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Many large-scale studies revealed that exogenous erythropoietin, erythropoiesis-stimulating agents, have no renoprotective effects. We reported the renoprotective effects of endogenous erythropoietin production on renal function in ischemic reperfusion injury (IRI) of the kidney using the prolyl hydroxylase domain (PHD) inhibitor, Roxadustat. The purpose of this study was to investigate the effects of daprodustat on the progression of chronic renal failure. We retrospectively investigated the effects of daprodustat on the progression of chronic renal failure and renal anemia in patients with stages 3a-5 chronic kidney diseases (estimated glomerular filtration rate, eGFR < 60 mL/min/1.73 m2). The results show that daprodustat largely slowed the reduction in eGFR. The recovery of renal function was observed in some patients. Daprodustat is useful not only for renal anemia but also for the preservation of renal function. The renoprotective effect of daprodustat was small in patients with serum creatinine larger than 3–4 mg/dL because of low residual renal function. The appearance of renal anemia would be a sign of the time to start using daprodustat. [ABSTRACT FROM AUTHOR]

Arginine vasopressin (AVP) plays a key role in the urine concentration mechanism via the vasopressin V2 receptor (V2R) and aquaporin 2 (AQP2) in the kidney. It is well known that V2R is localized on the basolateral side and the Via receptor (V1aR) is distributed on the luminal side of the collecting ducts. Previously, we reported an increase of V1aR mRNA and a decrease of V2R mRNA in the collecting ducts under chronic metabolic acidosis. However, the regulatory mechanism of V2R in acidic conditions has not yet been determined. In the present study, we investigated the effect of changes in pH on V2R promoter activity, using the LLC-[PK.sub.1] cell line stably expressing rat V1aR (LLC-[PK.sub.1]/rV1aR). The rV2R promoter activity was significantly increased at 12 h after the incubation in low-pH conditions, which was sustained for 24 h. mRNA and protein expressions of V2R were also increased in low-pH conditions. V1aR stimulation suppressed rV2R promoter activity in a pH-dependent manner. PKA and JNK inhibitors suppressed rV2R promoter activity in both neutral and low-pH conditions without FBS. However, a JNK inhibitor prevented the increase of V2R promoter activity only in low-pH conditions in the presence of FBS. In summary, V2R expression is increased at transcriptional, mRNA, and protein levels in LLC-[PK.sub.1]/rV1aR cells under low-pH conditions. Acidic condition-induced V2R enhancement was suppressed by V1aR stimulation, suggesting the crucial role of V1aR in water and electrolyte homeostasis in acidosis. collecting duct; transcription; Sp1; c-Jun N[H.sub.2]-terminal kinase; protein kinase A

Arginine vasopressin (AVP) and hypertonicity in the renal medulla play a major role in the urine concentration mechanism. Previously, we showed that rat vasopressin V2 receptor (rV2R) promoter activity was increased by vasopressin V2R stimulation and decreased by vasopressin Via receptor (V1aR) stimulation in a LLC-P[K.sub.1] cell line stably expressing rat V1aR (LLC-P[K.sub.1]/rV1aR). In the present study, we investigated the effects of hypertonicity on the rV2R promoter activity and on the suppression of rV2R promoter activity by VlaR stimulation in LLC-P[K.sub.1]/rV1aR cells, rV2R promoter activity was increased in NaCl- or mannitol-induced hypertonicity. The hypertonicity-responsive site in the rV2R promoter region was limited to 10 bp, including the Sp1 motif. The increase of V2R promoter activity by hypertonicity was significantly inhibited by a JNK inhibitor (SP600125) and PKA inhibitor (H89). In contrast, rV2R promoter activity was remarkably suppressed by V1aR stimulation in the hypertonic condition rather than in the isotonic condition. The AVP-stimulated intracellular [Ca.sup.2+] concentration was increased in the hypertonic condition, suggesting the functional activation of V1aR by hypertonicity. In conclusion, 1) V2R promoter activity is increased by hypertonicity via the JNK and PKA pathways, 2) suppression of V2R expression by the VlaR-[Ca.sup.2+] pathway is enhanced by hypertonicity, and 3) hypertonicity enhances the V1aR-[Ca.sup.2+] pathway. The counteractivity of V2R and V1aR could be required to maintain minimum urine volume in the dehydrated state. collecting ducts; transcription regulation; cell signaling

