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The molecular chaperone receptor-associated protein (RAP) is required for biosynthesis of megalin, an endocytic receptor for follicular thyroglobulin (Tg), the thyroid hormone precursor. RAP also binds to Tg itself, suggesting that it may affect Tg trafficking in various manners. To elucidate RAP function, we have studied the thyroid phenotype in RAP-knockout (RAP-KO) mice and found a reduction of Tg aggregates into thyroid follicles. Serum Tg levels were significantly increased compared with those of wild-type (WT) mice, suggesting a directional alteration of Tg secretion. In spite of these abnormalities, hormone secretion was maintained as indicated by normal serum thyroxine levels. Because Tg in thyroid extracts from RAP-KO mice contained thyroxine residues as in WT mice, we concluded that in RAP-KO mice, follicular Tg, although reduced, was nevertheless sufficient to provide normal hormone secretion. Serum TSH was increased in RAP-KO mice, and although no thyroid enlargement was observed, some histological features resembling early goiter were present. Megalin was decreased in RAP-KO mice, but this did not affect thyroid function, probably because of the concomitant reduction of follicular Tg. In conclusion, RAP is required for the establishment of Tg reservoirs, but its absence does not affect hormone secretion. low-density lipoprotein; knockout mice

A case of a 60-year-old man was evaluated in the rheumatology clinic due to rash and worsening renal function. Experts provide information on different tests they conducted on him, the diagnosis, treatments offered, and other pathological discussions on the case.

A 12-year-old boy admitted to the hospital with a two-day history of a rash and swelling of the face, hands and feet was aferbrile and hypertensive, with pitting edema of the legs. The differential diagnosis of acute renal failure in children is reviewed.

A 36-year-old former drug addict who began having seizures and high blood pressure was diagnosed with polyarteritis nodosa. This disease is an inflammation of small and medium blood vessels. He also had a history of hepatitis B and hepatitis C infection.

A 35-year-old woman admitted to a hospital with progressive kidney failure was diagnosed with antiphospholipid antibody syndrome. She also had a history of systemic lupus erythematosus.

A major cellular protein associated with endogenous WT1 has been identified by immunoprecipitation and protein microsequencing analysis as the inducible chaperone Hsp70. WT1, the Wilms tumor suppressor, codes a zinc finger transcription factor expressed in glomerular podocytes during a short time period in kidney development. WT1 and Hsp70 are close in primary Wilms tumor specimens, in rat embryo kidney cells, and in cells in culture with inducible expression of WT1. It appears that Hsp70 is an important cofactor for WT1 and that the chaperone may be a factor during kidney differentiation.

A soluble form of Alzheimer disease amyloid [Beta]-protein (sA[Beta]) is transported in the blood and cerebrospinal fluid mainly complexed with apolipoprotein J (apoJ). Using a well-characterized in situ perfused guinea pig brain model, we recently obtained preliminary evidence that apoJ facilitates transport of sA[[Beta].sub.1-40]-apoJ complexes across the blood-brain barrier and the blood-cerebrospinal fluid barrier, but the mechanisms remain poorly understood. In the present study, we examined the transport process in greater detail and investigated the possible role of glycoprotein 330 (gp330)/megalin, a receptor for multiple ligands, including apoJ. High-affinity transport systems with a Km of 0.2 and 0.5 nM were demonstrated for apoJ at the blood-brain barrier and the choroid epithelium in vivo, suggesting a specific receptor-mediated mechanism. The sA[[Beta].sub.1-40]-apoJ complex shared the same transport mechanism and exhibited 2.4- to 10.2-fold higher affinity than apoJ itself. Binding to microvessels, transport into brain parenchyma, and choroidal uptake of both apoJ and sA[[Beta].sub.1-40]-apoJ complexes were markedly inhibited (74-99%) in the presence of a monoclonal antibody to gp330/megalin and were virtually abolished by perfusion with the receptor-associated protein, which blocks binding of all known ligands to gp330. Western blot analysis of cerebral microvessels with the monoclonal antibody to gp330 revealed a protein with a mass identical to that in extracts of kidney membranes enriched with gp330/megalin, but in much lower concentration. The findings suggest that gp330/megalin mediates cellular uptake and transport of apoJ and sA[[Beta].sub.1-40]-apoJ complex at the cerebral vascular endothelium and choroid epithelium.

A 74-year-old woman was admitted to the hospital with an upper respiratory tract infection and progressive kidney failure and was diagnosed with microscopic polyarteritis. Polyarteritis is a form of systemic vasculitis characterized by the inflammation and cell death of blood vessels and associated organs. The woman had suffered a heart attack 14 months prior to admission and had a history of congestive heart failure and valvular diseases. X-rays revealed that her heart was enlarged but that her kidneys were normal in size. The normal size of her kidneys and the reduction in her urine volume suggested that her kidney failure was an acute form, not chronic. The multi-system involvement further suggested that her rapidly progressive kidney failure was due to either a bacterial infection or systemic vasculitis. She tested positive for antibodies to the enzyme myeloperoxidase, which confirmed the diagnosis of systemic vasculitis. At autopsy, vasculitis was also detected in her kidneys.

A 52-year-old man was diagnosed with Churg-Strauss syndrome. Churg-Strauss syndrome is an allergic disorder that causes inflammation of blood vessels. The patient was admitted to the hospital with asthma, inflammation of the peripheral nerves, fever and high levels of white blood cells (WBC). The patient had a long history of sinus inflammation and nasal polyps, and he had developed bronchial asthma three years earlier. Four months before admission to the hospital, he experienced shortness of breath, chest pain and tingling in the hands. He had an intermittent low-grade fever, and suffered from nerve inflammation in different parts of the body. A chest X-ray revealed a nodule in the lower lobe of the left lung. A blood test found that his blood contained antibodies against the enzymes myeloperoxidase and proteinase 3. These results in combination with his other symptoms seemed to indicate that he had Churg-Strauss syndrome. A sural-nerve and muscle biopsy confirmed this diagnosis. The patient was treated with corticosteroids.

Marino, Michele, and Robert T. McCluskey. Role of thyroglobulin endocytic pathways in the control of thyroid hormone release. Am J Physiol Cell Physiol 279: C1295-C1306, 2000.--Thyroglobulin (Tg), the thyroid hormone precursor, is synthesized by thyrocytes and secreted into the colloid. Hormone release requires uptake of Tg by thyrocytes and degradation in lysosomes. This process must be precisely regulated. Tg uptake occurs mainly by micropinocytosis, which can result from both fluid-phase pinocytosis and receptor-mediated endocytosis. Because Tg is highly concentrated in the colloid, fluid-phase pinocytosis or low-affinity receptors should provide sufficient Tg uptake for hormone release; high-affinity receptors may serve to target Tg away from lysosomes, through recycling into the colloid or by transcytosis into the bloodstream. Several apical receptors have been suggested to play roles in Tg uptake and intracellular trafficking. A thyroid asialoglycoprotein receptor may internalize and recycle immature forms of Tg back to the colloid, a function also attributed to an as yet unidentified N-acetylglucosamine receptor. Megalin mediates Tg uptake by thyrocytes, especially under intense thyroid-stimulating hormone stimulation, resulting in transcytosis of Tg from the colloid to the bloodstream, a function that prevents excessive hormone release. receptor; endocytosis