Obesity and Kidney Disease

Differential Effects of Obesity on Adipose Tissue and Kidney Inflammation and Fibrosis

Anne-Emilie Declèves; Kumar Sharma

Disclosures

Curr Opin Nephrol Hypertens. 2015;24(1):28-36. 

In This Article

Adipose and Kidney Matrix Accumulation

Hypoxia-inducible factor 1α (HIF-1α), a key mediator of hypoxia, has been also reported to act in adipose tissue fibrosis. As mentioned previously, an excessive metabolic challenge in adipose tissue induces a hypoxia in the tissue that leads to the initiation of inflammation and, in turn, to fibrosis. Halberg et al.[105] demonstrated that local adipose tissue hypoxia results in the stabilization of the transcription factor HIF-1α that is an important driving force to induce fibrosis.

However, the mechanisms underlying the adipose tissue fibrosis are still unclear.

The kidney is susceptible to fibrosis with a HFD and obesity. Renal fibrosis is marked by progressive tissue scarring, leading to glomerulosclerosis and tubulointerstitial fibrosis.[106] TGF-β is the major driver of matrix synthesis, inhibition of matrix degradation and stimulator of myofibroblast activation, and has been considered as the major mediator of chronic fibrosis in kidney disease. Recent studies demonstrate that with diet-induced obesity there is induction of TGF-β in the kidney in association with the upregulation of extracellular matrix (ECM) molecules, including fibronectin, type IV and type I collagens.[87] Inhibition of TGF-β as an interventional agent results in reduced matrix accumulation in diabetes, puromycin nephropathy, unilateral ureteral obstruction, anti-glomerular basement membrane disease, and hypertensive renal disease.[107–110] Many therapeutic approaches have been tested to inhibit TGF-β, such as the administration of neutralizing anti-TGF-β,[107,109,111,112] soluble TGF-β receptor,[113] or small-interfering RNA for TGF-β type II receptor[114] in the experimental model of CKD.

Similar to adipose tissue, mothers against decapentaplegic 3 (Smad3) has emerged as a key receptor-regulated phospho-Smad that has been tightly linked to matrix accumulation. It has been reported that deletion of Smad3 protects against diabetic kidney disease, hypertensive kidney disease, and obstructive nephropathy.[115] Smad4 is a co-Smad that mediates all Smad-mediated signaling and has emerged as a necessary co-factor to initiate the transcription of Smad3-targeted genes. Deletion of Smad4 in tubular epithelial cells, tubulointerstitial fibroblasts, and mesangial cells protects cells against TGF-β-induced matrix stimulation. Recently, we have found several interactions between the AMPK pathway and TGF-β. TGF-β1 gene stimulation by high glucose has been found to be regulated by the upstream stimulatory factor (USF) family of transcription factors. Upon exposure to high glucose, USF1 translocated to the nucleus; however, this nuclear translocation is blocked by AMPK activation. Similar findings were noted with Smad4, in that nuclear translocation stimulated by elevated glucose or TGF-β1 itself was blocked by AMPK activation (AJP in submission).

However, the role of fibrosis and TGF-β likely has potent effects in many organs outside the kidney, especially in obesity. In obesity-induced adipose tissue dysfunction, increased ECM has been demonstrated in rodent and in human WAT,[105,116] even though the role of the ECM of adipose tissue has received limited attention to date. Nevertheless, Khan et al.[117] demonstrated that adipose tissue exhibited an increased collagen content in the ECM, and especially collagen VI, a predominant component of adipose matrix, in obese mice as well as in Asian Indian patients. The role of collagen VI was then evaluated by the use of a genetic ob/ob mice model with collagen VI disruption. These mice presented an improved fasting blood glucose, insulin sensitivity, and lipid metabolism along with an altered level of many key fibrotic genes in adipose tissue. Luminican, involved in the epithelial–mesenchyme transition during fibrosis, was downregulated, whereas decorin, an antagonist of TGF-β-induced fibrosis, was upregulated.[117] TGF-β, itself, was downregulated in the mice with collagen VI deletion. This was associated with a reduced activation of downstream TGF-β signaling mediators, Smad2 and Smad3. These changes were accompanied by a decrease of adipose tissue inflammation.[117] Therefore, the decreased levels of TGF-β and its downstream mediators suggest a potential role of TGF-β in adipose tissue fibrosis.

A more recent study demonstrated the crucial role of TGF-β and Smad3 in regulating glucose and energy homeostasis using a Smad3 knockout mice.[118] Obesity was found to correlate with the circulating TGF-β1 levels in mice and humans. Upon exposure to diet-induced obesity, there was an increase in adipose tissue TGF-β and increased Smad3 phosphorylation. Interestingly, when mice were treated with anti-TGF-β neutralizing antibody (1D11), the mice had less weight gain, less insulin resistance and the WAT had features of brown fat, with increased uncoupling protein 1 (UCP1) and mitochondrial biogenesis.[118] The Smad3 knockout mice on the HFD exhibited an increase of insulin sensitivity, a reduced adipocyte size, reduced pro-inflammatory cytokines, and macrophage infiltration in adipose tissue compared with wildtype mice on the HFD.

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