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. 2010;32(1):83-94.
doi: 10.1159/000314635. Epub 2010 Jun 11.

Renal failure in mice with Gsalpha deletion in juxtaglomerular cells

Limeng Chen  1 , Robert Faulhaber-Walter, Yubing Wen, Yuning Huang, Diane Mizel, Min Chen, Maria Luisa Sequeira Lopez, Lee S Weinstein, R Ariel Gomez, Josephine P Briggs, Jurgen Schnermann
Affiliations

Renal failure in mice with Gsalpha deletion in juxtaglomerular cells

Limeng Chen et al. Am J Nephrol. 2010.

Abstract

Background: Mice with deletion of Gsalpha in renin-producing cells (RC/FF mice) have been shown to have greatly reduced renin production and lack of responsiveness of renin secretion to acute stimuli. In addition, young RC/FF mice are hypotensive and have a vasopressin-resistant concentrating defect. In the present study we have determined the long-term effect on renal function, blood pressure, and renal pathology in this low renin and diuretic mouse model.

Methods and results: Urine osmolarity of RC/FF mice was decreased in all age groups. GFR measured at 7, 14 and 20 weeks of age declined progressively. Single nephron GFR similarly declined while fractional proximal fluid absorption was maintained. Expression levels of extracellular matrix proteins (collagen I, IV and fibronectin) and alpha-smooth muscle actin were increased in kidneys of RC/FF mice at 20 weeks, and this was accompanied by focal segmental glomerulosclerosis and periglomerular interstitial fibrosis. RC/FF mice showed a progressive reduction of body weight, an increase in urine albumin excretion, and an increase of blood pressure with aging.

Conclusion: A chronic reduction of renin production in mice may be a risk factor in its own right, and does not protect renal function against the profibrotic influence of a chronically elevated urine flow.

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Figures

Fig. 1
Fig. 1
GFR in conscious WT (□) and RC/FF (█) mice at the ages of 7, 14 and 20 weeks. Significances are given for comparisons with GFR of WT mice of the same age (∗ p < 0.0001) and for comparisons with GFR of RC/FF mice at the age of 7 weeks (# p = 0.0095).
Fig. 2
Fig. 2
a SNGFR in anesthetized RC/FF and WT mice in the 16- to 20-week age range. b Relationship between SNGFR and proximal tubular fluid reabsorption in RC/FF (○) and WT (•) mice.
Fig. 3
Fig. 3
Systolic BP measured by tail-cuff inflation method in WT (□) and RC/FF (█) mice at 7, 14, and 20 weeks of age. Significances are given for comparison with BP of WT mice at the same age (∗ p < 0.01) and with mice of the same genotype at age 14 weeks (∗ p < 0.01, unpaired t test) and 20 weeks (# p < 0.05, unpaired t test).
Fig. 4
Fig. 4
Decrease of body weight in RC/FF mice (█) at 20 weeks; significance given for comparison with the body weight of WT mice (□) at the same age (p = 0.0026, unpaired t test).
Fig. 5
Fig. 5
Urine osmolarity of WT (□) and RC/FF (█) mice at different ages; significance given for comparisons with urine osmolarity of WT mice at the same age (p < 0.0001, unpaired t test).
Fig. 6
Fig. 6
A a Cross section of a kidney of a RC/FF (left) and WT mouse (right). Note hydronephrosis with atrophic papilla in the RC/FF kidney. b–d Kidney cortex of 20-week-old RC/FF (c, d) and WT mice (b) stained with Masson trichrome (d) or PAS (b, c). 200×. Note focal segmental glomerulosclerosis and periglomerular interstitial fibrosis in RC/FF mice (c, d). e Glomerular injury score in RC/FF (█) and WT (□) mice. B Kidney cortex of 6-week-old RC/FF (b, d, f) and WT mice (a, c, e) stained with HE (a, b), PAS (c, d) or Masson trichrome (e, f). 200×.
Fig. 6
Fig. 6
A a Cross section of a kidney of a RC/FF (left) and WT mouse (right). Note hydronephrosis with atrophic papilla in the RC/FF kidney. b–d Kidney cortex of 20-week-old RC/FF (c, d) and WT mice (b) stained with Masson trichrome (d) or PAS (b, c). 200×. Note focal segmental glomerulosclerosis and periglomerular interstitial fibrosis in RC/FF mice (c, d). e Glomerular injury score in RC/FF (█) and WT (□) mice. B Kidney cortex of 6-week-old RC/FF (b, d, f) and WT mice (a, c, e) stained with HE (a, b), PAS (c, d) or Masson trichrome (e, f). 200×.
Fig. 7
Fig. 7
Expression of collagen I in the kidney of WT and RC/FF mice at age 7 weeks (a, b) and 20 weeks (c, d). a, c Immunohistochemical staining for collagen I in WT mice. b, d Immunohistochemical staining for collagen I in RC/FF mice. 200×. e Quantification by morphometric analysis (20 weeks).
Fig. 8
Fig. 8
Expression of fibronectin in the kidney of WT and RC/FF mice at 7 weeks (a, b) and age 20 weeks (c, d). a, c Immunohistochemical staining for fibronectin in WT mice. b, d Immunohistochemical staining for fibronectin in RC/FF mice. 200×. e Quantification by morphometric analysis (20 weeks).
Fig. 9
Fig. 9
Expression of collagen IV in the kidney of WT and RC/FF mice at 7 weeks (a, b) and age 20 weeks (c, d). a, c Immunohistochemical staining for collagen IV in WT mice. b, d Immunohistochemical staining for collagen IV in RC/FF mice. 100×. e Quantification by morphometric analysis (20 weeks). f Collagen IV mRNA expression determined by real-time PCR.
Fig. 10
Fig. 10
Expression of α-SMA in kidneys of WT (a, c, e) and RC/FF mice (b, d, f). Note increased expression of α-SMA in blood vessels, and interstitial cells (representing myofibroblasts), and thicker arteries and arterioles in RC/FF mice (f); α-SMA-positive cells are also present in mesangial areas (upper arrow in f) and in periglomerular and interstitial areas (arrows in b and d). 400×.
Fig. 11
Fig. 11
Western blot quantification of α-SMA in the kidney cortex of WT and RC/FF mice. a Immunoblot of α-SMA in 3 RC/FF (left) and 3 WT (right) at age 20 weeks with Coomassie blue staining for total protein as loading control (bottom). b α-SMA protein expression in WT (□) and RC/FF (█) mice determined by Western blotting (∗ p < 0.01, n = 9).
Fig. 12
Fig. 12
a–d Evidence for apoptosis in kidneys of WT (a, c) and RC/FF mice (b, d) from TUNEL staining at 7 weeks of age (a, b, 200×), immunohistochemical expression of caspase-3 (c, d, 400×). e Quantification of immunohistochemical expression of caspase-3 in WT and RC/FF mice.
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