The neuropeptide hormone arginine-vasopressin (AVP) is well known to exert its antidiuretic effect via the vasopressin V2 receptor (V2R), whereas the role of the vasopressin Vla receptor (V1aR) in the kidney remains to be clarified. Previously, we reported decreased plasma volume and blood pressure in V1a receptor-deficient ([V1aR.sup.-/-]) mice (Koshimizu T, Nasa Y, Tanoue A, Oikawa R, Kawahara Y, Kiyono Y, Adachi T, Tanaka T, Kuwaki T, Mod T. Proc Natl Acad Sci USA 103: 7807-7812, 2006). In this study, we investigated the role of V 1 aR in urine concentration, renal function, and the renin-angiotensin system (RAS) using [V1aR.sup.-/-] mice. Urine volume of [V1aR.sup.-/-] mice was greater than that of wild-type mice, particularly when water was loaded, while the glomerular filtration rate (GFR), urinary NaCl excretion, AVP-dependent cAMP generation, V2R, and aquaporin 2 (AQP2) expression in the kidney were lower, indicating that the diminished GFR and V2R-AQP2 system led to impaired urinary concentration in [V1aR.sup.-/-] mice. Since the GFR and V2R-AQP2 system are regulated by RAS, we analyzed renin and angiotensin II in [V1aR.sup.-/-] mice and found that the plasma renin and angiotensin II were decreased. The expression of renin in granule cells was decreased in [V1aR.sup.-/-] mice, which led to a decreased level of plasma renin. In addition, the expression of renin stimulators such as neuronal nitric oxide synthase and cyclooxygenase-2 in macula densa (MD) cells, where V1aR was specifically expressed, was decreased in [V1aR.sup.-/-] mice. These data indicate that AVP regulates body fluid homeostasis and GFR via the V1aR in MD cells by activating RAS and subsequently the V2R-AQP2 system. renin-angiotensin system

Vasopressin [V.sub.1a] and [V.sub.2] receptors ([V.sub.1a]R and [V.sub.2]R, respectively) distribute in the collecting duct of the kidney. Although the function of [V.sub.2]R mediating the antidiuretic effect of AVP has been investigated in detail, the role of [V.sub.1a]R in the collecting ducts has not been elucidated. In the present study, we have investigated the role of the [V.sub.1a]R pathway in [V.sub.2]R promoter activity. We cloned the 5'-flanking region of rat [V.sub.1a]R (r[V.sub.2]R) and investigated r[V.sub.2]R promoter activity in the LLC-P[K.sub.1] cell line transfected to express rat [V.sub.1a]R (r[V.sub.1a]R) dominantly (LLC-P[K.sub.1]/ r[V.sub.1a]R). AVP induced a transient increase, followed by a sustained decrease, of r[V.sub.2]R promoter activity in these cells. This AVP-induced decrease of r[V.sub.2]R promoter activity was inhibited by [V.sub.1a]R, but not [V.sub.2]R, antagonist. PMA mimicked this decrease of r[V.sub.2]R promoter activity. On the contrary, 8-(4-chlorophenylthio)-cAMP increased r[V.sub.2]R promoter activity. These PMA- and 8-(4-chlorophenylthio)-cAMP-induced effects were not observed on the deletion segment of the 5'-flanking region lacking CAAT and SP1 sites. In conclusion, 1) expression of the [V.sub.2]R is downregulated via the [V.sub.1a]R pathway in LLC-P[K.sub.1]/r[V.sub.1a]R cells, and 2) expression of the [V.sub.2]R is downregulated by the PMA-induced PKC pathway and upregulated by the cAMP-PKA pathway. These opposite effects of PKC and PKA appear to be regulated by the same promoter region of CAAT and SP1. transcription regulation; collecting ducts doi:10.1152/ajprenal.00358.2006

