Figure 1. Hyperangiotensinemia in SCA promotes glomerulopathy (via AT₁R signaling), but plays an important role in sustaining urine concentrating ability (via both AT₁R and AT₂R signaling) in the setting of SCA-associated hyposthenuria.

a) Temporal progression of albuminuria, shown as urine albumin/creatinine ratio (Y-axis), in non-transplanted WT mice or SS mice (that were untreated, or treated with losartan or captopril). The weeks of drug treatment shown on the X-axis. SS mice were started on drug treatment at 8–12 weeks of age. UACR was determined on 24hr-urine samples by the urine albumin to creatinine ratio and data are expressed in μg albumin/mg creatinine. (b) H &E staining (60X magnification), PAS staining (60X magnification) and immunohistochemistry for phosphorylated Smad-2/3 (100X magnification) in the kidneys of WT mice, untreated -SS control mice, or SS mice treated with captopril or losartan for 12 weeks. A single representative glomerulus is shown. Improvement in glomerular pathology including congestion, FSGS and mesangial proliferation is seen in SS mice on captopril or losartan compared to the untreated SS mice. Increased pSmad2/3 expression (brown staining) is seen in untreated SS compared to SS mice on captopril/losartan. (c) C57Bl/6 mice (WT; recipient) were transplanted with SS or WT donor bone marrow at 8–12 weeks of age following lethal irradiation (1275cGy) in a donor: recipient ratio of 1:7. Only SS/WT chimeras determined to be fully chimeric for SS by HPLC for hemoglobin S, 3 months after transplantation, were further analyzed for experiments. Untreated WT/WT chimeras (WT/WT-Ctrl; red bar), untreated SS chimeric mice (SS/WT-Ctrl; black bar), SS chimeric mice placed on captopril 3 months after transplant (SS/WT-Cap; blue bar) and SS chimeric mice placed on losartan 3 months after transplant (SS/WT-Los; green bar) were compared. Urine albumin and creatinine was analyzed 12 months after establishment of chimerism. UACR was determined on 24-hr urine samples by the urine albumin to creatinine ratio and data are expressed in μg albumin/mg creatinine is shown (n= 6–8 mice/group. (d) UACR levels in WT, AT₁R^−/− and AT₂R^−/− recipient mice transplanted with WT (red bars) or SS (black bars) donor bone marrow. Mice fully chimeric for WT or SS bone marrow at three months were analyzed. UACR was determined on 24-hr urine samples by the urine albumin to creatinine ratio and data are expressed in μg albumin/mg creatinine is shown (n=6–20 mice per group). (e) Urine albumin in SS mice (untreated or placed on only AT₁R antagonist Losartan (Los) or placed on a combination of AT₂R agonist C21, and Los; n = 10–20 mice/group. (f) Temporal progression of UCA, measured by urine osmolality (Y-axis) in non-transplanted WT mice and SS mice (that were untreated, or treated with captopril or losartan) with weeks of drug treatment shown on the X-axis. Mice were started on drug treatment at 8–12 weeks of age. Urine osmolality could only be measured in captopril-treated mice if they were given additionally water without captopril, due to high mortality from severe dehydration. The urine osmolality data are expressed in mmol/kg and was measured in 24-hr urine collections (g) C57Bl/6 mice (WT; recipient) were transplanted with SS or WT donor bone marrow at 8–12 weeks of age following lethal irradiation (1275cGy) in a donor: recipient ratio of 1:7. Only SS/WT chimeras determined to be fully chimeric for SS by HPLC for hemoglobin S, 3 months after transplantation, were further analyzed for experiments. Untreated WT/WT chimeras (WT/WT-Ctrl; red bar), untreated SS chimeric mice (SS/WT-Ctrl; black bar), SS chimeric mice placed on captopril 3 months after transplant (SS/WT-Cap; blue bar) and SS chimeric mice placed on losartan 3 months after transplant (SS/WT-Los; green bar) were compared. Urine osmolality analyzed 12 months after establishment of donor chimerism. The urine osmolality data are expressed in mmol/kg and was measured in 24-hr urine (n= 6–20 mice/group). (h) Kaplan-Meier survival curve in non-transplanted WT mice and SS mice (that were untreated or treated with captopril or losartan) for 20 weeks (X-axis). The percentage of mice surviving at the end of the experiment is indicated against the survival curve of each group. (i) Urine osmolality in WT, AT₁R^−/− and AT₂R^−/− recipient mice transplanted with WT (red bars) or SS (black bars) donor bone marrow. Mice fully chimeric for WT or SS bone marrow at three months were analyzed for urine osmolality (n=5–9 mice per group), in a 24hr- urine collection sample. (j) Urine osmolality in SS mice (untreated or placed on only AT₁R antagonist Losartan (Los) or placed on a combination of AT₂R agonist C21 and Los; n = 10–20 mice/group. All data are plotted as mean ±SEM. Statistical analysis was done either using Mann Whitney U test, where two groups are compared or using ANOVA (Dunnet’s multiple comparisons test) while comparing between multiple groups. Statistical significance is denoted by *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.