Glomerular visceral epithelial cells (podocytes) play a critical role in the maintenance of glomerular permselectivity. Podocyte injury, manifesting as proteinuria, is the cause of many glomerular diseases. We reported previously that calcium-independent phospholipase A 2 ␥ (iPLA 2 ␥) is cytoprotective against complement-mediated glomerular epithelial cell injury. Studies in iPLA 2 ␥ KO mice have demonstrated an important role for iPLA 2 ␥ in mitochondrial lipid turnover, membrane structure, and metabolism. The aim of the present study was to employ iPLA 2 ␥ KO mice to better understand the role of iPLA 2 ␥ in normal glomerular and podocyte function as well as in glomerular injury. We show that deletion of iPLA 2 ␥ did not cause detectable albuminuria; however, it resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes as well as loss of podocytes in aging KO mice. Moreover, after induction of anti-glomerular basement membrane nephritis in young mice, iPLA 2 ␥ KO mice exhibited significantly increased levels of albuminuria, podocyte injury, and loss of podocytes compared with wild type. Thus, iPLA 2 ␥ has a protective functional role in the normal glomerulus and in glomerulonephritis. Understanding the role of iPLA 2 ␥ in glomerular pathophysiology provides opportunities for the development of novel therapeutic approaches to glomerular injury and proteinuria.
IRE1α is essential for maintaining podocyte and glomerular integrity as mice age and in glomerulonephritis. The mechanism is related, at least in part, to the maintenance of autophagy in podocytes.
Bowel preparations containing oral so− dium phosphate have gained increased favor among gastroenterology endosco− pists in preference to the traditional poly− ethylene glycol, likely due to greater pa− tient tolerability and improved cleansing and compliance [1]. Despite the availabil− ity of reports in the literature concerning life−threatening metabolic and cardiac abnormalities associated with the use of oral sodium phosphate in patients with renal insufficiency, less than half of re− spondents in a recent survey among gas− trointestinal endoscopists reported its ex− clusion in this patient population [2]. We report two cases of severe hyperphospha− temia and secondary hypocalcemia due to administration of an oral sodium phos− phate−containing bowel preparation in patients with chronic renal insufficiency.The first patient, a 51−year−old woman with end−stage renal disease requiring peritoneal dialysis, was evaluated for gen− eralized weakness, perioral tingling, elici− table Chvostek s sign, and a prolonged QT interval. The patient had ingested two 45− ml doses of Fleet s Phospho−Soda solution the previous night, in preparation for a screening colonoscopy. Laboratory evalu− ation revealed abnormal levels of calcium and phosphate in comparison with base− line values (Figure 1). Clinical symptoms and laboratory abnormalities of hypocal− cemic tetany resolved rapidly after the pa− tient received intravenous calcium and peritoneal dialysis. The patient subse− quently underwent colonoscopy without any complications and continued to be asymptomatic on follow−up.The second patient was a 57−year−old man with diabetes mellitus and chronic renal insufficiency who presented with hema− tochezia. Laboratory values on admission were unremarkable except for a serum creatinine of 2.1 mg/dl. At 2 days after in− gesting two doses of 45 ml of oral sodium phosphate for a colonoscopy, his metabol− ic profile demonstrated serum calcium and phosphate of 6.5 mg/dl and16.9 mg/ dl, respectively (Figure 1). He remained asymptomatic and received oral calcium acetate to bind phosphate. The patient was discharged in a stable condition with serum calcium and phosphate of 6.7 mg/ dl and 14.4 mg/dl, respectively. No fol− low−up information was available.Similar abnormalities in serum calcium and phosphate, associated with oral so− dium phosphate ingestion, have been re− ported in the absence of renal insufficien− cy. This may, however, be related to the dosage of oral sodium phosphate admi− nistered (greater than 90 ml) or to im− paired bowel motility leading to pro− longed intestinal transit time [3]. A 45− ml bottle of oral sodium phosphate con− tains approximately 6 g of inorganic phos− phate, while a person with normal renal function can handle an intake of phos− phate up to 4 g over a 24−hour period, due to reduced proximal tubular reab− sorption of phosphate [4]. A rise in serum phosphate is thought to be the primary etiology of hypocalcaemia in these pa− tients [5].Previously published literature does not report the magnitude of renal...
Mutations in α-actinin-4 (actinin-4) result in hereditary focal segmental glomerulosclerosis (FSGS) in humans. Actinin-4 mutants induce podocyte injury because of dysregulation of the cytoskeleton and proteotoxicity. Injury may be associated with endoplasmic reticulum (ER) stress and polyubiquitination of proteins. We assessed if the chemical chaperone 4-phenylbutyrate (4-PBA) can ameliorate the proteotoxicity of an actinin-4 mutant. Actinin-4 K255E, which causes FSGS in humans (K256E in the mouse), showed enhanced ubiquitination, accelerated degradation, aggregate formation, and enhanced association with filamentous (F)-actin in glomerular epithelial cells (GECs). The mutant disrupted ER function and stimulated autophagy. 4-PBA reduced actinin-4 K256E aggregation and its tight association with F-actin. Transgenic mice that express actinin-4 K256E in podocytes develop podocyte injury, proteinuria, and FSGS in association with glomerular ER stress. Treatment of these mice with 4-PBA in the drinking water over a 10-wk period significantly reduced albuminuria and ER stress. Another drug, celastrol, which enhanced expression of ER and cytosolic chaperones in GECs, tended to reduce actinin-4 aggregation but did not decrease the tight association of actinin-4 K256E with F-actin and did not reduce albuminuria in actinin-4 K256E transgenic mice. Thus, chemical chaperones, such as 4-PBA, may represent a novel therapeutic approach to certain hereditary glomerular diseases.
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