Role of platelet-derived growth factor-CC in capillary rarefaction in renal fibrosis.

We have identified platelet-derived growth factor (PDGF)-CC as a potent profibrotic mediator in kidney fibrosis and pro-angiogenic mediator in glomeruli. Because renal fibrosis is associated with progressive capillary rarefaction, we asked whether PDGF-CC neutralization in fibrosis might have detrimental anti-angiogenic effects leading to aggravated peritubular capillary loss. We analyzed capillary rarefaction in mice with and without PDGF-CC neutralization (using genetically deficient mice and neutralizing antibodies), in three different models of renal interstitial fibrosis, unilateral ureteral obstruction, unilateral ischemia-reperfusion, Col4a3-deficient (Alport) mice, and healthy animals. Independent of the effect of PDGF-CC neutralization on renal fibrosis, we found no difference in capillary rarefaction between PDGF-CC-neutralized mice and mice with intact PDGF-CC. We also found no differences in microvascular leakage (determined by extravasation of Evans Blue Dye) and in renal relative blood volume quantified using in vivo microcomputed tomography. PDGF-CC neutralization had no effects on renal microvasculature in healthy animals. Capillary endothelium did not express PDGF receptor-α, suggesting that potential PDGF-CC effects would have to be indirect. PDGF-CC neutralization or deficiency was not associated with preservation or accelerated loss of peritubular capillaries, suggesting no significant pro-angiogenic effects of PDGF-CC during renal fibrosis. From a clinical perspective, the profibrotic effects of PDGF-CC outweigh the pro-angiogenic effects and, thus, do not limit a potential therapeutic use of PDGF-CC inhibition in renal fibrosis.

Platelet-derived growth factor and renal disease.

PURPOSE OF REVIEW: This review focuses on the recent advances in our understanding of the role of platelet-derived growth factor (PDGF) in glomerular disease. RECENT FINDINGS: Accumulating evidence indicates a critical involvement of PDGF receptor-ß (PDGFR-ß) signaling in glomerular disease. Augmented signaling via PDGFR-ß is involved in the pathogenesis of IgA nephropathy. Therefore, targeting PDGFR-ß signaling is a viable therapeutic strategy for glomerular diseases. However, current PDGFR-ß antagonists are nonspecific, and their long-term effects remain to be elucidated. To develop effective intervention therapies targeting PDGF signaling, it is necessary to clarify the specific involvement of PDGF in the pathogenesis of glomerular disease. A novel PDGFR-ß targeting mouse model has provided new insight into the postnatal role of PDGFR-ß in aging-related mesangial sclerosis and the glomerular remodeling after nephrectomy. Furthermore, the same study indicated the redundancy of growth factor signals underlying glomerular remodeling. In this context, other studies have suggested a role for PDGFR-α signaling and collaborating growth factors to compensate for PDGFR-ß in the kidney glomerulus. SUMMARY: Intervention in growth factor signaling could be a valuable therapeutic strategy for kidney glomerular diseases. Further studies are required to characterize the pathogenesis of these diseases for the successful development of such a therapy.

Roles of PDGF receptor-beta in the structure and function of postnatal kidney glomerulus.

BACKGROUND: Mesangial cell functions are critically regulated by platelet-derived growth factor receptor (PDGFR)-ß signals. In contrast to the well-established role of PDGFR-ß in the development of kidney glomerulus, its role in adult kidney glomerulus remains controversial. METHODS: We deleted the PDGFR-ß gene postnatally using the Cre-loxP system and analysed the long-term effects of PDGFR-ß inhibition on glomerular changes associated with ageing and subtotal nephrectomy. RESULTS: Mice depleted of PDGFR-ß (Deletant) survived without showing apparent abnormalities. In glomerulus of Deletant, mesangial PDGFR-ß expression was decreased. The glomerular cell numbers were low, and the ageing-associated increment of mesangial matrix area was suppressed in Deletant as compared with control mice with conserved PDGFR-ß expression (Floxed) at 48 weeks of age. At 2 weeks after subtotal nephrectomy, albuminuria and the elevation of blood urea nitrogen were aggravated in Deletant. At this time, Deletant showed specific glomerular changes that included many hypertrophic podocytes and collapsed capillaries. At 12 weeks after subtotal nephrectomy, the kidney function in Deletant restored to the level of Floxed; however, the Deletant glomeruli showed dilated capillaries, decreased cell number and reduced mesangial matrix area with less extended mesangial cell processes as compared with Floxed. CONCLUSIONS: The long-term inhibition of mesangial PDGFR-ß prevented age-related mesangial expansion. On the other hand, the kidney glomeruli with decreased PDGFR-ß showed increased vulnerability to the acute nephron loss, and showed mesangial insufficiency in the following adaptive process.

