Autophagy in kidney health and disease

Abstract

Significance: Autophagy is emerging as an important pathway in many biological processes and diseases. This review summarizes the current progress on the role of autophagy in renal physiology and pathology.

Recent advances: Studies from renal cells in culture, human kidney tissues, and experimental animal models implicate that autophagy regulates many critical aspects of normal and disease conditions in the kidney, such as diabetic nephropathy and other glomerular diseases, tubular injuries, kidney development and aging, cancer, and genetic diseases associated with the kidney.

Critical issues: The importance of autophagy in the kidney has just started to be elucidated. How the process of autophagy is altered in the pathogenesis of kidney diseases and how this alteration is beneficial or detrimental to kidney functions still need to be fully understood.

Future directions: Investigations that uncover the precise mechanism and regulation of autophagy in various kidney diseases may lead to new strategies for therapeutic modulation.

FIG. 1.

Schematic illustration of the molecular process of autophagy. (A) Macroautophagy (generally referred as autophagy) sequesters and degrades cellular organelles and protein aggregates through the sequential formation of autophagophores, autophagosomes and autolysosomes. (B) Microautophagy degrades cellular organelles and protein aggregates by direct lysosomal engulfment. (C) CMA selectively degrades proteins containing KFERQ motif through the cooperation of heat shock cognate protein of 70 kDa (hsc70) and LAMP-2A. CMA, chaperone-mediated autophagy, LAMP, lysosome-associated membrane protein. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Structure of the glomerulus and proximal tubule. The resident renal cells and components of the glomerulus and proximal tubule are shown. Approximately 180 L of renal plasma is filtered by the glomerulus daily. Filtration begins with the glomerular endothelial cells which functions as part of the glomerular filtration unit (see inset), that also includes the glomerular basement membrane and the podocytes with foot processes, between which are proteins comprising the slit diaphragm. The resultant filtrate from glomerulus flows through the tubules with reabsorption and secretion of ions, carbonhydrates, amino acids, and eventual elimination of urine. Under normal condition, the ultrafiltrate is virtually free of plasma protein. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Autophagy in glomerular mesangial cells. (A) Autophagy contributes to cadmium-induced mesangial cell death through calcium-ERK and ROS-GSK-3β. (B) TGF-β1-induced autophagy promotes mesangial cell survival by inhibiting apoptosis and inducing degradation of p27^Kip1 during prolonged serum deprivation. (C) Autophagy negatively regulates matrix production in mesangial cells by promoting degradation of intracellular Col-I. ERK, extracellular signal-regulated kinase; GSK-3β, glycogen synthase kinase-3β; ROS, reactive oxygen species; Col-I, type I collagen; TGF-β1, transforming growth factor-β1. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Autophagy in podocytes. (A) Atg5 gene deletion in podocytes (Atg5^Δpodocyte) increases susceptibility to injury induced by PAN or adriamycin (ADR). (B) Autophagy is activated by ER stress induced by PHN or tunicamycin (TM). (C) Autophagy prevents angiotensin II (ANG-II)-induced apoptosis in podocytes. (D) Vps34 gene deletion in podocytes (Vps34^Δpodocyte) inhibits formation of autophagophore and the mTOR pathway, resulting in accumulation of autophagosomes (APs) and autolysosomes (ALs) in podocytes. (E) Mtor gene deletion (Mtor^Δpodocyte) or chronic use of rapamycin disrupt the recycling of lysosomes from autolysosomes, resulting in the accumulation of APs and ALs in podocytes. (F) PRR gene deletion in podocytes (PRR^Δpodocyte) inhibits acidification of lysosomes by inactivating H⁺-ATPase, resulting in accumulation of APs and unacidified ALs. Vps34, vacuolar protein sorting 34; PRR, prorenin receptor; PAN, puromycin aminonucleoside; PHN, passive Heymann nephritis; ER, endoplasmic reticulum. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Autophagy in tubular injuries. (A) Autophagy activation, through ROS or ER stress, protects tubular cells from cisplatin or ischemia-reperfusion (I/R)-induced injuries. Mice with Atg5 or Atg7 gene deletion in PTC developed more severe tubular damage and renal dysfunction (increased BUN and SCr), compared to control littermates. P53 inhibitor or Bcl-2 inhibits autophagy induced by cisplatin in tubular cells. Repetitive hypoxic conditioning, Bcl-xL, Bcl-2, or ischemic conditioning inhibits both autophagy, apoptosis and renal dysfunction. (B) TGF-β1 overexpression in tubular cells induces autophagy, through ROS, resulting in tubular apoptosis and decomposition. (C) Autophagy is activated in a model of renal fibrosis induced by UUO, and is associated with inhibition of tubular apoptosis and interstitial fibrosis in the obstructed kidney, and reduced cell proliferation in the contralateral kidney. Bcl-xL, B-cell lymphoma-extra large; UUO, unilateral ureteral obstruction; I/R, ischemia-reperfusion; BUN, blood urea nitrogen; SCr, serum creatinine; PTC, proximal tubular cells. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Autophagy in kidney homeostasis and aging. (A) Autophagy maintains podocyte homeostasis. Autophagy deficiency is compensated by elevated proteasome activity in podocytes with Atg5 gene deletion in adult mice (ages 8–12 months of age), resulting in mild proteinuria. In aged Atg5^Δpodocyte mice (20–24 months of age) compensatory proteasome activitydecreases, leading to severe proteinuria, loss of podocytes, and glomerulosclerosis. (B) Autophagy maintains tubular homeostasis. Double knockout of Atg5 in PTC and DTC results in kidney dysfunction. (C) Autophagy protects against aging-associated CKD. Activation of autophagy by calorie restriction protects aging kidney from hypoxia-induced oxidative stress and mitochondrial damage, and attenuates aging-associated kidney dysfunction. CKD, chronic kidney diseases; DTC, distal tubular cells. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 7.

Autophagy in kidney diseases. (A) Activation of autophagy ameliorates DN. Autophagic activity is inhibited in DN due to aberrant energy sensing pathways. Reactivation of autophagy, for instance by caloric restriction, reduces oxidative stress and protects against DN. (B) Autophagy in PKD and NC is impaired. Basal level of autophagy can be altered through aberrant activation of mTOR or HIF-1α, and the autophagic flux is impaired in PKD. Whether autophagy protects against apoptosis in cyst lining tubular cells and cystogenesis is unknown. Mitophagy is impaired in NC through impairment of autophagic flux, and leads to tubular cell apoptosis, ROS production, and ATP reduction. (C) Autophagy can promote cell survival and tumor growth, or autophagic cell death in RCC. Loss of miR-204, through inactivation of VHL tumor suppressor gene, induces autophagy and tumor growth. In VHL-deficient RCC cells, STF-62247, or sphingosine kinase 2 inhibitor inhibits tumor growth through autophagic cell death. PI3K/mTOR inhibition induces apoptosis and autophagy. HIF-1α, hypoxia-inducible factor-1α; PI3K, phosphoinositide-3 kinase; PKD, polycystic kidney disease; VHL, von Hippel-Lindau; RCC, renal cell carcinoma; NC, nephropathic cystinosis; DN, diabetic nephropathy. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars