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      Autophagy in Acute Kidney Injury and Repair

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          Acute kidney injury (AKI) is a major kidney disease associated with a poor clinical outcome both in the short and long term. Autophagy is a cellular stress response that plays important roles in the pathogenesis of various diseases. Autophagy is induced in proximal tubules during AKI. A renoprotective role of autophagy in AKI has been demonstrated by pharmacological and genetic inhibition studies. The role of autophagy in kidney recovery and repair from AKI, however, remains largely unknown. A dynamic change in autophagy during the recovery phase of AKI seems to be important for tubular proliferation and repair. In renal fibrosis, autophagy may either promote this via the induction of tubular atrophy and decomposition, or prevent it via effects on the intracellular degradation of excessive collagen. Further research is expected to improve the understanding of the regulation of autophagy in kidney injury and repair, elucidate the pathological roles of autophagy in renal fibrosis, and discover therapeutic targets for treating AKI and preventing its progression to chronic kidney disease.

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          Most cited references 13

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          Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells.

          Autophagy has emerged as another major "programmed" mechanism to control life and death much like "programmed cell death" is for apoptosis in eukaryotes. We examined the expression of autophagic proteins and formation of autophagosomes during progression of cisplatin injury to renal tubular epithelial cells (RTEC). Autophagy was detected as early as 2-4 h after cisplatin exposure as indicated by induction of LC3-I, conversion of LC3-I to LC3-II protein, and upregulation of Beclin 1 and Atg5, essential markers of autophagy. The appearance of cisplatin-induced punctated staining of autophagosome-associated LC3-II upon GFP-LC3 transfection in RTEC provided further evidence for autophagy. The autophagy inhibitor 3-methyladenine blocked punctated staining of autophagosomes. The staining of normal cells with acridine orange displayed green fluorescence with cytoplasmic and nuclear components in normal cells but displayed considerable red fluorescence in cisplatin-treated cells, suggesting formation of numerous acidic autophagolysosomal vacuoles. Autophagy inhibitors LY294002 or 3-methyladenine or wortmannin inhibited the formation of autophagosomes but induced apoptosis after 2-4 h of cisplatin treatment as indicated by caspase-3/7 and -6 activation, nuclear fragmentation, and cell death. This switch from autophagy to apoptosis by autophagic inhibitors further suggests that the preapoptotic lag phase after treatment with cisplatin is mediated by autophagy. At later stages of cisplatin injury, apoptosis was also found to be associated with autophagy, as autophagic inhibitors and inactivation of autophagy proteins Beclin 1 and Atg5 enhanced activation of caspases and apoptosis. Our results demonstrate that induction of autophagy mounts an adaptive response, suppresses cisplatin-induced apoptosis, and prolongs survival of RTEC.
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            Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells.

            We recently showed in a tetracycline-controlled transgenic mouse model that overexpression of transforming growth factor (TGF)-beta1 in renal tubules induces widespread peritubular fibrosis and focal degeneration of nephrons. In the present study we have analyzed the mechanisms underlying these phenomena. The initial response to tubular cell-derived TGF-beta1 consisted of a robust proliferation of peritubular cells and deposition of collagen. On sustained expression, nephrons degenerated in a focal pattern. This process started with tubular dedifferentiation and proceeded to total decomposition of tubular cells by autophagy. The final outcome was empty collapsed remnants of tubular basement membrane embedded into a dense collagenous fibrous tissue. The corresponding glomeruli survived as atubular remnants. Thus, TGF-beta1 driven autophagy may represent a novel mechanism of tubular decomposition. The fibrosis seen in between intact tubules and in areas of tubular decomposition resulted from myofibroblasts that were derived from local fibroblasts. No evidence was found for a transition of tubular cells into myofibroblasts. Neither tracing of injured tubules in electron micrographs nor genetic tagging of tubular epithelial cells revealed cells transgressing the tubular basement membrane. In conclusion, overexpression of TGF-beta1 in renal tubules in vivo induces interstitial proliferation, tubular autophagy, and fibrosis, but not epithelial-to-mesenchymal transition.
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              Regulation of autophagy by TGF-β: emerging role in kidney fibrosis.

               Yan Ding,  Mary E Choi (2014)
              Autophagy is a highly conserved homoeostatic mechanism for cell survival under conditions of stress, and is widely implicated as an important pathway in many biological processes and diseases. In progressive kidney diseases, fibrosis represents the common pathway to end-stage kidney failure. Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that has been established as a central mediator of kidney fibrosis. A recently emerging body of evidence from studies in renal cells in culture and experimental animal models suggests that TGF-β1 regulates autophagy and that autophagy regulates many critical aspects of normal and disease conditions associated with kidney fibrosis, such as tubulointerstitial fibrosis, glomerulosclerosis, and diabetic nephropathy. Here, we review the recent advances exploring the process of autophagy, its regulation by TGF-β1, and the implication in the pathogenesis of progressive kidney fibrosis and injury responses. Understanding the cellular and molecular bases of this process is crucial for identifying potential new diagnostic and therapeutic targets of kidney fibrosis.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                September 2014
                24 September 2014
                : 127
                : 1-4
                : 56-60
                aDepartment of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, PR China; bDepartment of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, Ga., USA
                Author notes
                *Zheng Dong, PhD, Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Boulevard, Augusta, GA 30912 (USA), E-Mail
                363677 PMC4274769 Nephron Clin Pract 2014;127:56-60
                © 2014 S. Karger AG, Basel

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                Page count
                Figures: 1, Pages: 5
                Original Paper

                Cardiovascular Medicine, Nephrology

                Fibrosis, Kidney repair, Acute kidney injury, Apoptosis, Autophagy


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