypertrophy. Collectively, our data show that the resistance of C57BL/6 mice to 5/6-Nx can be partially overcome by feeding the CPD, and that the CPD induces a profound, PTH-independent increase in FGF23 in 5/6-Nx mice, making it an interesting tool to assess the pathophysiological significance of FGF23 in CKD.

Long-Term Excessive Dietary Phosphate Intake Increases Arterial Blood Pressure, Activates the Renin–Angiotensin–Aldosterone System, and Stimulates Sympathetic Tone in Mice

“…Next, we examined two major regulators of arterial stiffness and vascular tone, the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system in our model of dietary phosphate excess. We reported previously that CKD mice fed the CPD have higher aldosterone levels compared with CKD mice on ND [ 32 ]. Besides the fact that the RAAS is a known regulator of blood pressure and vascular tone, it has been suggested that the RAAS is also an important determinant of arterial stiffness [ 33 ].…”

Dentoalveolar Alterations in an Adenine‐Induced Chronic Kidney Disease Mouse Model

“…Similar biochemical and skeletal changes have been reported in other CKD mouse models, including 5/6 nephrectomy model (5/6Nx), EC injury models, dietary induction/exacerbation, and transgenic models, as well as AD–CKD rat models. [ 28,45‐50 ]…”

“…Similar biochemical and skeletal changes have been reported in other CKD mouse models, including 5/6 nephrectomy model (5/6Nx), EC injury models, dietary induction/exacerbation, and transgenic models, as well as AD-CKD rat models. [28,[45][46][47][48][49][50] The changes from AD-CKD were consistently achieved with less than 2 months of treatment; conversely, 5/6Nx and EC models typically require longer periods of time and invasive surgeries that are accompanied by several limitations, including an increased risk of injury and mortality, alterations related to surgical ablation rather than loss of renal function, nonreversibility of the condition, a relatively large degree of variability, and, in some cases, the necessary use of an inducing agent (e.g., 1,25(OH) 2 D 3 ) and/or use of gene-edited mouse models to achieve biochemical changes and vascular calcification. [24,25] As concluded in previous publications with more comprehensive analyses of the (Figure legend continued from previous page.)…”

Comment on “Renail failure suppresses muscle irisin expression, and irisin blunts cortical bone loss in mice” by Kawao et al. ‐ the authors' reply

“…On the other hand, several previous studies showed that 5/6 Nx induces CKD‐related pathophysiology, including skeletal myopthy 6,7 and diminished cortical/trabecular bone microarchitecture 8,9 in C57BL/6 mice, although we have not shown the data of bone pathological features in our study. Moreover, 5/6 Nx induced renal fibrosis and decreased glomerular filtration rate in C57BL/6J mice 10,11 . We therefore believe that C57BL/6 mice could be used as a model to exhibit muscle atrophy and bone loss with the progression of CKD after 5/6 Nx.…”

“…Moreover, 5/6 Nx induced renal fibrosis and decreased glomerular filtration rate in C57BL/6J mice. 10 , 11 We therefore believe that C57BL/6 mice could be used as a model to exhibit muscle atrophy and bone loss with the progression of CKD after 5/6 Nx. We would like to plan the study to examine myokine expression using the other CKD model mice in the near future.…”