Obesity increases a chronic kidney disease patient's risk of developing kidney failure, but the mechanism underlying this connection has remained unclear.
Kosuke Yamahara, Takashi Uzu, MD, PhD (Shiga University of Medical Science, in Japan), and their colleagues suspected that decreased functioning of a process called autophagy might play a role. Autophagy is a degradation system within cells that removes damaged proteins and other defective cellular components, and autophagy insufficiency is common in obese individuals.
The researchers found that in normal-weight mice with kidney disease, autophagy was active in kidney cells. However, in obese mice with kidney disease, autophagy was suppressed and kidney cells became damaged. Normal-weight mice with kidney disease and defective autophagy (due to a gene deletion) also experienced kidney cell damage.
The investigators also discovered that a potent suppressor of autophagy (called mTOR) was hyperactivated in the kidneys of obese mice, and treatment with an mTOR inhibitor ameliorated autophagy insufficiency. Furthermore, both mTOR hyperactivation and autophagy suppression were observed in kidney specimens from obese patients with kidney disease.
"Obesity suppresses autophagy via an abnormal activation of nutrition sensing signals in the kidney," said Yamahara. "Our results suggest that restoring the kidney-protective action of autophagy may improve the kidney health of obese patients."
In an accompanying editorial, Ken Inoki, PhD (University of Michigan) stated that "the results of this study provide an important pathomechanism underlying obesity-associated renal cell damage."
Study co-authors include Shinji Kume, Daisuke Koya, Yuki Tanaka, Yoshikata Morita, Masami Chin-Kanasaki, Hisazumi Araki, Keiji Isshiki, Shin-ichi Araki, Masakazu Haneda, Taiji Matsusaka, Atsunori Kashiwagi, and Hiroshi Maegawa.
Disclosures: The authors reported no financial disclosures.
The article, entitled "Obesity-mediated Autophagy Insufficiency Exacerbates Proteinuria-induced Tubulointerstitial Lesions," will appear online at http://jasn.asnjournals.org/ on October 3, 2013, doi: 10.1681/ASN.2012111080.
The editorial, entitled "Proximal Tubules Forget 'Self-Eating' When They Meet Western Meals," will appear online at http://jasn.asnjournals.org/ on October 3, 2013, doi: 10.1681/ASN.2013070794.
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