Loss of biliverdin reductase-A promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells

Abstract

Obesity and increased lipid availability have been implicated in the development and progression of chronic kidney disease. One of the major sites of renal lipid accumulation is in the proximal tubule cells of the kidney, suggesting that these cells may be susceptible to lipotoxicity. We previously demonstrated that loss of hepatic biliverdin reductase A (BVRA) causes fat accumulation in livers of mice on a high-fat diet. To determine the role of BVRA in mouse proximal tubule cells, we generated a CRISPR targeting BVRA for a knockout in mouse proximal tubule cells (BVRA KO). The BVRA KO cells had significantly less metabolic potential and mitochondrial respiration, which was exacerbated by treatment with palmitic acid, a saturated fatty acid. The BVRA KO cells also showed increased intracellular triglycerides which were associated with higher fatty acid uptake gene cluster of differentiation 36 as well as increased de novo lipogenesis as measured by higher neutral lipids. Additionally, neutrophil gelatinase-associated lipocalin 1 expression, annexin-V FITC staining, and lactate dehydrogenase assays all demonstrated that BVRA KO cells are more sensitive to palmitic acid-induced lipotoxicity than wild-type cells. Phosphorylation of BAD which plays a role in cell survival pathways, was significantly reduced in palmitic acid-treated BVRA KO cells. These data demonstrate the protective role of BVRA in proximal tubule cells against saturated fatty acid-induced lipotoxicity and suggest that activating BVRA could provide a benefit in protecting from obesity-induced kidney injury.

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

“…In the present study, the loss of BVRA from WAT resulted in a reduction of mitochondria number. This result is consistent with previous studies in which the deletion of BVRA in both cultured renal proximal tubule cells, as well as cultured hepatocytes, resulted in the decrease in mitochondrial number, mitochondrial membrane potential, oxygen consumption, and extracellular acidification rate [66,67]. Furthermore, the loss of BVRA was shown to decrease the expression of several mitochondrial complex subunit genes as well as mitochondrial dynamin-like GTPase (Opa1), which codes for a protein of the inner mitochondrial membrane regulating mitochondrial stability and energy output [67].…”

“…If BVRA is not found in mitochondria, then why does the loss of BVRA have such a great impact on mitochondrial function? There are several potential mechanisms by which this may occur, including increased reactive oxygen species production in response to BVRA deletion [19,66,68,69]. In the present study, decreases in the metabolite of BVRA, bilirubin, may be responsible for this observed effect on mitochondria number in Blvra FatKO .…”

The association between dyslipidemia and the incidence of chronic kidney disease in the general Zhejiang population: a retrospective study

“…Current studies have shown that abnormal lipids in blood lead to the accumulation of ectopic lipids, which can be deposited in almost all cell types from mesangial cells to podocytes and proximal tubular epithelial cells [29]. Lipid-induced mitochondrial damage may also be more lethal to proximal tubule cells [30]. High cholesterol causes macrophage infiltration and foam cell formation in the kidney.…”

Obesity, kidney dysfunction and hypertension: mechanistic links

“…Excessive RSF and PRF may also cause lipotoxicity owing to the accumulation of intracellular triglycerides and toxic metabolites such as ceramides 57,58 . The mechanisms by which ectopic fat in the kidneys causes injury are still unclear, but increased levels of reactive oxygen species (ROS), mitochondrial dysfunction and endoplasmic reticulum stress may be important contributors.…”