Urinary Concentration Defect and Limited Expression of Sodium Cotransporter, rBSC1, in a Rat Model of Chronic Renal Failure

Abstract

Background: Renal urinary concentration is associated with enhanced expression of sodium cotransporter (rBSC1) in thick ascending limb of Henle. Overexpression of rBSC1 was reported recently in hypertrophied nephrons after unilateral nephrectomy (UNX) and in kidney isografts. Since urinary concentration defect and hypertrophy of residual nephrons are major manifestations of chronic renal failure (CRF), we investigated the rBSC1 signals for RNA and protein in a rat model of CRF. Methods: Rats underwent 5/6 nephrectomy and examined 8 weeks after operation. rBSC1 mRNA was examined by competitive PCR and in situ hybridization, and rBSC1 protein signals by western blotting and immunohistochemistry. Rats that underwent sham-operation, UNX, or 5/6 nephrectomy followed by a 3-week recovery period (acute renal failure), were used as control. Water intake was restricted for 24 h in subgroups of control and CRF rats. Results: Microscopic examination showed hypertrophy of residual nephrons in both UNX and CRF rats. Signals for rBSC1 mRNA and protein were enhanced at basal condition only in rats with UNX. Under basal conditions, CRF rats demonstrated low urinary osmolality in spite of high plasma arginine vasopressin levels. Water restriction resulted in increased signals for rBSC1 mRNA and protein and concentration of urine in sham-operated rats, but such increases were absent and urinary concentration was incomplete in CRF rats. Conclusions: Compensatory overexpression and upregulation of rBSC1 expression in response to dehydration are both absent in CRF rats. These limitations are thought to be the underlying mechanisms of urinary concentrating defect seen in CRF.

Residual Urinary Concentrating Ability and AQP2 Expression in a Rat Model for Chronic Renal Failure

“…The expression defects of AVP V2 receptor, BSC1, and AQP2 have been reported in a rat model for renal failure [5, 6, 7], indicating that the defect in urinary concentrating ability in renal failure is caused by a number of complex disorders.…”

“…Reduced AVP V2 receptor [5], AQP2 [6]and BSC1 [7]expression may supply sufficient evidence for the AVP resistance, because the expression of both BSC1 and AQP2 is closely associated with the plasma AVP level [10, 11, 12, 13, 14]. In our previous study on CRF rats, however, we noted a small but significant elevation of urine osmolality in response to water restriction [7]. This finding indicates the presence of residual urinary concentrating ability that is manifested in the dehydrated condition.…”

“…This expressional alteration of AQP2 in response to dehydration is much greater than that of rBSC1 [16, 18], and we have recently demonstrated that AQP2 expression is highly dependent on AVP stimulus, whereas rBSC1 expression is regulated by multiple mechanisms in addition to AVP [11]. Therefore, an examination of the expression of AQP2 in the dehydrated condition, which induces a small but significant urinary concentrating ability even in CRF rat [7], may reveal some of the mechanisms underlying the residual urinary concentrating ability in CRF. The present study is designed to investigate AQP2 expression in a rat model for CRF, in which regulation of rBSC1 expression in response to a reduction of nephron number [17]and to dehydration [16]is almost completely impaired [7].…”

“…Therefore, an examination of the expression of AQP2 in the dehydrated condition, which induces a small but significant urinary concentrating ability even in CRF rat [7], may reveal some of the mechanisms underlying the residual urinary concentrating ability in CRF. The present study is designed to investigate AQP2 expression in a rat model for CRF, in which regulation of rBSC1 expression in response to a reduction of nephron number [17]and to dehydration [16]is almost completely impaired [7]. …”

Renal Sodium Handling for Body Fluid Maintenance and Blood Pressure Regulation

“…27) The molecular cloning of BSC1 14) has enabled us to investigate the expression of this transporter. 5) We ex amined BSC1 expression in a normal rat kidney that achieved maximal urinary concentration in the de hydrated condition, 5) a kidney isograft (a rat with kidney transplantation), 7) and a remnant kidney after 5/6 nephrectomy (a rat model for chronic renal failure), 8) the latter two of which lost the ability to perform maximal urinary concentration even in the dehydrated condition. A marked increase in BSC1 ex pression was observed in the normal kidney from the dehydrated rat 5) and not the kidney isograft 7) or the remnant kidney 8) (Fig.…”