CONGENIC STRAIN DIFFERENCES OF RENAL MALFORMATIONS IN ACI/MNA RATS BY INTROGRESSION OF THE CHROMOSOMAL REGION OF BUF/MNA RATS CONTAINING PUR1

ABSTRACT

The ACI rats developed hereditary renal malformations including agenesis and hydronephrosis at moderate penetrance. During construction of a variety of congenic strains based on ACI/Mna (ACI), BUF/Mna (BUF), and WKY/NCrj (WKY) rats, we found that the renal malformations were significantly suppressed by introgression of a segment of chromosome 13 of BUF rats containing Pur1 locus. It is plausible that this region contain a modifier locus influencing development of renal malformations.

INTRODUCTION

Occurrences of renal agenesis and hydronephrosis are well known in ACI rats.^1-8) A semidominant locus in the vicinity of D14Rat65 of Chromosome 14 has been shown responsible for renal malformation.⁹⁾ However, the renal lesion is assumed to occur in a polygenic trait. In the course of the genetic study on thymoma developments of BUF/Mna rats,^10,11) we noticed that moderate substrain differences in the incidences of the renal malformations were found among congenic strains of control ACI/Mna rats with introgressed chromosomal segments from BUF/Mna rats.

MATERIALS AND METHODS

The rats of the inbred ACI/Mna (ACI), BUF/Mna (BUF) and WKY/NCrj (WKY) strains, and of congenic strains, in which genetic regions of rat nude (Rnu), thymus enlargement-1 (Ten1) and thymus enlargement-2 (Ten2), thymoma susceptible gene of rat-1 (Tsr1), atrophy of fast-twitch muscle-1 (Aftm1) and proteinuria-1 (Pur1) were transferred into ACI, BUF or WKY strain, respectively, were used.^10,11) The BUF-Rnu/+ rats were raised during the course of the establishment of the BUF-Rnu/Rnu strain, as described in the previous study.¹²⁾ They were housed with free access to food (CMF, Oriental Yeast, Tokyo, Japan) and tap water at the Animal Facility of Fujita Health University. All animal experiments were approved based on the approval of the Guide for the Care and Use of Laboratory Animals of Fujita Health University School of Medicine. Rats of these strains, as surpluses in the course of the maintenance of the strains, were killed at the age of 6–104 weeks, except 3 rats died of bilateral renal malformations 1–5 days after birth. Autopsies were performed and kidneys were macroscopically examined. The statistical analyses were carried out by the Fisher’s exact test.

RESULTS

ACI and their congenic rats developed unilateral renal agenesis and hydronephrosis (Fig. 1) in 1–13 %, but BUF and WKY, and their congenic rats hardly developed. Since there were no sex differences in the incidences in renal agenesis and hydronephrosis in these strains, the data for both sexes were accumulated (Table 1). Higher incidences of renal agenesis in the right side and hydronephrosis in the left side, respectively, were observed. Three rats died 1–5 days after birth; 1 developed no kidneys in bilateral sides and other 2 did bilateral hydronephrosis (Table 1). Statistically, lower incidences of these developmental abnormalities were found in rats of the ACI-Pur1 and ACI-Pur1-Ten2 strains than ACI, ACI-Tsr1, ACI-Ten1, and ACI-Aftm1 strains (Table 1).

Fig. 1.

Hydronephrosis of the left kidney of a male albino ACI-Aftm1 rat.

Table 1.

Incidences of renal agenesis and hydronephrosis in rats of both sexes of the ACI, BUF, and WKY strains and their congenic strains

Strain	No. of rats	No. & (%) of renal agenesis				No. & (%) of hydronephrosis
		Right	Left	Bilateral		Right	Left	Bilateral
ACI	84	5 (6)1	5 (6)7	0 (0)		1 (1)	7 (8)14	0 (0)
ACI-Tsr1	76	4 (5)2	3 (4)8	0 (0)		0 (0)	3 (4)	1* (1)
ACI-Ten1	251	23 (9)3	4 (2)	0 (0)		4 (2)	9 (4)	0 (0)
ACI-Aftm1	340	32 (9)4	12 (4)9	0 (0)		9 (3)11	33 (10)15	1** (0.3)
ACI-Pur1	180	1 (1)5	1 (1)10	0 (0)		0 (0)12	1 (1)16	0 (0)
ACI-Pur1-Ten2	165	4 (2)6	6 (4)	0 (0)		0 (0)13	1 (1)17	0 (0)
BUF	90	0 (0)	0 (0)	1# (1)		0 (0)	5 (6)	0 (0)
BUF-Rnu/+	185	0 (0)	0 (0)	0 (0)		1 (1)	3 (2)	0 (0)
WKY	162	0 (0)	0 (0)	0 (0)		0 (0)	0 (0)	0 (0)
WKY-Tsr1	346	0 (0)	0 (0)	0 (0)		0 (0)	0 (0)	0 (0)
WKY-Ten1-Ten2	71	0 (0)	0 (0)	0 (0)		0 (0)	0 (0)	0 (0)
WKY-Ten2	22	0 (0)	0 (0)	0 (0)		2 (9)	1 (5)	0 (0)
WKY-Pur1-Ten1-Ten2	213	0 (0)	0 (0)	0 (0)		0 (0)	0 (0)	0 (0)

The statistical analyses were carried out by the Fisher’s exact test.

^5:3,4 Highly significant; ^5:1,2 significant; ^6:3,4 highly significant;

^10:7,8,9 Significant; ^12:11 significant; ^13:11 significant;

^16:14,15 Highly significant; ^{17:14, 15} highly significant.

*Died 5 days after birth. The rats had bilateral hydronephrosis.

**Died 2 days after birth. The rats had bilateral hydronephrosis.

^#Died 1 day after birth. The rat had no kidneys in both sides.

DISCUSSION

The unilateral renal agenesis, hydronephrosis, and associated genitourinary anomalies in ACI rats were thought to be a part of a mesonephric duct defect.¹³⁾ The inheritance of the unilateral renal agenesis is believed to be polygenic²⁾ and one of the genes for unilateral renal agenesis was mapped on chromosome 14.^2,14) The present study revealed that the renal agenesis and hydronephrosis were significantly suppressed by the insertion of the genetic region of proteinuria in ACI-Pur1 and ACI-Pur1-Ten2 rats originated from BUF rats. Conversely, it means that the Pur1 region of ACI rats contains a second gene for the induction of renal malformations. We previously showed that genetic Pur1 region was located on the chromosome 13 and that the genetic Pur1 region contained 38 genes,¹⁵⁾ which should be analyzed by molecular methods.

The present study also showed that ACI rats developed unilateral hydronephrosis more in the left side. The exact mechanism why unilateral hydronephrosis occurs more in the left side is not known. Explanations for this difference between sides have to be elucidated.^16,17)

Abbreviations

Ten1

Thymus enlargement-1

Ten2

Thymus enlargement-2

Tsr1

Thymoma susceptible gene of rat-1

Pur1

Proteinuria-1