The vasopressin-aquaporin 2 system plays a key role in urine concentration in dehydration. In contrast to the upregulation of aquaporin 2, the downregulation of the vasopressin V2 receptor in dehydration is known. We investigated the mechanisms of this downregulation in dehydration using reverse transcription-competitive polymerase chain reaction (RT-competitive PCR) and Western blot analysis. The incubation of microdissected inner medullary collecting ducts (IMCDs) in a hypertonic medium or with vasopressin stimulated V2 receptor mRNA and protein expression, showing that dehydration-induced hyperosmolality in renal medulla and increased plasma arginine vasopressin (AVP) concentration should upregulate V2 receptor. The presence of inhibitory factors on the V2 receptor in dehydration was suggested. Prostaglandin [E.sub.2] (PG[E.sub.2]) is known to inhibit AVP-induced cAMP production and to increase production in dehydration. PG[E.sub.2] slightly stimulated V2 receptor mRNA expression in IMCD in vitro. However, PG[E.sub.2] inhibited V2 receptor mRNA expression in IMCD in the presence of [10.sup.-9] M vasopressin. The blockade of PG[E.sub.2] synthesis by indomethacin in dehydrated rats increased V2 receptor protein expression after 24-48 h with an early increase in V2 receptor mRNA expression. In summary, these data suggest that increased production of PG[E.sub.2] in renal medulla plays a key role in the downregulation of V2 receptor in dehydration. V2 receptor; aquaporin 2; prostaglandin [E.sub.2]; inner medullary collecting duct

Reverse transcriptase-polymerase chain reaction (RT-PCR) was utilized to examine the microlocalization of messenger RNA coding for adrenomedullin (AM) and the effects of the protein of cyclic adenylic acid. RT-PCR analysis of the intraglomerular site expression of AM in cultured rat mesanglial cells (MC) and microdissected nephron segments indicated the role of AM in the modulation of renal hemodynamics. AM also increased glomerular filtration rate and resultant water and sodium excretion via cyclic adenylic acid in the mesanglial cells.

Reverse transcription and polymerase chain reaction (RT-PCR) followed by Southern blot analysis on the localization of mRNA encoding IP3 receptors on microdissected nephron segments of rats reveals that type 1 IP3 receptor mRNA distribution, although widespread, is not uniform along the nephron. On the other hand type, 2 IP3 receptor mRNA is entirely confined to the collecting ducts, which suggests a specific expression of type 2IP3 receptor in collecting ducts. Thus different types of IP3 receptors have different functions in the rat kidney.

Northern blot analysis and reverse-transcription-polymerase chain reaction technique help examine the kallikrein-binding protein (kBP) mRNA distribution in the kidney of Sprague-Dawley rats, spontaneously hypertensive rats (SHR) and Wistar-Kyoto strain rats. KBP mRNA is distributed in the medullary domains of the distal nephron, and its distribution pattern is the reverse of kallikrein activity distribution in collecting ducts. SHR kidney shows a marked reduction in kBP mRNA expression, suggesting that modulation disruption at the transcriptional level causes reduction of kBP in spontaneous hypertension.

Reverse transcription-polymerase chain reaction studies on rat renal structures reveal the presence of C-type natriuretic peptide (CNP) mRNA and natriuretic peptide B-type receptor (ANPR-B) mRNA in glomeruli, VR bundle and the arcuate artery. ANPR-B mRNA is also present in distal nephron units. High levels of CNP enhance cGMP collection in glomeruli, outer medullary thick ascending limb, cortical collecting duct, inner medullary thin limb and the arcuate artery. CNP regulates renal function and cell multiplication in autocrine and paracrine modes.