Gene Description

Symbol:  Pkdr1

Gene:  polycystic kidney disease rat 1

Chromosome:  5

Background Strain:  Inbred strain from an outbred Han:SPRD stock

Strain Development:  This strain was developed by brother sister mating of Han:SPRD rats with a spontaneous autosomal dominant mutation for polycystic kidney disease. Inbreeding started in 1991 and the strain is beyond the F20 generation.

Other Strain Names:  PKD, Han:SPRD Cy

Summary of Phenotype

The published phenotype of this rat model consists of enlarged cystic kidneys in homozygous rats which is lethal at 3-4 weeks of age. Heterozygous rats develop progressive disease that shows a strong sex difference in which males develop renal failure and die around 6 months of age but in the female rats the disease only rarely progresses to renal failure and death.

Additional baseline phenotyping including gross and histomorphologic examination, hematology, clinical chemistry and behavioral analysis will be performed on this rat strain in the near future. This baseline phenotype information will be posted on this website as it is completed.

Summary - Histology

Pkdr1/Pkdr1: polycystic kidney characterized by marked cystic dilation of all renal tubular elements; dilated tubules are lined by flattened to cuboidal epithelium and separated by thin to inapparent stroma that occasionally contains scant lymphocytic infiltrates; cysts contain scant flocculent eosinophilic material with rare cysts containing epithelial cell debris; histologically normal glomeruli (albeit smaller than those seen in the wild type and heterozygous rats) are present throughout the sections; mild dilation of Bowman's space is present in about 1/2 of glomeruli

Pkdr1/+: polycystic kidney characterized by flattened to cuboidal epithelial linings (many exhibit cystic dilation) of approximately 75% of tubules (primarily cortical tubules); the remaining tubules are lined by "normal" proximal tubular epithelium (plump cuboidal epithelium with eosinophilic granular cytoplasm and apical to mid-cell nuclei) with some tubules exhibiting what is interpreted to be a transitional stage; these tubules often contain luminal and cytoplasmic hyaline proteinaceous droplets; other transitional tubules are partially lined by more basophilic cuboidal epithelium with decreased cytoplasm and basal nuclei; these cells often contain golden brown pigment (interpreted to be hemosiderin or lipofuscin); cystic and transitional tubules are often surround by a band of pale homogenous material (interpreted to be thickened basement membrane); cystic tubules contain flocculent to homogeneous proteinaceous material; the stroma separating diseased tubules is often infiltrated by lymphocytes; uncommon features include periglomerular basement membrane thickening, accumulation of suppurative debris in tubules and cysts with focal papillary proliferation of epithelium

+/+: within normal limits




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Summary - Clinical Chemistry

Serum Urea Nitrogen and Creatinine are elevated in male and female heterozygotes and the levels in males are significantly higher than in females.

Serum Urea Nitrogen Levels

Genotype	Sex	N	Age (weeks)
			4	6	9	12	15
Pkdr1/+	Male	5	15-16 (15.6)*	17-25 (20)	38-50 (44.2)	48-67 (58.4)	59-81 (64.4)
Pkdr1/+	Female	4	14-19 (16.25)	13-17 (15)	19-25 (22)	20-23 (21.25)	23-42 (35.25)
+/+	Male	2	13-16 (14.5)	14	16-18 (17)	20	18
+/+	Female	1	13	15	21	17	33

* range (mean)

Male heterozygotes (Pkdr1/+) demonstrated significant elevations in serum urea nitrogen at 6, 9, 12 and 15 weeks as compared to baseline 4 week levels from male heterozygotes (paired T test; P<0.05)

Female heterozygotes (Pkdr1/+) demonstrated significant elevations in serum urea nitrogen at 9, 12 and 15 weeks as compared to baseline 4 week levels from female heterozygotes (paired T test; P<0.05)

Male heterozygote serum urea nitrogen levels were significantly higher than levels from female heterozygotes at 6, 9, 12 and 15 weeks (T test; P<0.05)

Serum Creatinine Levels

Genotype	Sex	N	Age (weeks)
			4	6	9	12	15
Pkdr1/+	Male	5	0.2-0.3 (0.22)*	0.2	0.4-0.6 (0.48)	0.6-1 (0.76)	0.8-1.1 (0.92)
Pkdr1/+	Female	4	0.2	0.1-0.2 (0.175)	0.2-0.3 (0.25)	0.3 (0.3)	0.4-0.5 (0.425)
+/+	Male	2	0.2-0.3 (0.25)	0.1-0.2 (0.15)	0.3-0.4 (0.35)	0.3-0.4 (0.35)	0.3-0.4 (0.35)
+/+	Female	1	0.2	0.1	0.3	0.6	0.4

* range (mean)

Male heterozygotes (Pkdr1/+) demonstrated significant elevations in serum creatinine at 9, 12 and 15 weeks as compared to baseline 4 week levels from male heterozygotes (paired T test; P<0.05)

Female heterozygotes (Pkdr1/+) demonstrated significant elevations in serum creatinine at 12 and 15 weeks as compared to baseline 4 week levels from female heterozygotes (paired T test; P<0.05)

Male heterozygote serum creatinine levels were significantly higher than levels from female heterozygotes at 9, 12 and 15 weeks (T test; P<0.05)

Literature Review

• Schafer K, Gretz N, Bader M, Oberbaumer I, Eckardt KU, Kriz W, Bachmann S.
  
  Characterization of the Han:SPRD rat model for hereditary polycystic kidney disease. Kidney Int. 1994 Jul;46(1):134-52.



• Nagao S, Ushijima T, Kasahara M, Yamaguchi T, Kusaka M, Matsuda J, Nagao M, Takahashi H.
  
  Closely linked polymorphic markers for determining the autosomal dominant allele (Cy) in rat polycystic kidney disease. Biochemical Genetics. 1999 Aug;37(7-8):227-35.

Availability

Available at the Rat Research and Resource Center