Transforming growth factor ß3 deficiency promotes defective lipid metabolism and fibrosis in murine kidney.

Glomerulosclerosis and tubulointerstitial fibrosis are pathological features of chronic kidney disease. Transforming growth factor ß (TGFß) is a key player in the development of fibrosis. However, of the three known TGFß isoforms, only TGFß1 has an established role in fibrosis, and the pathophysiological relevance of TGFß2 and TGFß3 is unknown. Because Tgfb3 deficiency in mice results in early postnatal lethality, we analyzed the kidney phenotype of heterozygous Tgfb3-knockout mice (Tgfb3+/-) and compared it with that of matched wild-type mice. Four-month-old Tgfb3+/- mice exhibited incipient renal fibrosis with epithelial-mesenchymal transition, in addition to glomerular basement membrane thickening and podocyte foot process effacement associated with albuminuria. Also evident was insulin resistance and oxidative stress at the renal level, together with aberrant renal lipid metabolism and mitochondrial function. Omics analysis revealed toxic species, such as diacylglycerides and ceramides, and dysregulated mitochondrial metabolism in Tgfb3+/- mice. Kidneys of Tgfb3+/- mice showed morphological alterations of mitochondria and overactivation of non-canonical MAPK ERK1/2 and JNK cascades. Our study indicates that renal TGFß3 might have antifibrotic and renoprotective properties, opposing or counteracting the activity of TGFß1. This article has an associated First Person interview with the first author of the paper.

Underlying Mechanisms of Renal Lipotoxicity in Obesity.

The recent and ongoing worldwide increase in the prevalence of obesity parallels the increase in the incidence of chronic kidney disease (CKD). This association suggests an implication of lipotoxicity in the development of kidney diseases. The increased influx of lipids into the kidney can be explained in the context of the "Adipose Tissue Expandability Hypothesis". This hypothesis states that the adipose tissue has a limited expansion capability, which is different for each individual, and once this limit is reached, the adipose tissue cannot store any more lipids and will thus release them into the bloodstream. The accumulation of lipids in the kidney is known as renal lipotoxicity. Renal lipotoxicity is known to cause detrimental effects on the kidney by several mechanisms of action including reclusion of pro-inflammatory factors, oxidative and ER stress development, insulin resistance (IR), lipid metabolism deregulation or renin-angiotensin aldosterone system overactivation. Isoform peroxisome proliferator-activated receptor gamma (PPARγ) seems to play an important role in the development of this lipotoxicity as proven by several studies in -animals and cultured cells. Thus, PPARγ agonists are of -interest in the therapeutic approach to treat CKD in the context of obesity. This review aims to summarize our current knowledge of the mechanism by which lipotoxicity affects renal structure and function using in vivo and in vitro models as examples focusing on PPARγ.

HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis.

Cellular aspartate drives cancer cell proliferation, but signaling pathways that rewire aspartate biosynthesis to control cell growth remain largely unknown. Hypoxia-inducible factor-1α (HIF1α) can suppress tumor cell proliferation. Here, we discovered that HIF1α acts as a direct repressor of aspartate biosynthesis involving the suppression of several key aspartate-producing proteins, including cytosolic glutamic-oxaloacetic transaminase-1 (GOT1) and mitochondrial GOT2. Accordingly, HIF1α suppresses aspartate production from both glutamine oxidation as well as the glutamine reductive pathway. Strikingly, the addition of aspartate to the culture medium is sufficient to relieve HIF1α-dependent repression of tumor cell proliferation. Furthermore, these key aspartate-producing players are specifically repressed in VHL-deficient human renal carcinomas, a paradigmatic tumor type in which HIF1α acts as a tumor suppressor, highlighting the in vivo relevance of these findings. In conclusion, we show that HIF1α inhibits cytosolic and mitochondrial aspartate biosynthesis and that this mechanism is the molecular basis for HIF1α tumor suppressor activity.