Activin, a member of the TGF-β superfamily, regulates cell growth and differentiation in various cell types. Activin A acts as a negative regulator of renal development as well as tubular regeneration after renal injury. However, it remains unknown whether activin A is involved in renal fibrosis. To clarify this issue, we utilized a rat model of unilateral ureteral obstruction (UUO). The expression of activin A was significantly increased in the UUO kidneys compared to that in contralateral kidneys. Activin A was detected in glomerular mesangial cells and interstitial fibroblasts in normal kidneys. In UUO kidneys, activin A was abundantly expressed by interstitial α-SMA-positive myofibroblasts. Administration of recombinant follistatin, an activin antagonist, reduced the fibrotic area in the UUO kidneys. The number of proliferating cells in the interstitium, but not in the tubules, was significantly lower in the follistatin-treated kidneys. Expression of α-SMA, deposition of type I collagen and fibronectin, and CD68-positive macrophage infiltration were significantly suppressed in the follistatin-treated kidneys. These data suggest that activin A produced by interstitial fibroblasts acts as a potent profibrotic factor during renal fibrosis. Blockade of activin A action may be a novel approach for the prevention of renal fibrosis progression.

Abstract. The research described in this review suggests a novel and important role for activin A in the developmental and repair processes of the kidney ( Table 1). The results obtained in these studies indicate that activin A is a negative regulator of kidney development and plays an essential part in kidney diseases, such as acute renal failure or renal fibrosis. It is also possible that activin A is a key player in the pathophysiological processes of other kidney diseases, such as congenital urogenital abnormalities, renal cystic disease and renal cell carcinoma. Activin A is thus a potential target for therapeutic interventions in kidney diseases. To address this issue, more detailed analysis on the regulation of activin production, modulation of activin activity and activin target genes is required.

Recovery after acute kidney injury is impaired in the elderly, but the precise mechanism for such age-related incompetence remains unclear. By in vivo bromodeoxyuridine (BrdU) labeling, renal progenitor cells (label-retaining cells; LRCs) were identified in tubules of normal rat kidney and were shown to be the origin of proliferating cells after injury. In the present study, the involvement of LRCs in the age-related decline of tubular recovery after injury was examined. After 1 wk of BrdU labeling followed by a 2-wk chase period, ischemia-reperfusion injury was induced in 7-wk-, 7-mo-, and 12-mo-old rats. Age-related decreases in DNA synthesis and cell proliferation in renal tubules after injury were found. The number of LRCs also significantly declined with age. At 24 h after reperfusion, the number of LRCs significantly increased in all ages of rats tested. There was no significant difference in the ratio of LRC division among rats of different ages. The area of the rat endothelial cell antigen (RECA)-1-positive capillary network declined with age. When renal tubules isolated from rats treated with BrdU label were cocultured with human umbilical vein endothelial cells (HUVEC), the number of LRCs significantly increased compared with tubules cultured without HUVEC. These data suggest that the reduced capacity of tubular regeneration in the aging kidney is partly explained by the shortage of LRC reserves. The size of the LRC pool might be regulated by the surrounding peritubular capillary network.

in vitro human tubulogenesis by endothelial cell-derived factors: implications for in vivo tubular regeneration after injury. Am J Physiol

type Ca 2ϩ channels are densely distributed in sympathetic nerves that innervate renal tubules. However, the role of N-type Ca 2ϩ channels in renal fibrosis remains unknown. To address this issue, we examined the difference between the effects of amlodipine (an L-type Ca 2ϩ channel blocker) and cilnidipine (a dual L/N-type Ca 2ϩ channel blocker) on fibrotic changes using a rat unilateral ureteral obstruction (UUO) model. The expression of both L-type and N-type Ca 2ϩ channels was significantly upregulated in UUO kidneys compared with that in contralateral kidneys. There were no significant differences in mean blood pressure among the rats tested. Both amlodipine and cilnidipine significantly attenuated fibrotic changes in UUO kidneys. The antifibrotic effect of cilnidipine was more potent than that of amlodipine. Amlodipine as well as cilnidipine reduced type III collagen deposition, ␣-smooth muscle actin (␣-SMA) expression, and interstitial cell proliferation. In addition, cilnidipine significantly reduced deposition of type I collagen and macrophage infiltration in UUO kidneys. With the use of in vivo bromodeoxyuridine labeling, label-retaining cells (LRCs) were identified as a population of tubular cells that participate in epithelial-mesenchymal transition after UUO. Some LRCs migrated into the interstitium, expressed ␣-SMA and vimentin, and produced several extracellular matrixes in UUO kidneys. The number of interstitial LRCs was significantly decreased by cilnidipine but not amlodipine. These data suggest that N-type Ca 2ϩ channels contribute to multiple steps of renal fibrosis, and its blockade may thus be a useful therapeutic approach for prevention of renal fibrosis.N-type calcium channel; renal fibrosis; unilateral ureteral obstruction; epithelial-mesenchymal transition THE RENAL SYMPATHETIC NERVES innervate the tubules, the vessels, and the juxtaglomerular granular cells of the kidney (5). Renal sympathetic nerve activation reduces urinary sodium and water excretion by increasing renal tubular water and sodium reabsorption throughout the nephron. It also decreases renal blood flow and glomerular filtration rate by constricting the renal vasculature and activates the renin-angiotensin system (RAS) by stimulating renin release from juxtaglomerular granular cells. Conversely, angiotensin II stimulates sympathetic nerve activity through central mechanisms and by facilitating adrenergic neurotransmission at the sympathetic nerve terminal, thus suggesting significant interactions between renal sympathetic nerves and the RAS in the control of renal function (4). N-type Ca 2ϩ channels are densely distributed in the sympathetic nervous system and play a predominant role in neurotransmitter release from the nerve endings of sympathetic neurons (8). In patients with chronic renal diseases, increased sympathetic nerve activity and plasma renin activity are observed (10), thus suggesting that sympathetic nerve activity via N-type Ca 2ϩ channels is involved in renal injury. Renal fibrosis is the common end point o...