A rat model of chronic kidney disease-mineral bone disorder

Moe, Sharon M.; Chen, Neal X.; Seifert, Mark F.; Sinders, Rachel M.; Duan, Dana; Chen, Xianming; Liang, Yun; Radcliff, Jeff; White, Kenneth E.; Gattone, Vincent H.

doi:10.1038/ki.2008.456

Cited by 144 publications

(169 citation statements)

References 33 publications

Supporting

Mentioning

150

Contrasting

Order By: Relevance

“…(26,53,54) We have extended these studies by characterizing the natural progression of CKD-MBD in the jck mouse, a genetic model of PKD, (28) as a first step toward defining the mechanistic link between renal dysfunction, declining bone, and cardiovascular disease. Importantly, we confirm that changes in jck serums closely mirror those observed in clinical serum samples as reported by Craver and colleagues, (29) albeit with some differences (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…(16)(17)(18)(19)(20)(21)(22)(23) Additionally, soft-tissue calcification including vascular calcification is a common feature of genetic mouse and rat models harboring defects associated with bone mineralization. (24)(25)(26) Clinical improvements in bone health, regardless of the initial bone defect, ameliorate progression of cardiovascular disease. (23) Taken together, these observations support a mechanistic link between bone health and cardiovascular disease and have prompted the Kidney Disease: Improving Global Outcomes (KDIGO) organization to describe characteristics in mineral dysregulation as CKD-mineral bone disorder (CKD-MBD).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

237

224

View full text Add to dashboard Cite

Chronic kidney disease–mineral bone disorder (CKD‐MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft‐tissue calcification. Emerging evidence suggests that features of CKD‐MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild‐type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD‐MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild‐type mice. To capture the early molecular and cellular events in the progression of CKD‐MBD we examined cell‐specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor‐Ser33/37‐β‐catenin was observed both in mouse and human bones. Overall repression of Wnt/β‐catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF‐κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late‐stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD‐MBD and suggest that repression of the Wnt/β‐catenin pathway is involved in the pathogenesis of renal osteodystrophy. © 2012 American Society for Bone and Mineral Research.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

237

224

View full text Add to dashboard Cite

show abstract

“…58 -61 Pi overload accelerates calcification in CKD, and control of Pi reduces calcification in CKD. [62][63][64] Klotho exerts its phosphaturic effects by inhibiting renal NaPi-2a and NaPi-2c in the renal proximal tubule. 25,38 Maintenance of high Klotho in CKD preserves phosphaturia and lessens phosphate retention.…”

Section: Pathogenic Role Of Klotho In Progression Of Ckd and Its Compmentioning

confidence: 99%

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

Hu¹,

Shi²,

Zhang³

et al. 2011

Journal of the American Society of Nephrology

811

877

View full text Add to dashboard Cite

Soft-tissue calcification is a prominent feature in both chronic kidney disease (CKD) and experimental Klotho deficiency, but whether Klotho deficiency is responsible for the calcification in CKD is unknown. Here, wild-type mice with CKD had very low renal, plasma, and urinary levels of Klotho. In humans, we observed a graded reduction in urinary Klotho starting at an early stage of CKD and progressing with loss of renal function. Despite induction of CKD, transgenic mice that overexpressed Klotho had preserved levels of Klotho, enhanced phosphaturia, better renal function, and much less calcification compared with wild-type mice with CKD. Conversely, Klotho-haploinsufficient mice with CKD had undetectable levels of Klotho, worse renal function, and severe calcification. The beneficial effect of Klotho on vascular calcification was a result of more than its effect on renal function and phosphatemia, suggesting a direct effect of Klotho on the vasculature. In vitro, Klotho suppressed Na ϩ -dependent uptake of phosphate and mineralization induced by high phosphate and preserved differentiation in vascular smooth muscle cells. In summary, Klotho is an early biomarker for CKD, and Klotho deficiency contributes to soft-tissue calcification in CKD. Klotho ameliorates vascular calcification by enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle. Replacement of Klotho may have therapeutic potential for CKD.

show abstract

“…However, the casein-fed animals had increased urinary phosphorus excretion and elevated serum FGF23 compared to the grain-fed rats [17]. In a crossover trial 11 patients with CKD stages 3-4 ingested a diet with animal or vegetable protein for 7 days.…”

Section: Phosphorus Absorption and Protein Of Different Originsmentioning

confidence: 99%

Nutrition Therapy For Liver Diseases Based On The Status Of Nutritional Intake

2013

Clinical Nutrition

View full text Add to dashboard Cite

Patients with renal impairment progressively lose the ability to excrete phosphorus. Decreased glomerular filtration of phosphorus is initially compensated by decreased tubular reabsorption, regulated by PTH and FGF23, maintaining normal serum phosphorus concentrations. There is a close relationship between protein and phosphorus intake. In chronic renal disease, a low dietary protein content slows the progression of kidney disease, especially in patients with proteinuria and decreases the supply of phosphorus, which has been directly related with progression of kidney disease and with patient survival. However, not all animal proteins and vegetables have the same proportion of phosphorus in their composition. Adequate labeling of food requires showing the phosphorus-to-protein ratio. The diet in patients with advanced-stage CKD has been controversial, because a diet with too low protein content can favor malnutrition and increase morbidity and mortality. Phosphorus binders lower serum phosphorus and also FGF23 levels, without decreasing diet protein content. But the interaction between intestinal dysbacteriosis in dialysis patients, phosphate binder efficacy, and patient tolerance to the binder could reduce their efficiency.

show abstract

A rat model of chronic kidney disease-mineral bone disorder

Cited by 144 publications

References 33 publications

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

Nutrition Therapy For Liver Diseases Based On The Status Of Nutritional Intake

Contact Info

Product

Resources

About