Autophagy is a bulk protein degradation system that likely plays an important role in normal proximal tubule function and recovery from acute ischemic kidney injury. Using conditional Atg5 gene deletion to eliminate autophagy in the proximal tubule, we determined whether autophagy prevents accumulation of damaged proteins and organelles with aging and ischemic renal injury. Autophagy-deficient cells accumulated deformed mitochondria and cytoplasmic inclusions, leading to cellular hypertrophy and eventual degeneration not observed in wildtype controls. In autophagy-deficient mice, I/R injury increased proximal tubule cell apoptosis with accumulation of p62 and ubiquitin positive cytoplasmic inclusions. Compared with control animals, autophagy-deficient mice exhibited significantly greater elevations in serum urea nitrogen and creatinine. These data suggest that autophagy maintains proximal tubule cell homeostasis and protects against ischemic injury. Enhancing autophagy may provide a novel therapeutic approach to minimize acute kidney injury and slow CKD progression.

Renal fibrosis is the final common pathway of numerous progressive kidney diseases, and transforming growth factor-β (TGF-β) has an important role in tissue fibrosis by up-regulating matrix protein synthesis, inhibiting matrix degradation, and altering cell-cell interaction. Many strategies targeting TGF-β, including inhibition of production, activation, binding to the receptor, and intracellular signaling, have been developed. Some of them were examined in clinical studies against kidney fibrosis, and some are applied to other fibrotic diseases or cancer. Here, I review the approaches targeting TGF-β signaling in kidney fibrosis.

D-Amino acids, the enantiomers of L-amino acids, are increasingly recognized as novel biomarkers. Although the amounts of D-amino acids are usually very trace in human, some of them have sporadically been detected in blood from patients with kidney diseases. This study examined whether multiple chiral amino acids would be associated with kidney functions, comorbidities, and prognosis of chronic kidney disease (CKD) by enantioselective analyses of all chiral amino acids with a micro-two-dimensional high-performance liquid chromatograph (2D-HPLC)-based analytical platform. 16 out of 21 D-amino acids were detected in plasma from 108 CKD patients in a longitudinal cohort. The levels of D-Ser, D-Pro, and D-Asn were strongly associated with kidney function (estimated glomerular filtration ratio), the levels of D-Ala and D-Pro were associated with age, and the level of D-Asp and D-Pro were associated with the presence of diabetes mellitus. D-Ser and D-Asn were significantly associated with the progression of CKD in mutually-adjusted Cox regression analyses; the risk of composite end point (developing to ESKD or death before ESKD) was elevated from 2.7- to 3.8-fold in those with higher levels of plasma D-Ser and D-Asn. These findings identified chiral amino acids as potential biomarkers in kidney diseases.

Classically, urate nephropathy has been postulated to cause kidney disease by depositing intraluminal crystal in the collecting duct. Recently, molecular mechanisms of inflammasome have been investigated. Urate-induced inflammasome pathway is comprised of urate crystal uptake into intracellular lysosomes and subsequent lysosomal rupture with mitochondrial reactive oxygen species (ROS) production, which activates the NLRP3 inflammasome. Against the lysosomal rupture and mitochondrial ROS production, autophagy acts to protect proximal tubular cells by isolating them from expanding the inflammation. In addition, increased cellular urate, directly or indirectly via xanthine oxidase-induced oxidative stress, may be associated with inflammasome. In addition to the traditional therapy against hyperuricemia, management of urate-induced inflammasome or augmentation of autophagy may offer the new effective therapies.

Autophagy plays an essential role in cellular homeostasis through the quality control of proteins and organelles. Although a time-dependent decline in autophagic activity is believed to be involved in the aging process, the issue remains controversial. We previously demonstrated that autophagy maintains proximal tubular cell homeostasis and protects against kidney injury. Here, we extend that study and examine how autophagy is involved in kidney aging. Unexpectedly, the basal autophagic activity was higher in the aged kidney than that in young kidney; short-term cessation of autophagy in tamoxifen-inducible proximal tubule-specific autophagy-deficient mice increased the accumulation of SQSTM1/p62- and ubiquitin-positive aggregates in the aged kidney. By contrast, autophagic flux in response to metabolic stress was blunted with aging, as demonstrated by the observation that transgenic mice expressing a green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3B fusion construct, showed a drastic increase of GFP-positive puncta in response to starvation in young mice compared to a slight increase observed in aged mice. Finally, proximal tubule-specific autophagy-deficient mice at 24 mo of age exhibited a significant deterioration in kidney function and fibrosis concomitant with mitochondrial dysfunction as well as mitochondrial DNA abnormalities and nuclear DNA damage, all of which are hallmark characteristics of cellular senescence. These results suggest that age-dependent high basal autophagy plays a crucial role in counteracting kidney aging through mitochondrial quality control. Furthermore, a reduced capacity for upregulation of autophagic flux in response to metabolic stress may be associated with age-related kidney diseases.