Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice

Abstract

Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis, with the extent of tissue involvement depending on the duration of oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings established to reflect inflammation and fibrosis parallel the histological changes. Within 3 wk, the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 activation, hyperphosphatemia, and hyperparathyroidism. In addition, the model is characterized by profound arterial hypertension as well as cardiac fibrosis that persist following the switch to a control diet. Together, this new model of inducible CKD overcomes a number of previous experimental limitations and should serve useful in research related to CKD and its complications.

Regulated necrosis-related molecule mRNA expression in humans and mice and in murine acute tissue injury and systemic autoimmunity leading to progressive organ damage, and progressive fibrosis

“…To study the induction of RN-related molecules in chronic tissue remodelling, we used two well-characterized murine models of chronic kidney disease (CKD) viz. progressive CKD model of chronic oxalate nephropathy [36] and CKD long after AKI model [45]. The mRNA levels of necroptosis- and pyroptosis-related molecules (TNFR1, RIPK3, MLKL, CIAP1/2, NLRP3 and CASP1) were significantly induced during the progression of chronic oxalate nephropathy, except for MLKL, which was decreased in the later phase (Figures 4A and 4B).…”

“…For cisplatin nephropathy model, mice received a single intraperitoneal injection of 20 mg kg −1 of cisplatin (Sigma–Aldrich) and kidneys were harvested after 3 days for RNA isolation and histology analysis [35]. Chronic oxalate nephropathy was induced by feeding mice an oxalate-rich diet that was prepared by adding 50 μmol/g sodium oxalate to a calcium-free standard diet (Ssniff) as recently described [36]. Mice were killed at day 7, 14 and 21 [36].…”

“…Chronic oxalate nephropathy was induced by feeding mice an oxalate-rich diet that was prepared by adding 50 μmol/g sodium oxalate to a calcium-free standard diet (Ssniff) as recently described [36]. Mice were killed at day 7, 14 and 21 [36]. For the lupus model, groups of female MRL/WT or MRL/lpr mice with spontaneous lupus-like autoimmunity were killed at 6, 10 and 14 weeks as described [37,38].…”

Oxalate, inflammasome, and progression of kidney disease

“…This discovery proposes an interesting link between metabolism and the regulation of systemic inflammation. Given the profound protection against oxalate-induced progressive renal insufficiency in mice deficient for NLRP3, future studies should examine these compounds in the established murine models of oxalate-induced CKD and crystal-induced progressive renal failure [81, 108]. …”

“…Translating this concept to a clinical setting, it becomes possible or even likely that high plasma oxalate levels as observed in advanced CKD patients launch a vicious cycle of inflammasome mediated systemic inflammation and kidney damage resulting in progressive renal disease. In particular, the cardiovascular implications of such high oxalate levels in the circulation are of great concern: in our murine model of dietary oxalate-induced CKD, mice develop a clear presentation of cardiovascular disease including cardiac fibrosis and profound arterial hypertension [108]. Whether these findings are solely related to reduced renal function or elevated plasma oxalate levels remains to be defined.…”