[Case of distal renal tubular acidosis complicated with renal diabetes insipidus, showing aggravation of symptoms with occurrence of diabetes mellitus].

We report herein a 27-year-old male case of inherited distal renal tubular acidosis complicated with renal diabetes insipidus, the symptoms of which were aggravated by the occurrence of diabetes mellitus. At 2 months after birth, he was diagnosed as having inherited distal renal tubular acidosis and thereafter supplementation of both potassium and alkali was started to treat his hypokalemia and metabolic acidosis. At the age of 4 years, calcification of the bilateral renal medulla was detected by computed tomography. Subsequently his urinary volume gradually increased and polyuria of approximately 4 L/day persisted. At the age of 27 years, he became fond of sugar-sweetened drinks and also often forgot to take the medicine. He was admitted to our hospital due to polyuria of more than 10 L day, muscle weakness and gait disturbance. Laboratory tests disclosed worsening of both hypokalemia and metabolic acidosis in addition to severe hyperglycemia. It seemed likely that occurrence of diabetes mellitus and cessation of medications can induce osmotic diuresis and aggravate hypokalemia and metabolic acidosis. Consequently, severe dehydration, hypokalemia-induced damage of his urinary concentration ability and enhancement of the renin angiotensin system occurred and thereby possibly worsened his hypokalemia and metabolic acidosis. As normalization of hyperglycemia and metabolic acidosis might have exacerbated hypokalemia further, dehydration and hypokalemia were treated first. Following intensive treatment, these abnormalities were improved, but polyuria persisted. Elevated plasma antidiuretic hormone (12.0 pg/mL) and deficit of renal responses to antidiuretic hormone suggested that the polyuria was attributable to the preexisting renal diabetes insipidus possibly caused by bilateral renal medulla calcification. Thiazide diuretic or nonsteroidal anti-inflammatory drugs were not effective for the treatment of diabetes insipidus in the present case.

[Autopsy case of Henoch-Schönlein purpura nephritis complicated with intestinal cytomegalovirus infection].

A 55-year-old man was admitted to our hospital because of arthralgia, purpura, abdominal pain, melena and leg edema. Laboratory findings showed an increased serum creatinine level (2.4 mg/dL), hematuria and massive proteinuria (10.7 g/day). Renal biopsy revealed diffuse endocapillary proliferation and focal mesangial proliferation with IgA deposition predominantly in the glomerular capillary walls. Based on these findings, he was diagnosed as having Henoch-Schönlein purpura nephritis and steroid therapy was started. Following steroid therapy, his nephrotic state remained unchanged, although his renal function improved concomitantly with the disappearance of arthralgia, purpura and abdominal symptoms. Therefore, cyclosporine was added to the steroid therapy to enhance immunosuppression. However, melena recurred and anemia progressed. Endoscopy revealed multiple ulcers in the duodenum and jejunum, and clipping was performed at some bleeding sites. However, he died of hemorrhagic shock. The autopsy revealed that hemorrhagic lesions having cytomegalovirus infection spread widely in the stomach, duodenum and jejunum. Recurrence of gastrointestinal bleeding during the treatment of Henoch-Schönlein purpura nephritis is usually due to severe vasculitis or steroid ulcer. However, in patients receiving strong immunosuppressive therapy, cytomegalovirus infection needs to be considered as cause of gastrointestinal bleeding.

[Case of bladder pheochromocytoma with familial clustering].

We report herein a rare female case of bladder pheochromocytoma with familial clustering. Her mother had received an operation for bladder pheochromocytoma. When the present case was 20 years of age, body weight loss and fever appeared. Thereafter, nausea, vomiting and palpitation occurred especially at urination, and hypertension and tachycardia emerged. She was referred to our hospital for a further check up of hypertension at the age of 28 years. Her blood pressure was 176/130 mmHg, and pulse rate, 103/min. Hemorrhage and hard exudate were observed at the optic fundi. Twenty-four-hour ambulatory blood pressure monitoring disclosed that her hypertension was characterized by non-dipper type features and transient increases in both blood pressure and pulse rate occurring, especially at urination. Plasma noradrenalin level (14,399 pg/mL)was remarkably elevated, although the plasma adrenalin level (52 pg/mL) was within the normal limits. Computed tomography (CT) showed a mass lesion (7 cm in diameter) with central necrosis in the urinary bladder. 123I-MIBG showed strong uptake in the mass detected by CT. Venous blood sampling disclosed that the plasma noradrenalin concentration was highest at the lower level of the inferior vena cava. Therefore, a diagnosis of bladder pheochromocytoma with familial clustering was made and the pheochromocytoma was surgically removed.